Ionis Pharmaceuticals Q2 2025 Earnings Call Transcript

Quartr
Provided by Quartr
July 30, 2025

Key Takeaways

  • Positive Sentiment: Tringolza delivered $19 million in 2Q25 net product sales—a threefold quarter-over-quarter increase—fueling confidence and supporting a $75–$80 million full-year FCS revenue target.
  • Positive Sentiment: Donadvlorsen remains on track for FDA approval on August 21 as the first RNA-targeted prophylactic for hereditary angioedema, offering monthly or every-other-month self-administered dosing via auto-injector.
  • Positive Sentiment: Olasarsen met primary and key secondary endpoints in the ESSENCE Phase 3 study—achieving up to 61% placebo-adjusted triglyceride reductions—with pivotal CORE 1 and CORE 2 results expected in September for the SHTG indication.
  • Positive Sentiment: Ionis raised its 2025 revenue guidance to $8.25–$8.50 billion after reporting $452 million in 2Q25 revenues and $154 million in non-GAAP net income, and now projects an operating loss of $300–$325 million and ~$2 billion year-end cash.
  • Neutral Sentiment: Zilgarnirsen is progressing on schedule with a seamless Phase 1/3 study in Alexander disease—the first clinical trial in this ultra-rare leukodystrophy—with data anticipated later this year amid higher readout uncertainty.
AI Generated. May Contain Errors.
Earnings Conference Call
Ionis Pharmaceuticals Q2 2025
00:00 / 00:00

There are 8 speakers on the call.

Speaker 5

Good morning and welcome to Ionis Pharmaceuticals 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 the call. Please go ahead.

Speaker 2

Thanks Steve.

Speaker 6

Before we begin, I encourage everyone to.

Speaker 7

Go to the Investors 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 financial. 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 Jenne, Chief Global Product Strategy Officer, Richard S. Geary, Chief Development Officer, and Beth Hougen, 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 and A portion of the call. I would like to draw your attention to Slide 3, which contains a forward-looking language statement.

Speaker 7

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.

Speaker 2

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, Trengolza, the first and only FDA-approved treatment for familial chylomicronemia syndrome. Trengolza 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 Trengolza is addressing. The revenue and commercial performance of Trengolza to date, along with our confidence in Trengolza'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 Trengolza recently received a positive CHMP opinion, paving the way to bring this transformative therapy to patients across Europe.

Speaker 2

Shifting gears, we anticipate donidalorsen 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. Donidalorsen 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 auto-injector, and a convenient dosing schedule of monthly or every other month self-administration. We're well positioned to launch donidalorsen following approval. Additionally, our Phase 3 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.

Speaker 2

These include a second indication for olpasiran in severe hypertriglyceridemia, or SHTG, a condition with a large patient population and significant unmet need, and zilganersen for Alexander disease, a severe rare leukodystrophy with no approved disease-modifying therapies. Together, these programs, in addition to Trengolza in FCS and donidalorsen in HAE, represent major breakthroughs for patients and represent multi-billion 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-discovered medicines and have the potential to meaningfully increase total revenue.

Speaker 2

With our strong momentum across the business, including Trengolza and our upcoming independent and partnered 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. With that, turn the call over to Kyle.

Speaker 3

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. Trengolza reported $19 million in net product sales for the second quarter, reflecting a threefold increase in revenues quarter over quarter. In the second quarter, Trengolza continued to build launch momentum. This was a result of several factors, including effective patient identification efforts, a strong product profile, favorable payer dynamics, and overwhelmingly positive HCP-reported experience. Our patient identification initiatives are paying off. The breadth and depth of unique physicians prescribing Trengolza 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.

Speaker 3

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 Trengolza continuing to gain traction. Coverage and reimbursement trends have remained favorable. To date, the coverage mix for patients on Trengolza 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 payers' 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.

Speaker 3

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 Trengolza'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.

Speaker 3

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 Trengolza 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 Trengolza 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 olpasiran. 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 this includes individuals with triglyceride levels above 880 or above 500 with a history of acute pancreatitis.

Speaker 3

With a significant first-mover advantage, we believe olpasiran 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. Donidalorsen, 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 treatment. 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 donidalorsen is uniquely positioned to meet this demand.

Speaker 3

The donidalorsen clinical data have shown durable efficacy and a 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 donidalorsen to market, we are applying the same disciplined and innovative approach that has made the Trengolza launch a success. We have deployed our field team who are educating and preparing the market for the anticipated approval of donidalorsen 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 Trengolza and FCS.

Speaker 3

As we build on this momentum, we remain focused on maximizing Trengolza's full potential while preparing to successfully execute three additional launches by the end of next year, including donidalorsen in the coming weeks, enabling Ionis Pharmaceuticals to reach more people in need with our medicines. With that, I'll now turn it over to Richard.

Speaker 6

Thank you, Kyle. We are making excellent progress across our pipeline, positioning Ionis Pharmaceuticals to deliver on our mission of bringing transformational medicines to patients for years to come. Let me start with the recent updates from our wholly owned pipeline. As a reminder, donidalorsen is currently under regulatory review in both the U.S. and Europe, with submission supported by its robust clinical data. We remain confident in the August 21 PDUFA date based on the engagement we've had with the U.S. Food and Drug Administration at this stage in the process, pending approval. We look forward to making this potential best-in-class prophylactic treatment available to people living with hereditary angioedema (HAE). Beyond its approved use in familial chylomicronemia syndrome (FCS), olpasiran is also being evaluated for the treatment of severe hypertriglyceridemia (SHTG), with three separate Phase 3 studies supporting our planned sNDA filing.

Speaker 6

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 CORE 2 studies exclusively enrolled SHTG patients. Participants in these studies had triglycerides that were greater than 500 milligrams per deciliter, with approximately 43% of the participants across both studies with triglycerides greater than 880 milligrams per deciliter at baseline. Triglycerides at this level put people at high risk for acute pancreatitis. The ESSENCE 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.

Speaker 6

The vast majority of participants achieved triglyceride levels below 150 milligrams per deciliter, thus reaching the normal range. Olpasiran 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. The Phase 3 CORE and CORE 2 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 olpasiran in this population.

Speaker 6

Importantly, this feedback indicates that physicians understand that lowering triglycerides will reduce the risk of acute pancreatitis and that they would prescribe olpasiran if approved based solely on its ability to substantially lower triglycerides. Although the Core and Core 2 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 Core 2 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 olpasiran'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.

Speaker 6

The phase three 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 zilganersen using a seamless phase one to phase three 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, zilganersen would represent the first of what we expect to be many more independent launches from our leading neurology pipeline.

Speaker 6

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 1/2 open-label HALOS study results, we recently dosed the first patient in the global Phase 3 REVEAL study. We plan to have this study fully enrolled next year. Turning to our partner 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 and the positive data from higher dose Spinraza, we believe Spinraza is well positioned to continue to bring benefits to SMA patients around the world.

Speaker 6

Our partner Biogen also recently shared positive top-line interim results from the Phase 1 study of salinersen, an investigational antisense medicine being developed for the potential treatment of spinal muscular atrophy leveraging the same mechanism of action as Spinraza. We designed salinersen with novel Ionis 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 achieve meaningful improvements in function and attain new milestones. Biogen is actively engaging with regulatory agency to align on the Phase 3 study design. Notably, the initiation of a Phase 3 study would trigger a $45 million milestone payment to Ionis.

Speaker 6

Additionally, our royalty rates for salinersen are significantly higher than for Spinraza. If approved, salinersen 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.

Speaker 1

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 Trengolza and an improved outlook for the year. In the second quarter, we earned revenue of $452 million, a twofold 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 Trengolza launch continues to perform well. We earned $19 million in product sales, representing a threefold 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.

Speaker 1

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 pipeline. 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 Trengolza and preparations for the upcoming launch of donidalorsen. Our SG&A expenses also included our minority portion of Wainua's sales and marketing costs. R&D expenses decreased year over year as several of our late-stage studies have recently concluded.

Speaker 1

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 Trengolza performance. We expect to generate between $75 million and $80 million in Trengolza product sales this year. We are also on track to add initial product revenue from our second launch with the FDA action date for donidalorsen set for August 21, 2024.

Speaker 1

Given the timing of approval, we anticipate donidalorsen 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 % 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 million 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.

Speaker 1

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 Pharmaceuticals for substantial value creation in both the near and longer term. With that, I'll turn the call back over to Brett.

Speaker 2

Thank you, Beth. The second quarter marked another period of strong execution and momentum. The continued excellent performance of Trengolza 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 donidalorsen and with a deep and advancing Phase 3 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 7, we will be hosting an Innovation Day in New York City to highlight our pipeline advancements and our drug discovery capabilities and will provide additional insights into our ongoing and upcoming independent launches.

Speaker 2

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 SHTG. 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 31. Our quiet period will be lifted upon data announcement and with that we'll now open it up for questions.

Speaker 5

Thank you. We will now begin the question and answer session. To ask a question, you may press Star then one 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 our roster. The first question comes from Gary Nakman with Raymond James. Please go ahead.

Speaker 5

Hi guys, and congrats on the strong quarter.

Speaker 3

First, just talk a bit more.

Speaker 3

About how the Trengolza FCS launch is going in terms of finding these new patients and getting them through the reimbursement process. On drug, 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? First, a little bit more on.

Speaker 3

That.

Speaker 3

On the upcoming SHTG readout in September, what level of trig lowering are you expecting to see? What are you powered to see, and what do you believe will be considered clinically meaningful in these patients that physicians want to see? 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 a physician community on that.

Speaker 7

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

Speaker 3

Thanks, Gary. As we communicated, we're really off to an encouraging start again with the FCS launch in Trengolza 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. All of these things stack up very, very favorably in terms of the receptivity for Trengolza 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. You also asked about reimbursement.

Speaker 3

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, you know, greater than 90% of those patients are paying $0 out of pocket. 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 our omnichannel and marketing capabilities. We expect that to continue. 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.

Speaker 7

Thanks, Kyle.

Speaker 3

Gary.

Speaker 7

The triglyceride lowering that we're expecting in SHTG 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. 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. They already recognize that these patients need to be treated and they're not getting much triglyceride lowering with existing treatments. They want something to produce a substantial lowering of triglycerides. Anything north of 50% is a big win in this patient population on top of standard care. That is what we expect with respect to AP events and what we're hearing from physicians.

Speaker 7

We're hearing exactly what I just said, that they do not need to be convinced that substantial lowering, 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 CORE 2 studies were not designed as AP outcome studies, we are seeing, as Richard S. Geary 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 olpasiran's impact on AP within these studies.

Speaker 7

We look forward to discussing more when we read out the data in September.

Speaker 7

Okay, great. Just one quick one on donidalorsen with the PDUFA coming up on August 21, you're in labeling discussions. How you feel relative to your expectations, if you think the switch data will make it on there, if it'll be once every month and once every other month dosing, that option will be available for patients, and it sounds like you're ready to launch basically right after approval. Just confirm everything is in place for that. Thanks.

Speaker 6

I'll start.

Speaker 3

This is Richard.

Speaker 6

We're definitely on track for the PDUFA date on August 21st. Everything that we've been discussing with the U.S. Food and Drug Administration indicates that that data is on track. 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.

Speaker 7

It always is.

Speaker 6

We work with the agency. That has certainly been our position. Let's get that in there. We do not need it in the label because it is published. Now that we have a publication and it is related to the work that was done in the clinical trials, we have an opportunity to promote on that.

Speaker 7

Kyle, maybe touch on the launch preparations.

Speaker 3

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, as are market access, marketing, patient support, and our operations capabilities. Everything is ready to go in terms of launch readiness. As Richard S. Geary was describing the program from a regulatory standpoint, the overall totality of the data here for donidalorsen 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 is obviously the switch market in the U.S.

Speaker 3

The majority of patients are on a prophylactic treatment today. 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 donidalorsen. 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 donidalorsen over the existing treatment that they were on once they were switched. The totality of the data combined with the timing of the launch here upcoming, hopefully on August 21, we'll be ready to go.

Speaker 7

Thanks Kyle.

Speaker 7

Great. Thanks for all that color.

Speaker 7

Thanks Gary.

Speaker 5

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

Speaker 5

Oh, great. Thanks for taking our questions and congrats on a very strong quarter. Perhaps a first question about Core and Core 2. I think I heard in the prepared remarks that the cumulative AP event rate on a blinded basis is now above what you saw in FCS. 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 with across 1,000 plus patients, are we thinking about a rate above that? Could you also give us a sense that based on the Cohort 2 patient profile, what is the expected AP rate in an untreated population like that so that can help us prepare for the data and the AP data as a follow-up on the FCS and FHTG launch dynamic? Thanks.

Speaker 7

You said the rate is higher. It's not the rate. The rate is lower, of course, in SHTG. I think that's what you knew. What we're talking about is the accumulated number of AP events in the Core and Core 2 studies combined. I can confirm that there'll 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. Isn't that right, Eugene?

Speaker 3

No, absolutely right.

Speaker 7

There's no outcome data thus far that can inform us, so we're eagerly awaiting the core to read out.

Speaker 7

Got it, got it. Yeah. Yeah. Thanks. On the FCS launch and potentially the later launch of SHTG, 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? 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 FCS opportunity in terms of timing of launch and also any way to manage the pricing change, that would be super helpful. Thank you.

Speaker 3

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. 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. 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.

Speaker 3

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 related to our marketing and our omnichannel efforts. We're continuing to educate. The time that we're spending on FCS specifically is with physicians that are treating SHTG patients. 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. That work is ongoing, and that's what we'll need to do through the second half of this year.

Speaker 3

We've provided the guidance of $75 million 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. 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, and the treating physician population is much more significant. Greater than a million patients have high risk SHTG, which is inclusive of patients over 500 with a history of AP or patients over 880 milligrams per deciliter. 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.

Speaker 3

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. We'll work with the payer community to understand the budget impact of the patient population, their interpretation of the data, and the value that that represents to patients. 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.

Speaker 3

Great. Thanks for all the color. Congrats on the quarter again.

Speaker 7

Thank you.

Speaker 5

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

Speaker 3

Hi everyone, this is Stephen Ainov on for Yaron Werber, congrats again on a fantastic quarter. One more on donidalorsen and on competition specifically. It looks like Takhzyro revenues are stable and Orladeyo seems to be growing. Any visibility also as well on the Enfamiro launch, which was approved on June 16. Obviously that drug has a couple of disadvantages, including monthly dosing versus donidalorsen's two months and also requiring a loading dose, which donidalorsen does not. Any visibility on the competition and maybe insights from there on what the donidalorsen launch could look like.

Speaker 3

Thanks.

Speaker 3

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 clear 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. I think you're seeing that play out with a newly approved treatment already. We would expect to see the same from donidalorsen. The profile overall with donidalorsen 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.

Speaker 3

That is again another key differentiator here. Finally, I'll just mention the switch study. 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. Ultimately, when they've ended up on donidalorsen, they've preferred it over the treatment that they were on before. 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 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. We're really excited about the upcoming launch potentially with the approval on August 21. Thank you very much.

Speaker 5

Thank you. The next question is on the line of Michaels with Morgan Stanley. Please go ahead. Great.

Speaker 3

Good afternoon. Thanks for taking the question, and congratulations on the strong quarter as well.

Speaker 5

Maybe just a question on the phase.

Speaker 3

SHTG core data. Previously you suggested data 3Q. You're narrowing that a little bit to September. I guess first question, just what's the rationale there, anything behind that? Secondly, last quarter you suggested.

Speaker 5

AP data might not be available in.

Speaker 3

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.

Speaker 7

Sure, Mike. Just refining the timeline to September from the second half of the year is just blocking and tackling, getting the studies completed, database locked, clinic that they've cleaned and all that. We just felt it was appropriate to provide more specificity on the exact timing. Nothing significant behind there except operational in conducting the studies. We will provide a statement on ap in our top line press release. Our primary endpoint 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, 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.

Speaker 3

Very helpful, thank you.

Speaker 5

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

Speaker 7

Hey, Brandon on for Andy. On Wainua and polyneuropathy, where do you think those patients are coming from? Do you think that you're winning new to brand share?

Speaker 3

Or stealing patients from Alnylam?

Speaker 7

If you're going to provide any quantitative splits on those details, that'd be great. Thank you.

Speaker 3

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, 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.

Speaker 3

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. Our focus is growing the polyneuropathy market and making sure that newly identified patients get prescribed Wainua.

Speaker 7

Next question.

Speaker 5

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

Speaker 1

Thank you for taking my questions. Also, congrats on a very strong quarter. I have two questions regarding Trengolza. 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, 3Q4, only $5 million growth. Maybe give us a little bit more color. Are you in the guidance too conservative, or is there a reason that the new patient add-on was slowed down compared to 2Q over 1Q? That's the first question. The second, I don't know if you can comment. I think you mentioned that the total accumulative events for core and core two will be more than 13. Given certainly different disease and the prior history of AP in the two studies, how much more are we talking about? The total AP events in the teens, or could that be in the 20s?

Speaker 7

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

Speaker 1

Yeah, actually, I think I'll just toss that to Kyle because that's in his shop. He's responsible for that.

Speaker 3

I think what's most important here is the way that we've progressed throughout the launch. 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. You had a number of patients that were previously identified. 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. That takes some time. It takes a lot of education and it takes a lot of conversations. 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.

Speaker 3

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. 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.

Speaker 7

Yeah. Thanks, Kyle. On your second question, Gina, we're not going to go more than that. In this call today, we confirmed that we will see more AP events in the Core and Core 2 studies combined than we saw in FCS balance. We confirmed that we will make a statement summarizing, 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 see. We look forward to sharing the data in September.

Speaker 5

Thank you. Next question is on the line of Luca from RBC. Please go ahead.

Speaker 3

Oh, great. Thanks so much for taking my question and congrats on the record here. Maybe, Brett, if I can circle back on one statement you made earlier. You know, the physicians appreciate that triglycerides are the bad guys, sort of, and they don't need to see static 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 statsig or strong trend on AP, how should we think about the uptake of this drug outside the United States? I know I'm 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.

Speaker 7

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 in our top line press release and share the full data set at a medical congress this year. We're just going to hold off on that one. Your first question is an important question because really what you're getting at is payer dynamics outside of the U.S. Kyle will address that. 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.

Speaker 7

They're treating them with everything they have, whether it be fibrates or omega 3s. They're just not effective. They're looking for something on top of standard of care. As a reminder, our Core and Core 2 studies are on top of standard of care to get their triglycerides down. 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?

Speaker 3

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. We've obviously positive CHMP opinion and optimistic about the outcome where that goes in terms of the approval. 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. We've got information to be able to substantiate pricing and reimbursement from an FCS standpoint.

Speaker 3

We also have a very strong partner in SOBI 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. I think we're very optimistic that we'll be able to continue that success with a program like Trengolza. 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. There are a lot of dynamics and things to think through there.

Speaker 3

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.

Speaker 7

Thanks, Luke.

Speaker 5

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

Speaker 7

Thanks for taking my question. Given the strong early ramp of Trengolza in FCS, how are you thinking about.

Speaker 3

The pricing change that would inevitably happen.

Speaker 7

When it gets for severe hypertriglyceridemia?

Speaker 3

Is it just going to be a

Speaker 6

Pretty prompt drop or are you going?

Speaker 7

To try to find some way to.

Speaker 3

Preserve the revenues while you're dropping the.

Speaker 7

Price and ramping up?

Speaker 3

Yeah. Thanks, David. Our pricing work is ongoing. We've got more work to do there. 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 olpasiran 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. There's more work to do in terms of the execution of that. The FCS population ultimately will be consumed within the SHTG population. It will become anybody over 500 would be within the SHTG population.

Speaker 3

There is a question around 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.

Speaker 7

Thanks for taking that question.

Speaker 5

The next question is from the line of Jay Olson from OpenAimo. Please go ahead. Hey, congrats on the quarter and thank you for providing this update. Now that you have the early successful launch experience with Trengolza and you have several other launches that 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? 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.

Speaker 7

Thank you, Jay. We have an abundance of riches when it comes to our late-stage pipeline, our wholly owned pipeline, and our partner pipeline. It's a nice combination there, and our first independent launch is off to a really good start. We're expecting donidalorsen to be equally successful, as well as SHTG 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 the early-stage pipeline and bring them to phase three development in due course. Our focus remains as we set out five years ago, five and a half years ago. Our goal is to prioritize the wholly owned 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.

Speaker 7

We have such an excellent looking drug like donidalorsen, 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. Our resources are limited. We are committed to achieving positive cash flow in the next few years. Although we will prioritize our wholly owned 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. There is a lot of interest in partnering with Ionis Pharmaceuticals these days. Our platform is delivering over and over again. A great example of that is the SAPA Blursen transaction that we did earlier this year for polycythemia vera with Ono, $280 million up front.

Speaker 7

We did that because it's outside of our areas of focus. Hematology is not a focused area for us. 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 out there. 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 Trengolza, and we're looking forward to donidalorsen and SHTG 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. 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, and we'll do so.

Speaker 7

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.

Speaker 5

Thank you. Super helpful. Congrats again on the launch. The next question is from the line of Akash Tiwari from Jefferies. Please go ahead.

Speaker 5

Hi, this is Zaki on for Akash Tewari. Thanks so much for taking our question. In the balance study, it looks like there was one AP event that.

Speaker 6

Kind of leaked through towards the end of the study in the 80 mg arm in a patient who did have triglycerides lowered on drug, whereas placebo events seemed to cluster earlier on in.

Speaker 6

The first half of the study.

Speaker 6

I understand it's really small n.

Speaker 6

Here, now that you have the essence data and some sense of how.

Speaker 6

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?

Speaker 6

Thank you.

Speaker 7

I'll start and then Eugene, please jump in. 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 point. That's correct, right, Eugene. Although the primary endpoint for triglycerides is at six months, the AP secondary endpoint will be in 12 months in a combo with Core and Core 2 combined. We're trying to maximize time and maximize patient numbers. How much to add, Brett, the maximal power will be achieved by combining Core and Core 2 and ensuring that the N is much larger than two separate.

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