Ionis Pharmaceuticals, Inc.

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

Thanks, Steve. 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 GAAP to non-GAAP financials. We believe non-GAAP financial results better represent the economics of our business and how we manage our business. We've also posted slides on our website that accompany today's call. With me this morning are Brett Monia, Chief Executive Officer, Kyle Genet, Chief Global Product Strategy Officer, Richard Geary, Chief Development Officer, and Beth Haugen, Chief Financial Officer. Eugene Schneider, our Chief Clinical Development Officer, and Eric Swayze, Executive Vice President of Research, will also join us for the Q&A portion of the call. I would like to draw your attention to slide three, which contains a 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. 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. We have continued to build strong momentum across our business, highlighted by the excellent early commercial performance of our first independent launch, Tringolza, the first and only FDA-approved treatment for familial chydomyconemia syndromes. Tringolza exceeded revenue expectations during its second quarter on the market, underscoring its strong therapeutic profile, our well-executed commercial strategy, as well as the significant unmet need Tringolza is addressing. The revenue and commercial performance of Tringolza to date, along with our confidence in Tringolza's continued commercial success, supports the increase in our financial guidance for 2025, which Beth will cover in more detail shortly. We're also pleased that Tringolza recently received a positive CHMD opinion, paving the way to bring this transformative therapy to patients across Europe. Shifting gears, we anticipate Donna DeLorsen for hereditary angioedema, or HAE, will be our second independent launch by receiving FDA approval next month. Based on the progress of the review, we believe the approval and subsequent launch remains on track. Don DeLorsen has the potential to become a preferred prophylactic therapy for many HAE patients, with strong efficacy and favorable safety and tolerability in the pivotal studies, a patient-friendly autoinjector, and a convenient dosing schedule of monthly or every other month self-administration. We're well-positioned to launch Don DeLorsen following approval. Additionally, our Phase III pipeline continues to advance well, with data expected later this year from two wholly owned Ionis programs. If positive, these results would support the continued steady cadence of independent launches next year, bringing important new treatments to patients. These include a second indication for Olisarsen in severe hypertriglyceridemia, or SHTG, a condition with a large patient population and significant unmet need, and Zilgenersen for Alexander disease of severe rare leukodystrophy with no approved disease-modifying therapies. Together, these programs, in addition to two goals in FCS and Don Dolores and HAE, represent major breakthroughs for patients and represent multibillion-dollar revenue potential for Ionis. Additionally, by the end of 2027, we anticipate four potential launches from our rich late-stage partner pipeline, targeting serious life-threatening conditions for both rare and highly prevalent diseases. These will further expand the impact and reach of Ionis increase total revenue. With our strong momentum across the business, including Tringolza and our upcoming independent and partner launches, Ionis is well positioned to bring transformative medicines to patients for years to come and in turn achieve sustained revenue growth and positive cash flow. And with that, I'll turn the call over to Kyle.

Thank you, Brett. With our first independent launch now well underway and a second launch right around the corner, Our commercial team is executing on our strategy to capitalize on these significant growth opportunities. Tringolza reported $19 million in net product sales for the second quarter, reflecting a threefold increase in revenues quarter over quarter. In the second quarter, Tringolza continued to build launch momentum. This was a result of several factors, including effective patient identification efforts, a strong product profile, favorable payer dynamics, an overwhelmingly positive HCP reported experience. Our patient identification initiatives are paying off. The breadth and depth of unique physicians prescribing Tringolza continues to grow, and many of these physicians have prescribed the therapy to two or more patients, underscoring the positive experience of both clinicians and patients. This demand also spans a broad mix of specialties, with cardiologists and endocrinologists representing roughly 50% and 30% of prescribers, respectively, and lipidologists and internal medicine providers making up the balance. Overall, physician feedback remains highly favorable, with significant benefits reported and awareness of Tringolza continuing to gain traction. Coverage and reimbursement trends have remained favorable. To date, the coverage mix for patients on Tringolza is approximately 60% commercial and 40% government. Importantly, patients, whether clinically diagnosed or genetically confirmed, have gained access. Patients have obtained coverage through a growing number of formal policies or via the medical exception process. This highlights both the urgent unmet need and payer's willingness to support access even before formal policies are in place. Additionally, over 90% of patients have paid $0 out of pocket since launch, and timelines for patients obtaining the medicine are consistently beating our aggressive internal benchmarks. Nearly all patients have opted into our IONIS Every Step support program, a testament to the value the program is providing. We established the IONIS Every Step support program to ensure a positive patient experience by providing disease and nutrition education, auto-injector training, and reimbursement support, among other offerings. For healthcare providers, the program provides helpful support from insurance authorizations and coverage coordination to reauthorizations and refills. We're proud of Tringolza's early momentum, but we know we're still in the early innings. The vast majority of the estimated 3,000 people living with FCS in the U.S. remain unidentified. To close that gap, we're continuing to focus on our patient finding efforts and HCP education. Our customer-facing team has reached over 3,000 physicians, and over 30,000 HCPs have been targeted through our omnichannel capabilities. both intended to further increase awareness of FCS, expand patient identification, and educate on the potential benefits of Trangolza treatment. Backed by an experienced and high-performing team, we are well-positioned to continue to take advantage of our first-mover position to bring Trangolza to patients in need and keep them on treatment. Building on our early success in FCS, we are advancing toward a potential blockbuster opportunity in severe hypertriglyceridemia with holozarsin. SHTG represents a large patient population, many of whom struggle to manage their triglyceride levels with current treatments. In the U.S. alone, more than 1 million people have high-risk SHTG and includes individuals with triglyceride levels above 880 or above 500 with a history of acute pancreatitis. With a significant first-mover advantage, we believe Olizarsen is well-positioned to address the unmet needs of patients with severe hypertriglyceridemia. Our commercial team is making excellent progress as we prepare for a potential launch next year. Donnie Delorsen, our second independent launch, has the potential to transform the treatment paradigm for individuals with HAE as the first and only RNA-targeted prophylactic medicine. More than 20,000 people in the U.S. and in Europe are estimated to have HAE, with approximately 7,000 people in the U.S. alone. In the U.S., most patients are currently on prophylactic treatments. However, many HAE patients remain unsatisfied with up to 20% of patients switching therapies each year in search of a more effective and convenient option, highlighting a need for new treatments with enhanced profiles. We believe Donnie Delorsen is uniquely positioned to meet this demand. The Donnie Delorsen clinical data have shown durable efficacy and favorable safety and tolerability profile, with a patient-friendly monthly or every other month self-administration with an auto-injector. Importantly, as we prepare to bring Donnie Delorsen to market, we are applying the same disciplined and innovative approach that has made the Tringolza launch a success. We have deployed our field team who are educating and preparing the market for the anticipated approval of Donnie Delorsen and are energized to successfully execute the launch. Meanwhile, our market access team is actively engaging with payers, and our field medical team continues to lay the essential groundwork to ensure a smooth and successful launch. Our experienced and scalable commercial organization is already delivering excellent results supported by the early success seen with the launch of Tringolza and FCS. As we build on this momentum, we remain focused on maximizing Tringolza's full potential while preparing to successfully execute three additional launches by the end of next year. including Donnie Doloreson in the coming weeks, enabling Ionis to reach more people in need with our medicines. With that, I'll now turn it over to Richard.

Thank you, Kyle. We are making excellent progress across our pipeline positioning Ionis to deliver on our mission of bringing transformational medicines to patients for years to come. Let me start with recent updates from our wholly owned pipelines. As a reminder, Donna DeLorsen is currently under regulatory review in both the U.S. and EU with submissions supported by its robust clinical data. We remain confident in the August 21st PDUFA date based on the engagement we've had with the FDA at this stage in the process. Sending approval, we look forward to making this potential best-in-class prophylactic treatment available to people living with HAE. Beyond its approved use in FCS, olisarcin is also being evaluated for the treatment of severe hypertriglyceridemia, or SHTG, with three separate Phase III studies supporting our planned SNDA filing, assuming positive data. In May, we reported top-line results from the ESSENCE study, which will help satisfy the regulatory safety requirements for the broad SHTG population. Essence primarily enrolled patients with triglyceride levels between 150 and 500 milligrams per deciliter, a level of triglycerides that is generally not associated with high risk for acute pancreatitis. In contrast, the CORE and CORE2 studies exclusively enrolled SHTG patients. Participants in these studies had triglycerides that were greater than 500 milligram per deciliter and with approximately 43% of the participants across both studies with triglycerides greater than 880 mg per deciliter at baseline. Triglycerides at this level put people at high risk for acute pancreatitis. The ESSEN study met its primary endpoint, showing statistically significant placebo-adjusted mean reductions in triglyceride levels of 61% and 58%, at six months with the 80 and 50 milligram monthly dosing respectively. The vast majority of participants achieved triglyceride levels below 150 milligram per deciliter, thus reaching the normal range. Olisarcin also met all key secondary endpoints and demonstrated a favorable safety and tolerability profile. The results from this study were recently accepted as a hotline session at the ESC Congress 2025 We look forward to sharing additional details from the study then. Now, the Phase III Core and Core II studies have enrolled approximately 1,100 participants, making this pivotal program the largest ever conducted in SHTG. These studies remain on track with top-line results expected in September. We believe this indication represents a significant opportunity. as many SHTG patients are unable to adequately manage their triglycerides with current therapies. Physician feedback continues to highlight strong interest in more effective treatment options for managing triglyceride levels, underscoring the potential value of olisarcin in this population. Importantly, this feedback indicates that physicians understand that lowering triglycerides will reduce the risk of acute pancreatitis and that they would prescribe olisarcin, if approved, based solely on its ability to substantially lower triglycerides. Although the CORE and CORE2 studies were not designed as AP outcome studies, we are seeing acute pancreatitis events on a blinded basis. As a result, we expect to have accumulated more combined pancreatitis events for CORE and CORE2 than we had in the FCS balance study. This gives us confidence we could have sufficient data to observe at least a favorable trend in olosarcin's impact on AP within the studies. Turning our attention to zilganersen, our medicine to treat Alexander disease, an ultra-rare leukodystrophy that profoundly impacts patients and families who today have no approved disease-modifying treatments. The Phase III study remains on track, and we're looking forward to sharing data later this year. Given the ultra-rare nature of this disease, we implemented an innovative clinical development strategy for Zilkenersen using a seamless phase 1 to phase 3 study design. This is the first study of a disease-modifying therapy ever conducted in this patient group. While this approach allows us to move efficiently toward a potential registration-enabling study, It also means that the upcoming readout will represent the first clinical data in patients with Alexander disease. As such, there is a higher degree of uncertainty associated with this readout compared to other medicines we're advancing in late-stage development. Assuming positive data and approval, Zilgenersen would represent the first of what we expect to be many more independent launches from our leading neurology pipelines. ION582, an investigational medicine for the treatment of people living with Angelman syndrome, is the newest addition to our late-stage pipeline. Angelman syndrome is a serious and rare neurodevelopmental disorder that leads to significant and lifelong physical and cognitive impairments and impacts tens of thousands of people living with this disorder. Supported by the Phase I-II open-label HALOS study results, We recently dosed the first patient in the Global Phase III reveal study. We plan to have this study fully enrolled next year. Turning to our partnered programs, we are pleased that higher-dose Nusinersen is one step closer to market with FDA and EMA regulatory submissions under review. With the well-characterized profile of Spinraza established over the past 10 years, 10-plus years, and the positive data from higher-dose Spinraza. We believe Spinraza is well-positioned to continue to bring benefit to SMA patients around the world. Our partner, Biogen, also recently shared positive top-line interim results from the Phase I study of salinursin, an investigational antisense medicine being developed for the potential treatment of spinal muscular atrophy. Leveraging the same mechanism of action as Spinraza, we designed salinersin with novel ionous chemistry to achieve strong efficacy and once yearly dosing. In children previously treated with gene therapy, once yearly dosing with both the 40 and 80 milligram doses were well tolerated and led to rapid and substantial slowing of neurodegeneration as shown by reductions in neurofilament. Exploratory clinical outcome data also showed that children in the study achieved meaningful improvements in function and attained new milestones. Biogen is actively engaging with regulatory agency to align on the Phase III study design. Notably, the initiation of a Phase III study would trigger a $45 million milestone payment to Ionis. Additionally, our royalty rates for salinersin are significantly higher than for Spinraza. If approved, salinersin would also substantially extend the life cycle for the Ionis Biogen SMA franchise. The progress of this program underscores Ionis' deep expertise in oligonucleotide medicinal chemistry and reinforces the strength of our broader neurology pipeline. It also validates our approach as we advance new medicines with next-generation chemistries, including follow-on medicines for our wholly-owned programs. With multiple data readouts and regulatory milestones expected this year and next, our advancing pipeline underscores the strength of our science and our commitment to addressing serious diseases. With that, I'll turn it over to Beth.

Thank you, Richard. I'm pleased to report that for the second time this year, we are significantly raising our 2025 financial guidance. This time driven by strong revenue performance to date, including the early launch success of Tringolza and an improved outlook for the year. In the second quarter, we earned revenue of $452 million, a two-fold increase year over year, and $584 million for the first six months of 2025, an increase of nearly 70% versus prior year. The strong second quarter revenue we earned also enabled us to generate $154 million in non-GAAP net income for the quarter. As you heard from Kyle, the early Tringolza launch continues to perform well. We earned $19 million in product sales, representing a three-fold increase over the first quarter. Royalty revenues increased by approximately 10% to $70 million in the second quarter. anchored by meaningful contributions from both Spinraza and Wainua. We also generated substantial revenue from our R&D collaborations, including the $280 million upfront payment for the Sapa Blursen license, a medicine outside of our core areas of focus. Nearly 100% of this revenue dropped directly to the bottom line, underscoring the important financial contributions of our partnered pipelines. Total non-GAAP operating expenses in the second quarter increased 8% year-over-year, highlighting our commitment to disciplined investment and driving operating leverage. As planned, our sales and marketing expenses increased year-over-year, driven by our investments in the U.S. launch of Tringolza and preparations for the upcoming launch of Donna DeLorsen. Our SG&A expenses also included our minority portion of Wainui's sales and marketing costs. R&D expenses decreased year over year as several of our late-stage studies have recently concluded. Importantly, we continue to strategically fund our advancing pipeline with more than two-thirds of our total R&D expenses funding our late-stage programs. Based on our continued execution across the board, we have increased our revenue guidance range by $100 million and now expect to generate between $825 million and $850 million in revenue this year. Importantly, our improved revenue guidance is driving our improved operating loss and cash guidance for the year. Our revenue guidance includes sizable commercial revenue supported by Spinraza and the continued strong Tringolza performance. We expect to generate between $75 and $80 million in Tringolza product sales this year. We are also on track to add initial product revenue from our second launch with the FDA action date for Donna DeLorsen set for August 21st. Given the timing of approval, we anticipate Donna DeLorsen will modestly contribute to revenues this year with a greater contribution next year. We continue to project our full year 2025 operating expenses to increase in the high single digit percentage range compared to last year. driven by investments to support the success of our multiple ongoing and planned launches. With the increase to our revenue guidance, we now project an operating loss between $300 and $325 million and a year-end cash balance of approximately $2 billion, both substantially improved from our previous guidance as full-year projected revenue is growing faster than projected operating expenses. The strength of our balance sheet reinforces our disciplined capital management, which enables us to continue to invest for growth. To maintain this strength, we plan to refinance our 2026 convertible debt ahead of the maturity date. As always, we are rigorously evaluating a number of options against our objectives to minimize cost of capital, preserve our cash to support our products and pipelines, and maintain operational flexibility. We have historically used convertible debt and believe it remains an attractive option for us. With multiple product launches ahead, a rich pipeline, and continued disciplined investment, we are well-positioned to achieve significant revenue growth resulting in sustained positive cash flow in the next few years, positioning Ionis for substantial value creation in both the near and longer term. And with that, I'll turn the call back over to Brett.

Thank you, Beth. The second quarter marked another period of strong execution and momentum for Ionis. The continued excellent performance of Tringolza highlights the strength of our commercial execution and the value of our innovative science in addressing serious unmet needs. As we prepare for the potential approval and launch of Donna Dolores and the deep and advancing phase three pipeline, we're well positioned to deliver a steady cadence of independent and partnered launches over the next few years. These upcoming milestones reflect the significant progress we're making toward delivering additional transformative medicines to people with serious diseases and building a sustainable, high-growth company. Before I conclude, I'd like to provide two additional announcements. On October 7th, we'll be hosting an Innovation Day in New York City to highlight our pipeline, advancements in our drug discovery capabilities, and we'll provide additional insights into our ongoing and upcoming independent launches. We'll provide additional information as the date gets closer for what we believe will be a highly informative event. Additionally, we are eagerly awaiting results from the Core and Core 2 Phase 3 studies in SHCG. Given that we expect to report the results of both studies at one time in September, we will be initiating a quiet period starting tomorrow, July 31st. Our quiet period will be lifted upon data announcement, and with that, we'll now open it up for questions.

Thank you.

We will now begin the 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. If at any time your questions have been addressed and you would like to withdraw your question, please press star then two. At this time, we will pause momentarily to assemble a roster. First question comes from Gary Knacken. With Raymond James, please go ahead.

Hi, guys, and congrats on the strong quarter. So first, just talk a bit more about how the Tringolza FCS launch is going in terms of finding these new patients and getting them through the reimbursement process and on drug. So what gives you confidence we'll see that strong sequential growth in the back half of the year based on the fiscal year guidance of 75 to 80 million? So first, a little bit more on that. And then on the upcoming SHTG readout in September, just what level of trig lowering are you expecting to see? You know, what are you powered to see? And what do you believe will be considered clinically meaningful in these patients that physicians want to see? And it sounds like you're still confident there'll be enough pancreatitis events across both studies to show a positive trend. Do you think physicians need to see that? to use it for severe high trigs. Maybe give us a sense of what you're hearing in the physician community on that.

Thanks, Gary. Kyle, would you start with the FCS launch and what we're expecting second half of the year?

Yeah, thanks, Gary. So, as we communicated, we're really off to an encouraging start, again, with the FCS launch in Tringolza for the first half of the year. The $19 million in Q2 and a threefold increase over the previous quarter really demonstrates the early momentum that we're very proud of. The product profile, first of all, is playing through very effectively. The reductions in ApoC3, reductions in triglycerides, improvements in acute pancreatitis, a reduction in risk of acute pancreatitis, and reductions in hospitalizations. I mean, all of these things stack up very, very favorably in terms of the receptivity for Tringolza and the FCS population. In addition to that, a very strong commercial strategy. As I referenced, our customer-facing team has over 3,000 physicians that they're interacting with currently. Our marketing and our omnichannel capabilities, we're reaching greater than 30,000 HCPs right now with that education. And then you also asked about reimbursement. Access is going extremely well. Either clinically diagnosed or genetically confirmed patients are going through the process and getting reimbursement very quickly. Patient out-of-pocket expenses, greater than 90% of those patients are paying $0 out-of-pocket. So overall, what we're seeing is very strong execution from a very strong program. In terms of the second half, the real focus is on additional patient identification and continuing to get those patients diagnosed. And through the activities of our commercial team, be it customer-facing and or our omnichannel and marketing capabilities, we expect that to continue. But to continue to identify these upwards of 3,000 patients that potentially have FCS is going to take some work, and we expect that we'll continue that growth throughout the rest of the year.

Thanks, Kyle. Gary, the triglyceride lowering that we're expecting in SHTG, you know, is probably going to be similar to what we saw in Essence, where we saw 58 to 62% reduction based on the dose, 50 versus 80 milligrams. And what we know, based on extensive work we've done with the lipid specialists or the cardiologists or the endocrinologists that manage these patients, What they're looking for are any substantial reductions in triglycerides on top of the treatments they're already giving their patients, like omega-3 fatty acids or fibrates. So they're already recognized that these patients need to be treated, and they're not getting much triglyceride lowering with existing treatments, so they want something to produce a substantial lowering of triglycerides. Anything north of 50% is a big win in this patient population. expect. With respect to AP events and what we're hearing from physicians, we're hearing exactly what I just said, is that they do not need to be convinced that these patients are in harm's way for acute pancreatitis that can be fatal and that we need to lower their triglycerides substantially to get them out of that way. They don't need to see the AP events. However, with that said, although the CORE and CORE2 studies were not designed as AP outcome studies, We are seeing, as Richard mentioned in his formal remarks, we are seeing on a blinded basis acute pancreatitis events, and we expect to have more accumulated AP events in the combined core and core 2 study than we had in the FCS balance study. This gives us confidence we could have sufficient data to observe at least a favorable trend in oligosarcin's impact on AP within these studies, and we look forward to discussing more when we read out the data in September.

Okay, great. And then just one quick one on Donnie with the Bidoof coming up on August 21st. You're in labeling discussion, so how you feel relative to your expectations. You know, if you think the switch data will make it on there, if it'll be once every month and once every other month, those things, that option will be available for patients. And it sounds like you're ready to launch basically right after approval, so just confirm everything is in place for that. Thanks.

I'll start. This is Richard. We're definitely on track for the PDUFA date on August 21st. Everything that we've been discussing with FDA indicates that that date is on track. And then I can't speak to the launch, although everything looks to be in place, and we're excited about it. I think... Your other question in regard to what we get in the label is a matter of negotiation. It always is. And so we work with the agency. That's certainly been our position. Let's get that in there. But we don't need it in the label because it is published. And now that we have a publication and it's related to the work that was done in the clinical trials, we have an opportunity to promote on that.

Kyle, maybe touch on the launch preparations?

In terms of launch readiness, we're building on the synergies from our FCS capabilities. Our medical affairs teams have been out interacting with allergists and immunologists treating HAE. Our sales team is now in place, market access, marketing, patient support, operations capabilities. So everything is ready to go in terms of launch readiness. As Richard was describing the program from a regulatory standpoint, the overall totality of the data here for Donnie DeLorsen is very, very strong from an efficacy standpoint in terms of the durability and control of attacks, the tolerability using the easy-to-use self-administered auto-injector by the patient, and convenience. Here we have a program with the longest dosing interval available or potentially that will be available for patients living with HAE. The switch study is going to be helpful. This obviously is a switch market in the United States. The majority of patients are on a prophylactic treatment today. And what we were able to demonstrate is that, number one, patients are willing to switch. Number two, they can do so safely and move over to Donnie DeLorsen. they can have an additional reduction of upwards of 62% improvement from baseline on an existing prophylactic treatment. And 84% of the patients said that they preferred dinodilorsin over the existing treatment that they were on once they were switched. So the totality of the data combined with the timing of the launch year upcoming, hopefully on August 21st, we'll be ready to go.

Thanks, Kyle. Great. Thanks for all that, Kyle.

Thanks, Gary.

The next question is from the line of Yananzu from Wells Fargo Securities. Please go ahead.

Great. Thanks for taking our questions and congrats on a very strong quarter. Perhaps a first question about Core and Core 2. So I think I heard in a prepared remarks that the cumulative AP event rate on a blinded basis is now above what you saw in FCS. So I just want to confirm, it seems like in the balance study, you had 13 events across 66 patients. And just wanted to get a sense of in the core and core 2, it was across 1,000 plus patients. Are we thinking about a rate above that? And could you also give us a sense that based on a core, core two patient profile, what is the expected AP rate in an untreated population like that so that we can help us prepare for the data and the AP data? And I have a follow-up on the SDS and FHTG launch dynamic. Okay.

Thanks. Yannan, so you said the rate is higher. It's not the rate. The rate is lower, of course, in SHCG. I think that's why you knew that. What we're talking about is the accumulated number of AP events in the Core and Core 2 studies combined. And I can confirm that there will be more events in Core and Core 2 combined than in our FCS balance study. As far as what we think the AP, I mean, we don't really know what the AP rate is. This study will be the first to actually really definitively provide information on what the AP event rate is in SHTG. Ain't that right, Eugene?

No, absolutely right. There's no outcome data that can inform us.

So we're eagerly awaiting the core and core 2 readout.

Got it. Got it, yeah, thanks. And on the FCS launch and potentially the later launch of FHTG, congrats on a very strong second quarter of launch in FCS. It feels like the opportunity in FCS is actually pretty sizable given this momentum. Can you talk about is this opportunity relative to your anticipation? Is it bigger or in line? And more importantly, as we think about you going into SHTG with a much reduction in the pricing, presumably across the board for both indications, any strategy to protect the FCA S opportunity in terms of timing of launch and also any way to manage the pricing change. That would be super helpful. Thank you.

Yeah, let me first talk about the FCS population that you described. I still believe that it's represented as up to 3,000 potential patients. It's still early innings. The majority of these patients still are not diagnosed. Obviously, several hundred patients have either participated in a clinical trial or were waiting for a medication because they had been previously diagnosed and needed a treatment. First mover advantage here is very important, not only in FCS but also in SHTG. So our work for the first half of this year was to convert our clinical trial patients, which we did effectively. to help those patients that were previously identified with FCS to go on to treatment and then to continue to expand our patient identification efforts. We've been spending a lot of time on that, as I referenced, in terms of reaching greater than 3,000 HCPs with our sales team and reaching greater than 30,000 HCPs through our education program. you know, related to our marketing and our omni-channel efforts. So we're continuing to educate. The time that we're spending on FCS specifically is with physicians that are treating SHTG patients. And so what we're doing is having conversations around the implications of high triglycerides and how these patients present and ultimately looking for a phenotype of an FCS patient in order to either clinically diagnose them or get a genetic confirmation of their disease. So that work is ongoing, and that's what we'll need to do through the second half of this year. You know, we've provided the guidance of $75 to $80 million this year, which represents not only the patients that we've converted already in the first half, but the ongoing efforts that we believe will be successful through the second half of this year. So I believe that the FCS population is in line with the up to 3,000 that we've represented up to this point. As it relates to SHTG, this is a much broader patient population obviously and the treating physician population is much more significant. Greater than a million patients have high risk SHTG which is inclusive obviously of patients over 500 with a history of AP. or patients over 880 milligrams per deciliter. So there's a lot of effort already around education in this population and working to identify these potential patients within these practices as we go out and have these interactions. As it relates to the pricing dynamic, we're still working through that. There's more work for us to understand in terms of the data, which we are still waiting for, And then we'll work, obviously, with the payer community to understand the budget impact of the patient population, their interpretation of the data, and obviously the value that that represents to patients. So that's the work that we will do going into next year. And ultimately, we will announce price upon the approval of the SHTG indication pending positive outcome there.

Great. Thanks for the call. Congrats on the quarter again.

Thank you. The next question is from the line of Steven Ainov from TD Securities. Please go ahead.

Hi, everyone. This is Steven Ainov on for your own Werber. Congrats again on a fantastic quarter. One more on Donnie and on competition specifically. It looks like Taxairo revenues are stable and Orlodio seems to be growing significantly. Any visibility also as well on the Endembry launch, which was approved on June 16th? Obviously, that drug has a couple of disadvantages, including monthly dosing versus Donnie's two months and also requiring a loading dose, which Donnie does not. Any visibility on the competition and maybe insights from there on what the Donna DeLorsen launch could look like? Thanks.

Yeah, I'd be happy to talk about that. This is Kyle. I think what we know in this marketplace and what's come through very clearly is that patients on existing prophylactic treatments are not completely satisfied and that they would be willing to switch to a new therapy. A recent Harris poll said that greater than 90% of patients actually would look to switch to an improved therapy, and I think you're seeing that play out with the newly approved treatment already, and we would expect to see the same from Donnie DeLorsen. The profile overall with Donny-DeLorsen is very strong, as I mentioned. Not only the efficacy data, but also the ability for patients to self-administer. As you pointed out, this therapy is going to be potentially prescribed every four weeks or every eight weeks, depending upon how patients present and how stable they are with their disease. So that is, again, another key differentiator here. And then finally, I'll just mention the switch study. I mean, what we have demonstrated is that patients are willing to switch. When they do so, they can do so safely. They have the potential to improve the control of their disease. And ultimately, when they've ended up on Dottie Dolores and they've preferred it over the treatment that they were on before. So I believe from a competitive standpoint, we're in really good shape. And we've got a great team. We've hired a sales organization that has experience in the allergy and immunology space, many of whom have direct HE experience for many years. And they know the treating physicians, and they've got not only existing relationships, but they understand how to competitively sell. So we're really excited about the upcoming launch, potentially with the approval on August 21st.

Thank you very much. Thank you.

The next question is from the line of Michaels with Morgan Stanley. Please go ahead.

Great. Good afternoon. Thanks for taking the question, and congratulations on the strong quarter as well. Maybe just a question on the Phase III SHTG core data. You know, previously you suggested Data 3Q. You're narrowing that a little bit to September. I guess first question, just, you know, any, you know, what's the rationale there or anything behind that? And then secondly, last quarter you suggested AP data, you know, might not be available in the top line release. I guess just maybe give us a sense of what level of AP data you plan to share in the top line release in September. Thanks.

Sure, Mike. So just refining the timeline to September from the second half of the year is just blocking and tackling, getting the studies completed, database locked, the data cleaned and all that. So we just felt it was appropriate to provide more specificity on the exact timing. So nothing significant behind there except operational and conducting research the studies, we will provide a statement on AP in our top line press release. Our primary input, again, is triglyceride lowering. We will provide top line information on triglycerides as well as safety, overall safety, and we'll provide a statement on AP. What's also, I think, even more important is that we will provide and present the full data set at a medical congress in the second half of this year. And we look to publish the data in the second half of this year as well.

Very helpful. Thank you.

The next question is from the line of Andy Chen from Wolfi Research. Please go ahead.

Hey, Brandon on for Andy. On Wainui and polym neuropathy, Where do you think those patients are coming from? Do you think that you're winning new to brand share or stealing patients from Anilam? If you're going to provide any quantitative splits on those details, that'd be great. Thank you.

I'd be happy to talk about that, Brandon. Thanks. This is Kyle again. First, I'll just say Wainua continues to perform very well. Strong demand. The polyneuropathy market is a growth market. The majority of these patients are not diagnosed yet, and that's exactly where AstraZeneca is spending the time, is looking for and educating HCPs around hereditary polyneuropathy patients. $44 million in Q2, which obviously was growth over Q1. The feedback that we're getting from HCPs is continuing to be very positive around quality of life, and efficacy in the control of the polyneuropathy symptoms on a consistent basis. The ability to self-administer with an auto-injector continues to be a differentiating factor, and physicians and patients very much appreciate the opportunity to manage their disease on their own without having to come into the HCP's office in order to have a simple injection provided to that patient. So in a simple response here, these are new-to-brand patients. These are patients that are newly identified predominantly. We are seeing some switches, as you would expect, and we are seeing some combination use along with patients that are progressing on the stabilizers today. But really our focus is growing the polyneuropathy market and making sure that newly identified patients get prescribed Waynua.

Next question.

The next question is from the line of Jenna Wang from Barclays. Please go ahead.

Thank you for taking my questions. Also, congrats on a very strong quarter. So I have two questions regarding Trangoza. When I look at the guidance for FCS this year, 75 to 80 million, even if we're using 80 million, it seems every quarter is 3Q for only 5 million growth. So maybe give us a little bit more color, you know, is the guidance too conservative or is there a reason that why, you know, the new patient add-on was slowed down compared to 2Q over 1Q? So that's the first question. And a second, I don't know if you can comment. I think you mentioned that the total accumulative events for core and core 2 would be more than 13. So giving, you know, certainly different disease and prior history of AP in the two studies. So maybe, like, how much more? Are we talking about the total AP events in the teens, or could that be in the 20s?

Thanks, Gina.

Beth, do you want to touch on the $75 to $80 million guidance?

Yeah, actually, I think I'll just toss that to Kyle, because That's in his chat.

He's responsible for that. So I think what's most important here is the way that we've progressed throughout the launch, right? As I referenced, we converted the clinical trial patients. We've been working very effectively with patients that were identified prior to the approval in order to get those patients formally diagnosed and put on to treatment. So you had a number of patients that were previously identified. So where we're at right now at the launch is really looking for newly identified and newly diagnosed patients in order to penetrate deeper into that up to 3,000 FCS patient population that we believe exists in the U.S. So that takes some time. It takes a lot of education and it takes a lot of conversations. And then it also takes a little bit of time for physicians to get potential patients into the practice in order to be either clinically or genetically confirmed with their condition. So we've done a nice job throughout the first half of the year. We expect to continue to identify these patients, but it just might take us a little bit of time because of the complexity of the rare disease that we're dealing with. And being first to market and having a great product with positive physician and patient experience is helping us to increase that patient identification over time.

Yeah, thanks, Kyle. And on your second question, Gina, We're not going to go more than that. I mean, in this call today, we confirmed that we will see more AP events in the Core and Core 2 studies combined, and we saw an FCS balance, and we confirmed that we will make a statement summarizing, you know, to some extent, top-line summary of AP findings in Core and Core 2. We're not going to go further than that on how many more AP events

We look forward to sharing the data in September. Thank you.

Next question is from the line of Luca Isi from RBC. Please go ahead.

Well, great. Thanks so much for taking my question and congrats on the great quarter here. Maybe, Brett, if I can circle back on one of the statements you made earlier, you know, the physicians appreciate that triglycerides are the bad guys, so to speak, and, you know, they don't need to see stat-sig on acute pancreatitis. Is that a U.S. comment, or do you think that is applicable also to the rest of the world? I guess in a scenario where you don't show stat-sig or strong trend on AAP, how should we think about the uptake of this drug outside the United States? And then I know a Probably pushing my luck here, but you mentioned you'll have a statement on AP in the press release. Will that be a qualitative statement or a quantitative statement? Thanks so much.

We're not going to go more than that, Luca, on what we're going to say. We will speak to our findings in Core and Core 2 on AP and our top-line press release and share for the full data set at a medical congress this year. So we're just going to hold off on that one. Your first question is a very important question because really what you're getting at is payer dynamics outside of the U.S. Kyle will address that, but I can tell you that in the U.S., and I have spent a lot of time with lipid specialists over the last two years who treat SHTG patients. They are convinced that they need to get patients on the most effective triglyceride lowering agents possible if they're SHTG patients, because they are convinced, they know that their patients are in harm's way for acute pancreatitis. In fact, they're already treating them. They're treating them with everything they have, whether it be fibrates or omega-3s, they're just not effective. So they're looking for something on top of standard of care. As a reminder, our core and core two studies are on top of standard of care. to get their triglycerides down. And that's true for payers in the United States, too. Outside the U.S., let me focus on Europe, it's a little bit more complex, right?

It is. From a regulatory standpoint, though, obviously triglyceride lowering is going to be sufficient for a label in the EU. And that filing is there. And we've obviously positive CHMP opinion and optimistic about the outcome and where that goes in terms of the approval. So from a payer and reimbursement dynamic standpoint in the European countries, for example, it's really about the breadth of the population that you're ultimately going to be able to treat. Who to treat and why to treat those patients is the key thing here in order to demonstrate outcomes in the patient population. One thing that's very positive already is if we are able to secure an indication in Europe is we've got FCS. FCS already has AP data. It already has very strong hospitalization data. And so we've got information to be able to substantiate pricing and reimbursement from an FCS standpoint. We also have a very strong partner in Sobe who has been in this market for many years. And they've navigated pricing and reimbursement very successfully in the FCS population already across numerous countries. across Europe, and I think we're very optimistic that we'll be able to continue that success with a program like Tringolza. So then the question becomes SHTG, if you have a potential label expansion, and what do you need to show there? Outcomes in AP are obviously going to be important for the broad population, but could you potentially look at a different population, a little bit more narrow than anybody over 500, For example, patients that are at high-risk SHTG, such as patients over 880, patients with 500 and a history of AP, or potentially patients with other comorbidities. So there are a lot of dynamics and things to think through there. And pending the data, obviously, we'll work through putting that body of evidence together and supporting SOBI in their pricing and reimbursement efforts across each country as they go to launch.

Got it. Thanks so much.

The next question is from the line of David Lebowitz from Citi. Please go ahead.

Thanks for taking my question. Given the strong early ramp of Trimgolza and SCS, how are you thinking about the pricing change that would inevitably happen when it gets approved for severe hypertriglycerides? Is it just going to be a pretty prompt drop, or are you going to try to find some way to the revenues while you're dropping the price and wrapping up.

Yeah, thanks, David. So our pricing work is ongoing. We've got more work to do there. You know, what we've communicated up to this point is in a disease that has 3 to 4 million patients, typically the U.S. payers are accepting of a price somewhere in the $10,000 to $20,000 price range. However, when we're looking at SHTG specifically and the data that Olazarsen can potentially have in the SHTG population, we'd like to go back to the payers and do more testing and understand exactly where this price point could land based on the value to patients and the value to the payers. So there's more work to do. In terms of the execution of that, you know, the FCS population ultimately will be, you know, consumed within the SHTG population. So it will become, you know, anybody over 500 would be within the SHTG population. So there is a question around, you know, how do you execute that and the pricing dynamics and do you bring the price down? I think regardless of what the decision is there, if we do it immediately, or if it's done over time, what we do know is that the SHTG population is quite substantial. And I think what we believe is that we'll be able to maintain enough patient population to be able to continue the revenues that we're producing at the time of an SHTG potential approval.

Thanks for taking my question.

The next question is from line of Jay Olson from Oppenheimer. Please go ahead.

Oh, hey, congrats on the quarter and thank you for providing this update. Now that you have the early successful launch experience with Tringolza and you have several other launches you're planning in the near term, how does that impact your thinking about your earlier stage pipeline and deciding between out-licensing earlier stage assets versus retaining full ownership and launching them independently? And then as a follow-up, can you discuss any plans to build out your ex-U.S. infrastructure for any future global product launches in the long term? Thank you.

Thank you, Jay. You know, we have, you know, an abundance of riches when it comes to, you know, our late stage pipeline, our wholly owned pipeline, our partner pipeline. It's a nice combination there. And our first independent launch is off to a really good start. and we're expecting Donald Wilson to be equally successful as well as SHCG coming up next year. With that said, our research organization is incredibly innovative and prolific. We have to continue to bring in potentially transformational medicines continuously into in due course. Our focus remains, as we set out five years ago, five and a half years ago, to do is to prioritize the whole young pipeline. We'll continue to do so, and we will focus on cardiology and cardiometabolic diseases as well as neurology. We will always have room for exceptions, like hereditary angioedema, when we have such an excellent-looking drug like Don and Polarsen, but those will be our focus. Those areas will be our focus, and it will be the priority. With that said, we still need to ensure that we live within our means. We have limited, you know, our resources are limited. We are committed to achieving a positive cash flow in the next few years. And although we will prioritize our holding on pipeline early stage through phase three development, there will always be assets that either are outside of our means or outside of our priority areas where we will make decisions to partner. A lot of interest in partnering with IONIS these days. Our platform is delivering over and over again. A great example of that is the SAP person transaction that we did earlier this year. Always at the Minivera with Ono. $280 million up front. And we did that because it's outside of our areas of focus. Hematology is not a focused area for us. So you'll see us continue to partner, but that's not our priority. Our priority is our wholly owned pipeline, early to late stage, and our launches. With respect to outside the U.S., I'd like to just put that one on pause. We're thrilled with the early launch of Tringolza And we're looking forward to Donna Dolores and SHCG launches in the U.S. And we'll know when it's time to emerge from the U.S. and maybe start building external or ex-U.S. commercial infrastructure. But now is not the time to be distracted with that. We need to get these launches right. We're committed to get these launches right. We will do so. With that said, we, of course, are having discussions internally on when and what that asset might be that we emerge from the U.S. market with. But we're in the early innings in those discussions.

Thank you. That's super helpful. Congrats again on the launch.

The next question is from the line of Akash Tiwari from Jefferies. Please go ahead.

Hi. This is Zaki on for Akash Tiwari. Thanks so much for taking our question. So in the balance study, it looks like there was one AP event that kind of leaked through towards the end of the study in the 80-milligram arm in a patient who did have triglycerides lowered on drug, whereas placebo events, they seemed to cluster earlier on in the first half of the study. So I understand it's a really small end here, but now that you have the essence data and some sense of how blinded events are tracking in core 1 and 2, How confident are you that this kind of variability won't be a swing factor on AP powering in Core 1 and 2? Thank you.

I'll start, and then Eugene, please jump in. So we're doing everything we can to increase the power for AP in our study if possible. AP analysis will be combined Core and Core 2 and will be at the 12-month time frame. correct, right, Eugene? So although the primary endpoint for triglycerides is six months, AP secondary endpoint will be at 12 months with core and core 2 combined. So what we're trying to do is maximize time and maximize patient numbers.

I must add, Brad, the maximal power will be achieved by combining core and core 2 and ensuring that the N is much larger than two separate events.

Thank you.

Our last question comes from Debji Tachatoje from Guggenheim Partners. Please go ahead.

Hey, good afternoon. Sorry, good morning in the West Coast. I'm just wondering if the second interim analysis in the LPA horizon study has happened already, and I believe this was after 745 events. Thank you.

Thanks, Deji. Yes, it has. And there are no more interim analyses planned for the Pella-Carson Horizon Study. So we're fully expecting that study to read out in the first half of next year. And we're very much looking forward to it. So both interim analyses have been completed. So with that, I think we'll close the call. I'd like to thank everybody for joining us today. We look forward to building on our strong momentum throughout the year, sharing additional achievements, progress along the way. And until the next time we talk, thank you again for joining and have a great day, everybody.