Ionis Pharmaceuticals Q2 2025 Earnings Report

Ionis Pharmaceuticals EPS Results

• Actual EPS: $0.70
• Consensus EPS: $0.19
• Beat/Miss: Beat by +$0.51
• One Year Ago EPS: -$0.45

Ionis Pharmaceuticals Revenue Results

• Actual Revenue: $452.00 million
• Expected Revenue: $270.90 million
• Beat/Miss: Beat by +$181.10 million
• YoY Revenue Growth: +100.90%

Ionis Pharmaceuticals Announcement Details

• Quarter: Q2 2025
• Date: 7/30/2025
• Time: Before Market Opens
• Conference Call Date: Wednesday, July 30, 2025
• Conference Call Time: 11:30AM ET

Ionis Pharmaceuticals (NASDAQ:IONS) is a biotechnology company focused on the discovery and development of RNA-targeted therapies designed to modulate gene expression. The company’s proprietary antisense oligonucleotide (ASO) technology enables the selective binding of short synthetic strands of nucleic acids to messenger RNA (mRNA), thereby inhibiting or altering the production of disease-causing proteins. Ionis’ pipeline spans a range of therapeutic areas, including neurological disorders, cardiovascular conditions, metabolic diseases and rare genetic disorders.

Since its founding in 1989 by Dr. Stanley T. Crooke, Ionis has advanced more than 40 investigational drugs into clinical development, successfully bringing several treatments to market through strategic partnerships. Notably, the company collaborated with Biogen on the launch of Spinraza® (nusinersen), the first approved treatment for spinal muscular atrophy, and has licensed other products to global biopharmaceutical companies such as AstraZeneca and Roche. Ionis also established Akcea Therapeutics as a subsidiary to commercialize assets in rare diseases, reflecting its commitment to specialized patient populations.

Headquartered in Carlsbad, California, Ionis operates research and development centers in the United States and maintains partnerships that enable commercial reach in North America, Europe and Asia-Pacific regions. The company employs teams of scientists, clinicians and manufacturing experts to advance RNA-modulating therapies from early discovery through late-stage clinical trials. Ionis’ integrated manufacturing capabilities support both internal programs and external collaborations, reinforcing its role as a leader in oligonucleotide production.

Under the leadership of Executive Chairman Stanley T. Crooke and President & Chief Executive Officer Brett P. Monia, Ionis continues to invest in next-generation RNA platforms, including ligand-conjugated ASOs and splice-modulating compounds. The company’s strategic focus on precision medicine and its platform-derived pipeline position Ionis to address unmet medical needs and expand the application of RNA-targeted therapies worldwide.

Ionis Pharmaceuticals Q2 2025 Earnings Call Transcript

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.

Presentation

[Operator]

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 the call. Please go ahead.

[Wade Walke, Senior VP of Investor Relations at Ionis]

Thank you, Steve. Before we begin, I encourage everyone to 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 financials. We believe non-GAAP financial results better represent the economics of our business and how we manage our business. We have also posted slides on our website that accompany today's call. With me this morning are Brett Monia, Chief Executive Officer, Kyle Jenne, Chief Global Product Strategy Officer, Richard 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&A portion of the call. I would like to draw your attention to slide three, which contains a forward-looking language statement.

[Wade Walke, Senior VP of Investor Relations at Ionis]

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

[Brett Monia, CEO at Ionis]

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, TRYNGOLZA, the first and only FDA-approved treatment for familial chylomicronemia syndrome. TRYNGOLZA exceeded revenue expectations during its second quarter on the market, underscoring its strong therapeutic profile and our well-executed commercial strategy, as well as the significant unmet need TRYNGOLZA is addressing. The revenue and commercial performance of TRYNGOLZA to date, along with our confidence in TRYNGOLZA's continued commercial success, support the increase in our financial guidance for 2025, which Beth will cover in more detail shortly. We are also pleased that TRYNGOLZA recently received a positive CHMP opinion, paving the way to bring this transformative therapy to patients across Europe.

[Brett Monia, CEO at Ionis]

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 autoinjector, and a convenient dosing schedule of monthly or every other month self-administration. We are well positioned to launch donidalorsen following approval. Additionally, our phase three 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.

[Brett Monia, CEO at Ionis]

These include a second indication for olezarsen 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 TRYNGOLZA in FCS and donidalorsen in 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 discovered medicines and have the potential to meaningfully increase total revenue.

[Brett Monia, CEO at Ionis]

With our strong momentum across the business, including TRYNGOLZA 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, I'll turn the call over to Kyle.

[Kyle Jenne, EVP and Chief Global Product Strategy Officer at Ionis]

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. TRYNGOLZA reported $19 million in net product sales for the second quarter, reflecting a threefold increase in revenues quarter over quarter. In the second quarter, TRYNGOLZA 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 TRYNGOLZA 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.

[Kyle Jenne, EVP and Chief Global Product Strategy Officer at Ionis]

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

[Kyle Jenne, EVP and Chief Global Product Strategy Officer at Ionis]

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, autoinjector 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 TRYNGOLZA's early momentum, but we know we're still in the early innings. The vast majority of the estimated 3,000 people living with FCS in the U.S. remain unidentified. To close that gap, we're continuing to focus on our patient-finding efforts and HCP education.

[Kyle Jenne, EVP and Chief Global Product Strategy Officer at Ionis]

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 TRYNGOLZA 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 TRYNGOLZA 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 olezarsen. 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.

[Kyle Jenne, EVP and Chief Global Product Strategy Officer at Ionis]

With a significant first mover advantage, we believe olezarsen 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.

[Kyle Jenne, EVP and Chief Global Product Strategy Officer at Ionis]

The donidalorsen 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 autoinjector. Importantly, as we prepare to bring donidalorsen to market, we are applying the same disciplined and innovative approach that has made the TRYNGOLZA 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 experience and scalable commercial organization is already delivering excellent results, supported by the early success seen with the launch of TRYNGOLZA and FCS.

[Kyle Jenne, EVP and Chief Global Product Strategy Officer at Ionis]

As we build on this momentum, we remain focused on maximizing TRYNGOLZA'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.

[Richard Geary, Chief Development Officer at Ionis]

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 pipeline. As a reminder, donidalorsen 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. Pending 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, olezarsen 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.

[Richard Geary, Chief Development Officer at Ionis]

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 mg and 500 mg 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 mg per deciliter, 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 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.

[Richard Geary, Chief Development Officer at Ionis]

The vast majority of participants achieved triglyceride levels below 150 mg per deciliter, thus reaching the normal range. olezarsen 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 CORE2 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 olezarsen in this population.

[Richard Geary, Chief Development Officer at Ionis]

Importantly, this feedback indicates that physicians understand that lowering triglycerides will reduce the risk of acute pancreatitis and that they would prescribe olezarsen 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 olezarsen'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 three study remains on track, and we're looking forward to sharing data later this year.

[Richard Geary, Chief Development Officer at Ionis]

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. Now, 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 who are 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. Ion 582, an investigational medicine for the treatment of people living with Angelman syndrome, is the newest addition to our late-stage pipeline.

[Richard Geary, Chief Development Officer at Ionis]

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 one two open-label HALOS study results, we recently dosed the first patient in the global phase three 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+ 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.

[Richard Geary, Chief Development Officer at Ionis]

Our partner, Biogen, also recently shared positive top-line interim results from the phase I study of salanersen, an investigational antisense medicine being developed for the potential treatment of spinal muscular atrophy. Leveraging the same mechanism of action as SPINRAZA, we designed salanersen 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 mg and 80 mg 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 three study design. Notably, the initiation of a phase III study would trigger a $45 million milestone payment to Ionis.

[Richard Geary, Chief Development Officer at Ionis]

Additionally, our royalty rates for salanersen are significantly higher than for SPINRAZA. If approved, salanersen 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.

[Beth Hougen, Senior VP of Finance and CFO at Ionis]

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 TRYNGOLZA 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 TRYNGOLZA 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.

[Beth Hougen, Senior VP of Finance and CFO at Ionis]

We also generated substantial revenue from our R&D collaborations, including the $280 million upfront payment for the olezarsen 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 TRYNGOLZA 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.

[Beth Hougen, Senior VP of Finance and CFO at Ionis]

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 TRYNGOLZA performance. We expect to generate between $75 million and $80 million in TRYNGOLZA 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 21st. Given the timing of approval, we anticipate donidalorsen will modestly contribute to revenues this year, with a greater contribution next year.

[Beth Hougen, Senior VP of Finance and CFO at Ionis]

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 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. 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.

[Beth Hougen, Senior VP of Finance and CFO at Ionis]

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. I'll turn the call back over to Brett.

[Beth Hougen, Senior VP of Finance and CFO at Ionis]

Thank you, Beth. The second quarter marked another period of strong execution and momentum for Ionis Pharmaceuticals. The continued excellent performance of TRYNGOLZA 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 three pipeline, we are 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.

[Beth Hougen, Senior VP of Finance and CFO at Ionis]

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 day gets closer for what we believe will be a highly informative event. Additionally, we are eagerly awaiting results from the CORE and CORE2 phase three 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 31st. Our quiet period will be lifted upon data announcement, and with that, we'll now open it up for questions.

[Operator]

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. First question comes from Gary Nachman with Raymond James. Please go ahead.

[Gary Nachman, Managing Director - Biopharma and Biotech Equity Research at Raymond James]

Hi, guys, and congrats on the strong quarter. First, just talk a bit more about how the TRYNGOLZA FCS launch is going in terms of finding these new patients and getting them through the reimbursement process and 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 million-$80 million? First, a little bit more on that. On the upcoming SHTG readout in September, just 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?

[Gary Nachman, Managing Director - Biopharma and Biotech Equity Research at Raymond James]

Maybe give us a sense of what you're hearing in the physician community on that.

[Brett Monia, CEO at Ionis]

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

[Kyle Jenne, EVP and Chief Global Product Strategy Officer at Ionis]

Yeah, thanks, Gary. As we communicated, we're really off to an encouraging start again with the FCS launch in TRYNGOLZA 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 TRYNGOLZA in 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.

[Kyle Jenne, EVP and Chief Global Product Strategy Officer at Ionis]

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. 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. Through the activities of our commercial team, be it customer-facing and/or 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.

[Brett Monia, CEO at Ionis]

Thanks, Kyle. Gary, the triglyceride lowering that we're expecting in SHTG is probably going to be similar to what we saw in ESSENCE, where we saw a 58%-62% reduction based on the dose, 50 versus 80 mg. What we know, based on extensive work we've done with the lipid specialists or the cardiologists or the endocrinologists that manage these patients, is 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, so 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 of care, and that is what we expect.

[Brett Monia, CEO at Ionis]

With respect to AP events and what we're hearing from physicians, 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 CORE2 studies were not designed as AP outcome studies, we are seeing, as Richard mentioned in his formal remarks, on a blinded basis acute pancreatitis events, and we expect to have more accumulated AP events in the combined CORE and CORE2 study than we had in the FCS balance study.

[Brett Monia, CEO at Ionis]

This gives us confidence we could have sufficient data to observe at least a favorable trend in olezarsen's impact on AP within these studies, and we look forward to discussing more when we read out the data in September.

[Gary Nachman, Managing Director - Biopharma and Biotech Equity Research at Raymond James]

Okay, great. Just one quick one on donidalorsen with the PDUFA coming up on August 21. You're in labeling discussions, so how do 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 dosing, that option will be available for patients. It sounds like you're ready to launch basically right after approval, so just confirm everything is in place for that. Thanks.

[Richard Geary, Chief Development Officer at Ionis]

Now, I'll start. This is Richard. We're definitely on track for the PDUFA date on August 21. Everything that we've been discussing with the FDA indicates that that date 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. It always is. We work with the agency. That's certainly been our position. Let's get that in there. We don't need it in the label because it is published. 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.

[Brett Monia, CEO at Ionis]

Kyle, maybe touch on the launch preparations.

[Kyle Jenne, EVP and Chief Global Product Strategy Officer at Ionis]

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, our operations capabilities. 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 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 autoinjector 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.

[Kyle Jenne, EVP and Chief Global Product Strategy Officer at Ionis]

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. 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 21st, we'll be ready to go.

[Brett Monia, CEO at Ionis]

Thanks, Kyle.

[Wade Walke, Senior VP of Investor Relations at Ionis]

Great. Thanks for all that color.

[Kyle Jenne, EVP and Chief Global Product Strategy Officer at Ionis]

Thanks, Gary.

[Operator]

The next question is from the line of [Yuman Tzu] from Wells Fargo Securities. Please go ahead.

[Operator]

Oh, great. Thanks for taking our questions and congrats on a very strong quarter. Perhaps a first question about CORE and CORE2. 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. I just wanted to get a sense of in the CORE and CORE2 with across 1,000+ patients, are we thinking about the rate above that? Could you also give us a sense that based on the CORE, CORE2 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 have a follow-up on the FCS and SHTG launch dynamic? Thanks.

[Brett Monia, CEO at Ionis]

Yeah, you said the rate is higher. It's not the rate. The rate is lower, of course, in SHTG. I think you knew that. What we're talking about is the accumulated number of AP events in the CORE and CORE2 studies combined. I can confirm that there'll be more events in CORE and CORE2 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?

[Eugene Schneider, EVP and Chief Clinical Development Officer at Ionis]

No, absolutely right. There's no outcome data so far that can inform us. We're eagerly awaiting the CORE and CORE2 readout.

[Eugene Schneider, EVP and Chief Clinical Development Officer at Ionis]

Thanks. On the FCS launch and potentially the later launch of SHTG, 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? 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.

[Kyle Jenne, EVP and Chief Global Product Strategy Officer at Ionis]

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. 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.

[Kyle Jenne, EVP and Chief Global Product Strategy Officer at Ionis]

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.

[Kyle Jenne, EVP and Chief Global Product Strategy Officer at Ionis]

We've provided the guidance of $75 million-$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 we'll be successful with 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 acute pancreatitis or patients over 880 mg 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.

[Kyle Jenne, EVP and Chief Global Product Strategy Officer at Ionis]

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.

[Kyle Jenne, EVP and Chief Global Product Strategy Officer at Ionis]

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

[Brett Monia, CEO at Ionis]

Thank you.

[Operator]

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

[Steven Ayanov, VP and Equity Analyst at TD Securities]

Hey, everyone. This is Steven on for Werber. Congrats again on a fantastic quarter. One more on doni and on competition specifically. It looks like TAKHZYRO revenues are stable, and ORLADEYO seems to be growing. Any visibility also as well on the endeavor launch, which was approved on June 16th, 2023? 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 donidalorsen launch could look like? Thanks.

[Kyle Jenne, EVP and Chief Global Product Strategy Officer at Ionis]

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, and 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.

[Kyle Jenne, EVP and Chief Global Product Strategy Officer at Ionis]

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 HAE experience for many years. 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 21st.

[Steven Ayanov, VP and Equity Analyst at TD Securities]

Thank you very much.

[Operator]

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

[Operator]

Great. Good afternoon. Thanks for taking the question, and congratulations on the strong quarter as well. Maybe just a question on the phase three SHTG CORE data. You know, previously you suggested data 3Q. You're narrowing that a little bit to September. I guess first question, just what's the rationale there or anything behind that? Secondly, last quarter you suggested AP data 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.

[Brett Monia, CEO at Ionis]

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, the data 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 acute pancreatitis 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 acute pancreatitis. What's also, I think, even more important is that we will provide and present the full dataset, full dataset 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.

[Brett Monia, CEO at Ionis]

Very helpful. Thank you.

[Operator]

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

[Operator]

Hey, Brendan 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 or stealing patients from an island? If you're going to provide any quantitative splits on those details, that'd be great. Thank you.

[Kyle Jenne, EVP and Chief Global Product Strategy Officer at Ionis]

Yeah, 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 has continued to be very positive around quality of life and efficacy and the control of the polyneuropathy symptoms on a consistent basis. The ability to self-administer with an autoinjector continues to be a differentiating factor. 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.

[Kyle Jenne, EVP and Chief Global Product Strategy Officer at Ionis]

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.

[Brett Monia, CEO at Ionis]

Next question.

[Operator]

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

[Gena Wang, Managing Director of Biotech Equity Research at Barclays]

Thank you for taking my questions. Also, congrats on a very strong quarter. I have two questions regarding TRYNGOLZA. When I look at the guidance for FCS this year, $75 million-$80 million, even if we're using $80 million, it seems every quarter is 3Q for only $5 million growth. Maybe give us a little bit more color. Is the guidance too conservative, or is there a reason why the new patient add-on was slowed down compared to 2Q over 1Q? That's the first question. Second, I don't know if you can comment. I think you mentioned that the total accumulative events for CORE and CORE2 would be more than 13. Given certainly a different disease and the prior history of acute pancreatitis in the two studies, how much more are we talking about the total acute pancreatitis events?

[Gena Wang, Managing Director of Biotech Equity Research at Barclays]

Is it in the teens or could that be in the 20s?

[Brett Monia, CEO at Ionis]

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

[Beth Hougen, Senior VP of Finance and CFO at Ionis]

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

[Kyle Jenne, EVP and Chief Global Product Strategy Officer at Ionis]

No, 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. You had a number of patients that were previously identified. Where we're at right now with the launch is really looking for newly identified and newly diagnosed patients, right, 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, you know, either clinically or genetically confirmed with their condition.

[Kyle Jenne, EVP and Chief Global Product Strategy Officer at Ionis]

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.

[Brett Monia, CEO at Ionis]

Yeah, thanks, Kyle. On your second question, Gene, 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 CORE2 studies combined. We saw an FCS balance, and we confirmed that we will make a statement summarizing, to some extent, top-line summary of AP findings in CORE and CORE2. We're not going to go further than that on how many more AP events we see. We'll look forward to sharing the data in September.

[Operator]

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

[Luca Issi, Senior Biotechnology Analyst at RBC]

Great, thanks so much for taking my question and congrats on a great quarter 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, 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 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.

[Brett Monia, CEO at Ionis]

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 CORE2 on AP at the end of our top-line press release and share for the full dataset at a medical congress this year. 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. That's really Kyle will address that. I could 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 do not, 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.

[Brett Monia, CEO at Ionis]

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. They're looking for something on top of standard of care. As a reminder, our CORE and CORE2 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 maybe focus on Europe. It's a little bit more complex, right?

[Kyle Jenne, EVP and Chief Global Product Strategy Officer at Ionis]

It is. From a regulatory standpoint, though, obviously, triglyceride lowering is going to be sufficient for a label in the EU. 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. From a payer and reimbursement dynamic standpoint, you know, 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. You know, who to treat and why to treat those patients, right, 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.

[Kyle Jenne, EVP and Chief Global Product Strategy Officer at Ionis]

We've got information to be able to substantiate pricing and reimbursement from an FCS standpoint. 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 TRYNGOLZA. The question becomes SHTG. If you have a potential label expansion, then 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 of 500 and a history of AP, or potentially patients with other comorbidities.

[Kyle Jenne, EVP and Chief Global Product Strategy Officer at Ionis]

There are a lot of dynamics and things to think through there. 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.

[Kyle Jenne, EVP and Chief Global Product Strategy Officer at Ionis]

Got it. Thanks so much.

[Kyle Jenne, EVP and Chief Global Product Strategy Officer at Ionis]

Thanks, Luca.

[Operator]

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

[David Lebowitz, Senior Research Analyst - Biotechnology at Citi]

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

[Kyle Jenne, EVP and Chief Global Product Strategy Officer at Ionis]

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 olezarsen 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.

[Kyle Jenne, EVP and Chief Global Product Strategy Officer at Ionis]

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. 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.

[Operator]

Thanks for taking my question. The next question is from the line of Jay Olson from Oppenheimer. Please go ahead.

[Jay Olson, Research Analyst at Oppenheimer]

Oh, hey, congrats on the quarter, and thank you for providing this update. Now that you have the early successful launch experience with TRYNGOLZA 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.

[Brett Monia, CEO at Ionis]

Thank you, Jane. We have an abundance of riches when it comes to our late-stage pipeline, our wholly owned pipeline, our partner pipeline. It's a nice combination there. Our first independent launch is off to a really good start, and we're expecting donidalorsen to be equally successful as well as SHTG coming up next year. 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, 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.

[Brett Monia, CEO at Ionis]

We will always have room for exceptions like hereditary angioedema, and 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. 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's 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 Sappho-Blurson transaction that we did earlier this year for polycythemia vera with Ono, $280 million upfront.

[Brett Monia, CEO at Ionis]

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. 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 TRYNGOLZA, and we're looking forward to donidalorsen and SHTG launches in the U.S. 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. We, of course, are having discussions internally on when and what that asset might be that we emerge from the U.S. market with.

[Brett Monia, CEO at Ionis]

We're in the early innings in those discussions.

[Jay Olson, Research Analyst at Oppenheimer]

Thank you. Super helpful. Congrats again on the launch.

[Operator]

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

[Keyan Patel, Investment Banking Analyst at Jefferies]

Hi, this is Keyon for Akash Tewari. Thanks so much for taking our question. In the BALANCE study, it looks like there was one acute pancreatitis event that 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, they seem to cluster earlier on in the first half of the study. I understand it's a really small N here, but now that you have. Asset

[Keyan Patel, Investment Banking Analyst at Jefferies]

data and, you know, some sense of how blinded events are tracking in CORE and CORE2. How confident are you that this kind of variability won't be a swing factor on acute pancreatitis powering in CORE and CORE2? Thank you.

[Brett Monia, CEO at Ionis]

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 CORE2, and we'll include, we'll be at the 12-month time point. That's correct, right, Eugene?

[Eugene Schneider, EVP and Chief Clinical Development Officer at Ionis]

Yes.

[Brett Monia, CEO at Ionis]

Although the primary endpoint for triglycerides is at six months, the acute pancreatitis secondary endpoint will be at 12 months in combination with CORE and CORE2 combined. We're trying to maximize time and maximize patient numbers.

[Eugene Schneider, EVP and Chief Clinical Development Officer at Ionis]

I'll go ahead, Brett. The maximal power will be achieved by combining CORE and CORE2 and ensuring that the N is much larger than two separate points.

Participants

Executives

• Kyle Jenne, EVP and Chief Global Product Strategy Officer
• Brett Monia, CEO
• Richard Geary, Chief Development Officer
• Eugene Schneider, EVP and Chief Clinical Development Officer

Analysts

• Analyst at Morgan Stanley
• Beth Hougen, Senior VP of Finance and CFO at Ionis
• David Lebowitz, Senior Research Analyst - Biotechnology at Citi
• Keyan Patel, Investment Banking Analyst at Jefferies
• Jay Olson, Research Analyst at Oppenheimer
• Analyst at Wells Fargo Securities
• Wade Walke, Senior VP of Investor Relations at Ionis
• Gary Nachman, Managing Director - Biopharma and Biotech Equity Research at Raymond James
• Analyst at Wolfe Research
• Luca Issi, Senior Biotechnology Analyst at RBC
• Gena Wang, Managing Director of Biotech Equity Research at Barclays
• Steven Ayanov, VP and Equity Analyst at TD Securities