Q2 2026 Ionis Pharmaceuticals Inc Earnings Call

Speaker #1: Good morning and welcome to Ionis Q2 2026 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 Walk, Senior Vice President of Investor Relations, to lead off the call.

Speaker #1: Please go ahead.

Speaker #2: Thank you, Andrea. Before we begin, I encourage everyone to go to the investor section of the Ionis website to view the press release and related financial tables we will be discussing today.

Speaker #2: Including a reconciliation of gap-to-non-gap financials. We believe non-gap financials 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.

Speaker #2: With me this morning are Brett Monya, Chief Executive Officer; Kyle Janay, Chief Global Product Strategy Officer; Ole Kordasevic, Chief Development Officer; and Beth Haugen, Chief Financial Officer.

Speaker #2: Eugene Schneider, Chief Clinical Development Officer; and Eric Swayze, Executive Vice President of Research, will also join us for the Q&A portion of the call.

Speaker #2: I would like to draw your attention to slide 3, which contains our forward-looking language statement. During this call, we will be making forward-looking statements that are based on our current expectations and beliefs.

Speaker #2: These statements are subject to certain risks and uncertainties and are actual results may differ materially. I encourage you to consult the risk factors contained in our SEC filings for additional detail.

Speaker #2: With that, I'll turn the call over to Brett.

Speaker #3: Thanks, Wade. Good morning, everyone. And thank you for joining us on today's call. Ionis Enter is the second half of 2026, well-positioned to achieve the strategic opportunities that lie ahead.

Speaker #3: We have the R&D engine, the pipeline, commercial capabilities, and financial discipline we need to execute on and achieve our goals. We are continuing to build momentum across our commercial medicines and, in parallel, we continue to strengthen and advance our Holy On pipeline to deliver our next wave of important medicines.

Speaker #3: Last month, we achieved a landmark milestone with the approval of Trengulza as the first and only FDA-approved medicine to reduce triglycerides and the risk of acute pancreatitis in adults with severe hypertriglyceridemia, or SHTG.

Speaker #3: Although still early days, we are highly encouraged with our launch momentum today; in fact, we began receiving prescriptions for Trengulza on the day of approval.

Speaker #3: We are also pleased that both the 50 mg and 80 mg doses were in the channel within 1 week. Based on a strong profile and the enthusiasm we are seeing in prescribing, we are confident that Trengulza is well-positioned to help a large population of patients in need and become the first Ionis-owned multi-billion-dollar medicine.

Speaker #3: Gonzera, for hereditary angioedema, also continues to gain momentum. We expect Gonzera to continue driving growth as it becomes more established in the HAE prophylactic treatment landscape.

Speaker #3: We also continue to advance our leadership in the development of breakthrough treatments for a wide range of neurological diseases. We remain on track for the anticipated launch of Zilgen Nursing coming up soon, which is positioned to be the first disease-modifying treatment for Alexander disease and the first independent launch from our neurological disease pipeline.

Speaker #3: Following closely behind Zilgen Nursing is Obada Nursing, our medicine for Angelman syndrome, which completed enrollment in the Phase 3 Reveal study last month, keeping it on track for data next year.

Speaker #3: Earlier this month, we also announced the initiation of clinical development for Ion337 in Dravet syndrome, expanding our clinical stage neurology pipeline which now includes 8 medicines that are Holy On.

Speaker #3: Complementing our Holy On pipeline is our partnered pipeline, which includes medicines targeting both rare and highly prevalent diseases, providing significant additional value for Ionis.

Speaker #3: This includes biparaverse in our medicine for chronic hepatitis B. With a PDUFA target action date of October 26 and additional global filings under review, biparaverse is on track for a global launch this year, positioning it to be a first in-class medicine for the millions of people around the world living with this disease.

Speaker #3: Data from the Phase 3 Pelicarsen LP Little A Horizon study in patients with elevated LP Little A and cardiovascular disease is also a key catalyst coming up in the second half of this year.

Speaker #3: We were disappointed with the outcome of the cardiotransform Phase 3 study for Epilon Tursen in ATTR cardiomyopathy that we reported earlier this month. Although Epilon Tursen demonstrated substantial and durable reductions in TTR, nominally significant results in the monotherapy subgroup and favorable safety did not meet the primary efficacy endpoint in the overall population.

Speaker #3: We and AstraZeneca continue to analyze the data and will present the results at ESC in August. Our strong commercial execution continued pipeline progress and our strong Q2 financial performance underscored the many opportunities we have to continue building substantial value.

Speaker #3: We remain on track to deliver on our 2026 financial guidance and achieve our goal of cash flow break-even in 2028. With that, I'll now turn the call over to Kyle, who will speak to the commercial execution of Trengulza and Donzera and launch preparations for Zilgen Nursing.

Speaker #3: Holly will then discuss how we are advancing our pipeline, highlighting several important catalysts ahead. And Beth will review our financial results and outlook. And with that, I'll turn it over to Kyle.

Speaker #4: Thank you, Brett. Our commercial momentum continues to build, positioning us to deliver even greater impact in the second half of the year and beyond.

Speaker #4: We are executing well against our commercial priorities, including strong progress on the Trengulza and Donzera launches, and preparation for the Zilgen Nursing launch. Beginning with Trengulza, demand continues to build, and FCS, driven by an increasing number of patients initiating and remaining on treatment.

Speaker #4: As expected, Q2 product sales reflected the reduced Trengulza wholesale acquisition cost that went into effect on April 1. We updated the price ahead of the anticipated SHTG approval to align with annual payer contracting cycles to accelerate access to Trengulza.

Speaker #4: Underlying demand in FCS remains strong, with the second quarter delivering the highest number of patient starts since launch began. Together with our commercial execution and FCS and early market access efforts, we've established a strong foundation for the next phase of Trengulza growth as we launch in the broader patient population.

Speaker #4: The recent approval of Trengulza for SHTG marked a defining moment for Ionis. Importantly, it expanded our opportunity to serve millions of people living with severely elevated triglycerides.

Speaker #4: We were particularly pleased with the Trengulza label, which includes prevention of acute pancreatitis and the indication statement. The label is supported by the groundbreaking results from the Phase 3 core and core 2 studies which further underscores the importance of preventing acute pancreatitis in people with SHTG.

Speaker #4: Building on this strong foundation, I'm happy to share that the SHTG launch is off to an encouraging start in the first few weeks. Thanks to the exceptional execution of our commercial team, we began receiving prescriptions on day 1 in both the 50 mg and 80 mg doses were in the channel within approximately 1 week.

Speaker #4: Since the approval, our team has already engaged with many of our top physician targets who care for the majority of high-risk patients. In addition, our omnichannel launch campaign has produced strong engagement, which has further helped to rapidly build awareness of SHTG, APOC3 biology, and Trengulza.

Speaker #4: There are an estimated 3 million people in the US with SHTG, including approximately 1 million people with high-risk SHTG who have triglycerides above 880 mg/dL or triglycerides above 500 and a history of acute pancreatitis or other comorbidities.

Speaker #1: And of our commercial team, we began receiving prescriptions on day 1 in both the 50 mg and 80 mg doses were in the channel within approximately 1 week.

Speaker #1: Since the approval, our team is already engaged with many of our top physician targets who care for the majority of high-risk patients. In addition, our omnichannel launch campaign has produced strong engagement, which is further helping to rapidly build awareness of SHTG, APOC3 biology, and Trengulza.

Speaker #4: The risk of acute pancreatitis begins to increase at triglyceride levels above 500 and rises exponentially in people with triglycerides above 880. As the first-to-market therapy with a novel mechanism proven to reduce the risk of painful costly and potentially fatal acute pancreatitis attacks, Trengulza is well-positioned to serve patients across both segments.

Speaker #1: There are an estimated 3 million people in the U.S. with SHTG, including approximately 1 million people with high-risk triglycerides above 880 mg/dL or triglycerides above 500 and a history of acute pancreatitis or other comorbidities.

Speaker #4: The majority of high-risk SHTG patients are treated by approximately 20,000 cardiologists, endocrinologists, and lipidologists across the US, with additional patients treated by primary care physicians.

Speaker #4: Early in the launch, we were seeing prescriptions from all three specialties in addition to a meaningful contribution from primary care physicians. We've also seen physicians prescribe Trengulza to people with high-risk SHTG and those with TGs between 500 and 800 mg/dL with no history of acute pancreatitis.

Speaker #1: The risk of acute pancreatitis begins to increase at triglyceride levels above 500, and rises exponentially in people with triglycerides above 880. As the first-to-market therapy with a novel mechanism proven to reduce the risk of painful, costly, and potentially fatal acute pancreatitis attacks, Trengulza is well-positioned to serve patients across both segments.

Speaker #4: Physicians are prescribing both the 50 and 80 mg doses, highlighting the importance of dosing flexibility. Which enables treating physicians to tailor treatment to the individual needs of each patient.

Speaker #1: The majority of high-risk SHTG patients are treated by approximately 20,000 cardiologists, endocrinologists, and lipidologists across the U.S., with additional patients treated by primary care physicians.

Speaker #4: Importantly, we are executing on our market access strategy as planned. We have made good progress obtaining coverage for the broad population in patients with triglycerides above 500 mg/dL and across both commercial and government plans.

Speaker #1: Early in the launch, we were seeing prescriptions from all 3 specialties, in addition to a meaningful contribution from primary care physicians. We've also seen physicians prescribe Trengulza to people with high-risk SHTG and those with TGs between 500 and 800 mg/dL with no history of acute pancreatitis.

Speaker #4: Ultimately, we expect the SHTG market to comprise approximately 60% commercial and 40% government-covered patients. We also expect payer coverage to continue expanding through the remainder of this year and into next year as payers complete the reviews.

Speaker #1: Physicians are prescribing both the 50 and 80 mg doses, highlighting the importance of dosing flexibility, which enables treating physicians to tailor treatment to the individual needs of each patient.

Speaker #4: We're also making progress in expanding access to Trengulza outside the US. In the EU, SOBI is continuing to advance the launch in FCS while also actively laying the groundwork for a strong launch in the broader SHTG indication anticipated next year.

Speaker #1: Importantly, we are executing on our market access strategy as planned. We have made good progress obtaining coverage for the broad population in patients with triglycerides above 500 mg/dL and across both commercial and government plants.

Speaker #4: With this early SHTG launch momentum, Trengulza is on track to meet our full-year 2026 revenue guidance and positioned to achieve our projections for more than $3 billion in peak annual revenue.

Speaker #1: Ultimately, we expect the SHTG market to comprise approximately 60% commercial and 40% government-covered patients. We also expect payer coverage to continue expanding through the remainder of this year and into next year as payers complete the reviews.

Speaker #4: The Donzera launch also continued to gain momentum. In less than 1 year on the market, Donzera has already captured a meaningful share of the US HEE prophylaxis market, which is largely a switch market.

Speaker #1: We're also making progress in expanding access to Trengulza outside the U.S., in the EU, with Soviets continuing to advance the launch in FCS, while also actively laying the groundwork for a strong launch in the broader SHTG indication anticipated next year.

Speaker #4: This growth is driven by increasing adoption across all patient segments, including patients switching from existing prophylactic therapies to patients who were previously only using on-demand treatment and treatment-naive patients.

Speaker #1: With this early SHTG launch momentum, Trengulza is on track to meet our full-year 2026 revenue guidance and position to achieve our projections for more than $3 billion in peak annual revenue.

Speaker #4: Physicians and patients consistently provide positive feedback on Donzera, highlighting Donzera's strong efficacy and favorable safety profile, its differentiated RNA-targeting mechanism, the positive switch data which HCPs describe as "differentiating and motivating" and Donzera's patient-friendly profile that includes a self-administered auto-injector that can be stored at room temperature for up to 6 weeks.

Speaker #1: The Donzera launch also continued to gain momentum. In less than one year on the market, Donzera has already captured a meaningful share of the U.S.

Speaker #1: HEE prophylaxis market, which is largely a switch market. This growth is driven by increasing adoption across all patient segments, including patients switching from existing prophylactic therapies to patients who were previously only using on-demand treatment and treatment-naive patients.

Speaker #4: The base of repeat prescribers continues to grow. This is a key indicator that Donzera is providing substantial benefit for patients and HCPs are having a positive experience prescribing it.

Speaker #1: Physicians and patients consistently provide positive feedback on Donzera, highlighting Donzera's strong efficacy and favorable safety profile, its differentiated RNA-targeted mechanism, the positive switch data—which HCPs describe as "differentiating and motivating"—and Donzera's patient-friendly profile that includes a self-administered auto-injector that can be stored at room temperature for up to six weeks.

Speaker #4: Given that most patients on HEE prophylactic medicines are already established on existing therapies, continued penetration will take time. However, the launch fundamentals give us confidence that Donzera will contribute meaningfully to our commercial revenue growth in 2026 and beyond.

Speaker #4: Outside the US, our partner Otsuka is making good progress with Donzera in the launch in the EU. Over time, we expect ex-US countries to become an important contributor to overall Donzera growth.

Speaker #1: The base of repeat prescribers continues to grow. This is a key indicator that Donzera is providing substantial benefit for patients and HCPs are having a positive experience prescribing it.

Speaker #4: During the Zilgenersen, we were well-prepared for the launch for the treatment of Alexander disease coming up later this year. Based on the positive Phase 3 results for Zilgenersen, we received FDA priority review with Bidufidei of September 22nd.

Speaker #1: Given that most patients on HEE prophylactic medicines are already established on existing therapies, continued penetration will take time. However, the launch fundamentals give us confidence that Donzera will contribute meaningfully to our commercial revenue growth in 2026 and beyond.

Speaker #4: We have an expanded access program underway, and our commercial preparations are right on track, centered around four key priorities. First, pending approval, we will work to transition patients who are currently receiving Zilgenersen through the clinical study or the expanded access program to commercial therapy.

Speaker #1: Outside the U.S., our partner Otsuka is making good progress with Donzera in the launch in the EU. Over time, we expect ex-U.S. countries to become an important contributor to overall Donzera growth.

Speaker #4: Second, we will focus on getting patients already diagnosed with Alexander disease in the US on Zilgenersen. It's estimated that about half of the approximately 300 patients in the US are already identified through ICD-10 codes and patient registries.

Speaker #1: Turning to Zilga Nursing: we are well-prepared for the launch for the treatment of Alexander disease coming up later this year. Based on the positive phase 3 results for Zilga Nursing, we received FDA priority review with Fiducia ia Date of September 22.

Speaker #4: Third, we will drive disease awareness among physicians who care for people with rare neurological diseases prioritizing engagement with the dozen US leukodystrophy centers. Following approval, we expect these centers, as key referral and treatment hubs, to play a central role in identifying more patients and providing them with treatment.

Speaker #1: We have an expanded access program underway, and our commercial preparations are right on track, centered around four key priorities. First, pending approval, we will work to transition patients who are currently receiving ZilgaNursing through the clinical study or the expanded access program to commercial therapy.

Speaker #4: And fourth, we are building a dedicated patient services platform, which we have designed based on feedback from stakeholders to address the specific needs of the Alexander disease community.

Speaker #1: Second, we will focus on getting patients already diagnosed with Alexander disease in the U.S. on Zilga Nursing. It's estimated that about half of the approximately 300 patients in the U.S.

Speaker #4: Additionally, our customer-facing team is now in place, and prepared to rapidly reach patients upon our potential Zilgenersen approval. Importantly, we expect to leverage many of the capabilities we are building for Zilgenersen for our future neurology medicine launches.

Speaker #1: are already identified through ICD-10 codes and patient registries. Third, we will drive disease awareness among physicians who care for people with rare neurological diseases, prioritizing engagement with the dozen U.S.

Speaker #1: leukodystrophy centers. Following approval, we expect these centers, as key referral and treatment hubs, to play a central role in identifying more patients and providing them with treatment.

Speaker #4: We also recently took an important step toward bringing Zilgenersen to people with Alexander disease outside the US through our agreement with Recordadi. Recordadi plans to file for regulatory approval for Zilgenersen in the EU and Japan next year with additional global filings to follow.

Speaker #1: And fourth, we are building a dedicated patient services platform, which we have designed based on feedback from stakeholders to address the specific needs of the Alexander disease community.

Speaker #4: With our first broad patient population launch now underway, growing momentum across our commercial portfolio and a strong pipeline behind it, we believe Ionis is well-positioned to bring more important medicines to people with serious diseases.

Speaker #1: Additionally, our customer-facing team is now in place and prepared to rapidly reach patients upon our potential Zilga Nursing approval. Importantly, we expect to leverage many of the capabilities we are building for Zilga Nursing for our future neurology medicine launches.

Speaker #4: And with that, I'll turn the call over to Holly.

Speaker #1: Thank you, Kyle. This quarter, we made meaningful progress across our pipeline. Trengulza's approval for the treatment of SHTG is a significant milestone for Ionis and for patients.

Speaker #1: We also recently took an important step toward bringing zilganirsin to people with Alexander disease outside the U.S. through our agreement with Recordati.

Speaker #1: Trengulza's approval was supported by the unprecedented results from the Phase 3 core and core 2 studies, in which Trengulza achieved rapid, substantial, and clinically meaningful placebo-adjusted main reductions in triglycerides of up to 72%.

Speaker #1: Record Oddy plans to file for regulatory approval for Zilga Nursing in the EU and Japan next year with additional global filings to follow. With our first broad patient population launch now underway, growing momentum across our commercial portfolio and a strong pipeline behind it, we believe IONIS is well-positioned to bring more important medicines to people with serious diseases.

Speaker #1: These triglyceride reductions resulted in a profound reduction in acute pancreatitis events by up to 91%. Trengulza treatment also led to 86% of patients reaching triglyceride levels below 500 mg/dL, the threshold that defines SHTG.

Speaker #1: And with that, I'll turn the call over to Holly.

Speaker #1: Up to 54% of patients reaching normal triglyceride levels below 150 mg/dL, in favorable safety and tolerability, which resulted were further reinforced by longer-term data from the core and core 2 open label extension study, which we recently presented at the National Lipid Association Scientific Sessions.

Speaker #2: Thank you, Kyle. This quarter we made meaningful progress across our pipeline. Trengulza's approval for the treatment of SHTG is a significant milestone for IONIS and for patients.

Speaker #2: Trengulza's approval was supported by the unprecedented results from the phase 3 core and core 2 studies, in which Trengulza achieved rapid, substantial, and clinically meaningful placebo-adjusted main reductions in triglycerides of up to 72%.

Speaker #1: We will share additional data from the OLE at ESC in August. As Kyle mentioned, the Trengulza label includes acute pancreatitis risk reduction in the indication statement.

Speaker #2: These triglyceride reductions resulted in a profound reduction in acute pancreatitis events by up to 91%. Trengulza treatment also led to 86% of patients reaching triglyceride levels below 500 mg/dL, the threshold that defines SHTG.

Speaker #1: With underscores the importance of preventing these debilitating and potentially fatal attacks and further validates our unprecedented results. With its groundbreaking clinical profile, Trengulza is poised to redefine the treatment of this underserved disease.

Speaker #2: Up to 54% of patients reaching normal triglyceride levels below 150 mg/dL, in favorable safety and tolerability, which resulted were further reinforced by longer-term data from the core and core 2 open label extension study, which we recently presented at the National Lipid Association Scientific Sessions.

Speaker #1: Beyond Trengulza, we are advancing a number of promising wholly-owned cardiometabolic disease medicines, including IN775, our next-generation medicine for the treatment of SHTG. We recently advanced IN775 into a Phase 2b study in patients with SHTG or moderately elevated triglycerides based on positive Phase 1 data and healthy volunteers with elevated triglycerides.

Speaker #2: We will share additional data from the OLE at ESC in August. As Kyle mentioned, the Trengulza label includes acute pancreatitis risk reduction in the indication statement.

Speaker #1: These results showed the potential for an optimized profile characterized by substantial durable and sustained reductions in APOC3 and triglycerides with the potential for semiannual or less frequent dosing.

Speaker #2: With underscores the importance of preventing these debilitating and potentially fatal attacks and further validates our unprecedented results. With its groundbreaking clinical profile, Trengulza is poised to redefine the treatment of this underserved disease.

Speaker #1: We look forward to presenting these data on IN775 at ESC next month. And as Brett mentioned, we will also share detailed data from the Apple & Thurston CardioTransform study at ESC.

Speaker #2: Beyond Trengulza, we are advancing a number of promising wholly-owned cardiometabolic disease medicines, including ION-775, our next-generation medicine for the treatment of SHTG. We recently advanced ION-775 into a phase 2b study in patients with SHTG or moderately elevated triglycerides based on positive phase 1 data in healthy volunteers with elevated triglycerides.

Speaker #1: Turning next to our neurology franchise, we remain on track to bring Zilgenersen to patients with Alexander disease later this year, assuming approval. This rare progressive and often fatal leukodystrophy profoundly affects patients and families, and today there are no approved disease-modifying therapies.

Speaker #2: These results showed the potential for an optimized profile, characterized by substantial, durable, and sustained reductions in APOC3 and triglycerides, with the potential for semiannual or less frequent dosing.

Speaker #1: Our positive Phase 3 results marked the first time any therapy demonstrated a disease-modifying impact in these patients. Our next wholly-owned Phase 3 program is Obadenersen for the treatment of Angelman syndrome.

Speaker #2: We look forward to presenting these data on ION-775 at ESC next month. And as Brett mentioned, we will also share detailed data from the Apple & Thurston Cardiotransform study at ESC.

Speaker #1: Angelman syndrome is a neurodevelopmental disorder that causes profound and lifelong physical and cognitive impairments, estimated to affect more than 100,000 people globally. We recently announced that enrollment in the Phase 3 Reveal study is complete, which keeps us on track to report data in the second half of next year.

Speaker #2: Turning next to our neurology franchise, we remain on track to bring Zilga Nursing to patients with Alexander disease later this year, assuming approval. This rare progressive and often fatal leukodystrophy profoundly affects patients and families, and today there are no approved disease-modifying therapies.

Speaker #1: Bringing us an important step closer to potentially delivering this medicine to families in need. We recently advanced our medicine for the treatment of Gervais syndrome, a rare, severe, and lifelong neurological disorder, into a Phase 1-2 first-in-human study.

Speaker #2: Our positive Phase 3 results marked the first time any therapy demonstrated a disease-modifying impact in these patients. Our next wholly owned Phase 3 program is OBI-TA Nursing for the treatment of Angelman syndrome.

Speaker #1: We advanced IN337 based on encouraging preclinical data, which we believe physicians this program to become a best-in-class treatment for this devastating disease. IN337 is our first wholly-owned medicine that uses our proprietary NMA chemistry, designed to achieve maximal and sustained modulation of SDN1A with a long dosing interval.

Speaker #2: Angelman syndrome is a neurodevelopmental disorder that causes profound and lifelong physical and cognitive impairments, estimated to affect more than 100,000 people globally. We recently announced that enrollment in the phase 3 reveal study is complete, which keeps us on track to report data in the second half of next year.

Speaker #1: Our NMA chemistry is the same breakthrough technology that enabled Salonersen to achieve substantial efficacy in favorable safety with annual dosing in a Phase 1 study in patients with spinal muscular atrophy.

Speaker #2: Bringing us an important step closer to potentially delivering this medicine to families in need. We recently advanced our medicine for the treatment of Dravet syndrome, a rare, severe, and lifelong neurological disorder, into a Phase 1/2 first-in-human study.

Speaker #1: Our partner Biogen recently advanced Salonersen into Phase 3 development based on these positive results. Positioning it to meet the remaining unmet needs of people living with spinal muscular atrophy.

Speaker #2: We advanced ION-337 based on encouraging preclinical data, which we believe physicians this program to become a best-in-class treatment for this devastating disease. ION-337 is our first wholly-owned medicine that uses our proprietary NMA chemistry, designed to achieve maximal and sustained modulation of SDN1A with a long dosing interval.

Speaker #1: We were also encouraged by the Phase 2 Celio data Biogen presented at AAIC for Diurnersen in early Alzheimer's disease. These results are the first to demonstrate the significant potential of targeting intracellular tau as a treatment for AD.

Speaker #1: Diurnersen showed significant reductions in CSF tau levels, accompanied by a reversal of tau pathology as measured by tau-PAT. We also saw remarkable effects on cognition, as shown by a 34 to 50% slowed decline in MMSE versus placebo, and a meaningful effect on composite endpoints that include both cognitive and functional domains.

Speaker #2: Our NMA chemistry is the same breakthrough technology that enabled Stella Nursing to achieve substantial efficacy in favorable safety with annual dosing in a phase 1 study in patients with spinal muscular atrophy.

Speaker #2: Our partner Biogen recently advanced Stella Nursing into phase 3 development based on these positive results. Positioning it to meet the remaining unmet needs of people living with spinal muscular atrophy.

Speaker #1: Although the Phase 2 study did not meet the primary endpoint, the totality of these data support Biogen's plan to initiate Phase 3 development. We are also pleased with the recent initiation of the Phase 3 Intrepid study of Sappa Blurson by our partner ONO.

Speaker #2: We were also encouraged by the phase 2 Celia data Biogen presented at AAIC for Dear Nursing in early Alzheimer's disease. These results are the first to demonstrate the significant potential of targeting intracellular tau as a treatment for AD.

Speaker #1: This study is evaluating Sappa Blurson in people with phlebotomy-dependent polysemia vera, a rare but potentially life-threatening hematologic disease with significant unmet needs. Assuming positive data, Sappa Blurson would represent an important value driver from our partnered pipeline.

Speaker #2: Dear Nursing showed significant reductions in CSF tau levels, accompanied by a reversal of tau pathology as measured by tau-PAT. We also saw remarkable effects on cognition, as shown by a 34 to 50 percent slowed decline in MMSE versus placebo, and a meaningful effect on composite endpoints that include both cognitive and functional domains.

Speaker #1: In Bethel-Pearson, our medicine for the treatment of chronic hepatitis B partnered with GSK is on track for approval in the US and Japan later this year, with multiple additional global approvals anticipated next year.

Speaker #2: Although the phase 2 study did not meet the primary endpoint, the totality of these data support Biogen's plan to initiate phase 3 development. We are also pleased with the recent initiation of the phase 3 Intrepid study of Sappho Blurson by our partner ONO.

Speaker #1: Based on positive data from the Phase 3 B well studies, demonstrating unprecedented functional cure rates, Bethel-Pearson is positioned to become a first-in-class treatment for chronic hepatitis B, a disease affecting millions of people around the world.

Speaker #2: This study is evaluating Sappho Blurson in people with phlebotomy-dependent polysemia vera, a rare but potentially life-threatening hematologic disease with significant unmet needs. Assuming positive data, Sappho Blurson would represent an important value driver from our partnered pipeline.

Speaker #1: Also in the second half, we expect late-stage readouts from several partnered programs, including Pellicarsen for LPAA-driven cardiovascular disease with Novartis, Wooliff-Nersen for FUS ALS with Otsuka, and Cefaxirsen for IgA nephropathy with Roche.

Speaker #1: Overall, the progress we have made across the pipeline this year reinforces both the strength of our R&D engine and our confidence in the next wave of opportunities to reach more and more patients in need and drive future growth.

Speaker #2: And bepirovirsen, our medicine for the treatment of chronic hepatitis B partnered with GSK, is on track for approval in the U.S. and Japan later this year, with multiple additional global approvals anticipated next year.

Speaker #1: And with that, I'll turn the call over to Beth.

Speaker #2: Based on positive data from the Phase 3 B-Well studies demonstrating unprecedented functional cure rates, Betel Pearson is positioned to become a first-in-class treatment for chronic hepatitis B, a disease affecting millions of people around the world.

Speaker #2: Thank you, Holly. We delivered strong financial results in the first half of this year, supported by increased revenue from our commercial medicines and meaningful R&D revenue from our partnered programs, while we continued to invest in our long-term growth.

Speaker #2: Also in the second half, we expect late-stage readouts from several partnered programs, including Pella Carson for LPAA-driven cardiovascular disease with Novartis, Lewis Nursing for FUS ALS with Otsuka, and Sefaxrisin for IgA nephropathy with Roche.

Speaker #2: Revenues in the second quarter and first half of this year were $268 million, and $514 million respectively. Representing significant year-over-year growth of 56% and 69% compared to the same period last year.

Speaker #2: Overall, the progress we have made across the pipeline this year reinforces both the strength of our R&D engine and our confidence in the next wave of opportunities to reach more and more patients in need, and drive future growth.

Speaker #2: Excluding the $280 million one-time payment we received from ONO in the first half of last year for Sappa Blurson. Commercial revenue increased to $119 million in the second quarter, and $226 million in the first half.

Speaker #2: And with that, I'll turn the call over to Beth.

Speaker #3: Thank you, Holly. We delivered strong financial results in the first half of this year, supported by increased revenue from our commercial medicines and meaningful R&D revenue from our partnered programs, while we continued to invest in our long-term growth.

Speaker #2: Up 15% and 27% respectively from the same period last year. These increases were driven primarily by Danzera product sales. Tringulza generated product sales of $5 million and $32 million in the second quarter and first half of this year.

Speaker #3: Revenues in the second quarter and first half of this year were $268 million and $514 million, respectively, representing significant year-over-year growth of 56 percent and 69 percent compared to the same periods last year.

Speaker #2: The decrease in revenues in the second quarter followed the April 1st reduction in the Tringulza WACC price, which we implemented strategically ahead of our expansion into the broader SHTG indication.

Speaker #3: Excluding the $280 million one-time payment, we received from ONO in the first half of last year for Sappho Blurson. Commercial revenue increased to $119 million in the second quarter.

Speaker #2: We continue to expect Tringulza to return to revenue growth in the second half of this year as the SHTG launch gains momentum. Danzera generated $26 million in the second quarter and $42 million in the first half, with second-quarter sales increasing by 63% compared to this year's first quarter.

Speaker #3: And $226 million in the first half. Up 15 percent and 27 percent, respectively, from the same period last year. These increases were driven primarily by Donzera product sales.

Speaker #3: Tringulza generated product sales of $5 million and $32 million in the second quarter and first half of this year. The decrease in revenues in the second quarter followed the April 1st reduction in the Tringulza wax price, which we implemented strategically ahead of our expansion into the broader SHTG indication.

Speaker #2: Research and development revenue was $149 million in the second quarter and $288 million year-to-date. Reflecting continued progress across our partnered pipeline. Operating expenses increased as expected in the second quarter and first half of this year, compared to the same period last year.

Speaker #3: We continue to expect Tringulza to return to revenue growth in the second half of this year as the SHTG launch gains momentum. Donzera generated $26 million in the second quarter and $42 million in the first half, with second quarter sales increasing by 63 percent compared to this year's first quarter.

Speaker #2: Driven by costs associated with commercializing Tringulza and Danzera, preparations to launch Zilgen-Nersen later this year, and advancing medicines in our rich pipeline. We ended the second quarter with $2.1 billion in cash, cash equivalents, and short-term investments.

Speaker #2: Enabling us to continue investing in our commercial medicines and wholly-owned pipeline. Looking to the remainder of the year, our strong first-half results keep us on track to achieve our full year 2026 financial guidance.

Speaker #3: Research and development revenue was $149 million in the second quarter and $288 million year-to-date. Reflecting continued progress across our partnered pipeline. Operating expenses increased as expected in the second quarter and first half of this year, compared to the same period last year.

Speaker #2: We continue to project full-year revenue in the range of $875 to $900 million with results weighted slightly more toward commercial revenues. We remain on track to achieve our Tringulza and Danzera product-level guidance.

Speaker #3: Driven by costs associated with commercializing Tringulza and Donzera, preparations to launch Zilgen Nursing later this year, and advancing medicines in our rich pipeline. We ended the second quarter with $2.1 billion in cash, cash equivalents, and short-term investments.

Speaker #2: This includes full-year Tringulza product sales of $100 to $110 million with Tringulza expected to return to revenue growth in the second half of this year as the SHTG launch gains momentum.

Speaker #3: Enabling us to continue investing in our commercial medicines and wholly owned pipeline. Looking to the remainder of the year, our strong first half results keep us on track to achieve our full-year 2026 financial guidance.

Speaker #2: And full-year Danzera product sales of $110 to $120 million with continued growth forecasted in the second half of this year. Additionally, we anticipate meaningful R&D revenue from existing collaborations, including the potential for additional milestones tied to Bepiravirson, Pellicarsen, and other partnered programs as they advance.

Speaker #3: We continue to project full-year revenue in the range of $875 to $900 million with results weighted slightly more toward commercial revenues. We remain on track to achieve our Tringulza and Donzera product-level guidance.

Speaker #2: On the expense side, we continue to expect 2026 operating expenses to increase in the low teens percentage range, compared to last year. Driven primarily by sales and marketing expenses related to our ongoing and upcoming commercial launches.

Speaker #3: This includes full-year Tringulza product sales of $100 to $110 million with Tringulza expected to return to revenue growth in the second half of this year as the SHTG launch gains momentum.

Speaker #3: And full-year Donzera product sales of $110 to $120 million with continued growth forecasted in the second half of this year. Additionally, we anticipate meaningful R&D revenue from existing collaborations, including the potential for additional milestones tied to Bepiraversen, Pelacarsen, and other partnered programs as they advance.

Speaker #2: We project R&D expenses to remain consistent with last year, at several of our late-stage studies conclude and we redeploy resources to earlier-stage programs, within our wholly-owned pipeline.

Speaker #2: And as a result of our focus on improving our operating leverage, we expect a non-GAAP operating loss between $425 and $475 million. This is similar to our 2025 operating loss after adjusting for the one-time Sappa Blurson license fee.

Speaker #3: On the expense side, we continue to expect 2026 operating expenses to increase in the low teens percentage range compared to last year, driven primarily by sales and marketing expenses related to our ongoing and upcoming commercial launches.

Speaker #2: We are at last year. And finally, we are projecting a 2026 year-end cash balance of greater than $1.6 billion. With our strong first-half financial performance and our outlook for the remainder of this year, we remain on track to achieve our full year 2026 financial guidance and cash flow break-even in 2028 while continuing to drive substantial growth and longer-term value creation.

Speaker #3: We project R&D expenses to remain consistent with last year, as several of our late-stage studies conclude and we redeploy resources to earlier-stage programs within our wholly owned pipeline.

Speaker #3: And as a result of our focus on improving our operating leverage, we expect a non-GAAP operating loss between $425 and $475 million. This is similar to our 2025 operating loss after adjusting for the one-time Sappho Blurson license fee.

Speaker #2: With that, I'll turn the call back over to Beth.

Speaker #3: Thank you, Beth. Our outlook for the remainder of 2026 and beyond reflects Ionis's strength in the substantial opportunity for continued success that lies ahead.

Speaker #3: We aren't last year. And finally, we are projecting a 2026 year-end cash balance of greater than $1.6 billion. With our strong first half financial performance and our outlook for the remainder of this year, we remain on track to achieve our full-year 2026 financial guidance and cash flow break-even in 2028 while continuing to drive substantial growth and longer-term value creation, with that, I'll turn the call back over to Bret.

Speaker #3: We are executing well on our independent launches for Tringulza and Danzera, and are well prepared for our next launch, Zilgen-Nersen in Alexander disease, anticipated later this year.

Speaker #3: In addition to driving value through commercial success, we also have many important near and mid-term catalysts from across our development pipeline, each with the potential to further drive substantial value.

Speaker #3: We are well positioned to continue executing successfully on our commercial launches and to deliver a steady cadence of breakthrough medicines to patients. Now, before we move to Q&A, I'd like to take a moment to recognize Frank Bennett, our Chief Scientific Officer whose plans retirement we announced earlier this morning.

Speaker #1: Thank you, Beth. Our outlook for the remainder of 2026 and beyond reflects Ionis's strength and the substantial opportunity for continued success that lies ahead.

Speaker #1: We are executing well on our independent launches for Tringulza and Donzera, and are well prepared for our next launch, Zilgen Nursing in Alexander disease, anticipated later this year.

Speaker #3: Frank is one of Ionis's founding scientists and has helped shape Ionis and advance the field of RNA-targeted medicines. While his leadership helped create this new sector for human therapeutics, some of his greatest contributions were in the field of neurology, which led to the approvals of Spinraza, her SMA, and Calzati for site 1 ALS.

Speaker #1: In addition to driving value through commercial success, we also have many important near- and mid-term catalysts from across our development pipeline, each with the potential to further drive substantial value.

Speaker #1: We are well positioned to continue executing successfully on our commercial launches and to deliver a steady cadence of breakthrough medicines to patients. Now, before we move to Q&A, I'd like to take a moment to recognize Frank Bennett, our Chief Scientific Officer, whose planned retirement we announced earlier this morning.

Speaker #3: Along with the establishment of a rich pipeline poised to deliver a steady stream of breakthrough treatments for neurological diseases. On behalf of the entire Ionis team, I want to thank Frank for his many contributions, his dedication to patients, and the lasting impact he has had on Ionis and the field of oligonucleotid therapeutics.

Speaker #1: Frank is one of Ionis’s founding scientists and has helped shape Ionis and advance the field of RNA-targeted medicines. While his leadership helped create this new sector for human therapeutics, some of his greatest contributions were in the field of neurology, which led to the approvals of Spinraza for SMA and Qalsody for SOD1 ALS.

Speaker #3: And with that, we'll open the call up for questions.

Speaker #1: We will now begin the question and answer session. To ask a question, you may press star, then 1 on your telephone keypad. If you are using a speakerphone, please pick up your handset before pressing the keys.

Speaker #1: Along with the establishment of a rich pipeline poised to deliver a steady stream of breakthrough treatments for neurological diseases. On behalf of the entire IONIS team, I want to thank Frank for his many contributions, his dedication to patients and the lasting impact he has had on IONIS and the field of oligonucleotide therapeutics.

Speaker #1: To withdraw your question, please press star, then 2. And our first question will come from Jason Gerberry of Bank of America. Please ahead.

Speaker #4: Hey, guys. Thanks for taking my question. I just wanted to key in a little bit on an early adoption of Tringulza. How much of that's being driven by physicians with overlapping FCS patients that they were treating?

Speaker #1: And with that, we'll open the call up for questions.

Speaker #4: Is that sort of the core early prescriber in this initial kind of 6 to 9 months? And where physicians are attempting to write prescriptions?

Speaker #2: We will now begin the question and answer session. To ask a question, you may press star, then 1, on your telephone keypad. If you are using a speakerphone, please pick up your handset before pressing the keys.

Speaker #4: Can you talk a little bit about the average processing time for them to go from an enrollment form to getting a script covered? Is that through medical exceptions, I assume?

Speaker #2: To withdraw your question, please press star, then 2. And our first question will come from Jason Gerberry of Bank of America. Please go ahead.

Speaker #4: So those are my questions. Thanks.

Speaker #3: Thanks, Jason. This is Kyle. Happy to cover off on those. First, I'll say that the FCS launch really was important to the launch now in SHTG.

Speaker #4: Hey, guys. Thanks for taking my question. I just wanted to key in a little bit on an early adoption of Tringulza. How much of that's being driven by physicians with overlapping FCS patients that they were treating?

Speaker #3: Obviously, that laid the groundwork and the foundation for the readiness to bring the drug forward to a prevalent population. Many of the early prescribers are previous treaters of FCS.

Speaker #4: Is that sort of the core early prescriber in this initial kind of six to nine months? And where physicians are attempting to write prescriptions?

Speaker #3: They have experience using the drug, and they've had really, really positive results from doing so. But we're also seeing more physicians than just the FCS prescribers starting to use Tringulza for SHTG.

Speaker #4: Can you talk a little bit about the average processing time for them to go from an enrollment form to getting a script covered? Is that through medical exceptions I assume?

Speaker #4: So those are my questions. Thanks.

Speaker #1: Thanks, Jason. This is Kyle. Happy to cover off on those. First, I'll say that the FCS launch really was important to the launch now in SHTG.

Speaker #3: The other thing that I'll just mention here is the FCS growth in Q2 and the demand continue to accelerate significantly. Having more treaters and more patients on drug obviously will help us accelerate the SHTG launch as well.

Speaker #1: Obviously, that laid the groundwork and the foundation for the readiness to bring the drug forward to a prevalent population. Many of the early prescribers are previous treaters of FCS.

Speaker #3: So the short answer to your question is yes, there are treaters of FCS that are also prescribing, but it goes well beyond that. In terms of process time, it's really too early to discuss those details.

Speaker #1: They have experience using the drug, and they've had really, really positive results from doing so. But we're also seeing more physicians than just the FCS prescribers starting to use Tringulza for SHTG.

Speaker #3: We're just a couple of weeks into the launch. What we've seen from payers so far is very encouraging. Not only in terms of the RX to approval time so far, but also just in terms of our conversations that we're having with the payers, where they are beginning to assess SHTG and assess to put coverage criteria in place so that there's a clear pathway for approval.

Speaker #1: The other thing that I'll just mention here is the FCS growth in Q2, and the demand continues to accelerate significantly. Having more treaters and more patients on drug, obviously, will help us accelerate the SHTG launch as well.

Speaker #1: So the short answer to your question is yes, there are treaters of FCS that are also prescribing, but it goes well beyond that. In terms of process time, it's really too early to discuss those details.

Speaker #3: Here early in the launch, the majority of the coverage criteria is going to be through medical exception. That was to be anticipated. And we expect to see continued coverage improve through the back half of this year and as we start 2027, it it should look much better.

Speaker #1: We're just a couple of weeks into the launch. What we've seen from payers so far is very encouraging. Not only in terms of the Rx to approval time so far, but also just in terms of our conversations that we're having with the payers, where they are beginning to assess SHTG and assess to put coverage criteria in place so that there's a clear pathway for approval.

Speaker #4: Thank you.

Speaker #1: The next question comes from Ellie Merrill of Barclays. Please go ahead.

Speaker #5: Hey, guys. Thanks for taking my question and congrats on all the progress. Can you just elaborate a little bit more in terms of what you're seeing in terms of reimbursement?

Speaker #5: I know you mentioned that you're seeing reimbursement for Tringulza, sorry, in patients with triglycerides over 500. But are you seeing any differences in how payers are treating the coverage of patients with triglycerides over 880 versus those over 500?

Speaker #1: Here early in the launch, the majority of the coverage criteria is going to be through medical exception. That was to be anticipated. And we expect to see continued coverage improved through the back half of this year and as we start 2027, should look much better.

Speaker #5: And then just a second question. What are your expectations for Wayne US sales in polyneuropathy now after the cardio transform data? Given much of the polyneuropathy patients are mixed phenotype.

Speaker #4: Thank you.

Speaker #2: The next question comes from Ellie Merrill of Barclays. Please go ahead.

Speaker #5: Thanks.

Speaker #5: Hey, guys. Thanks for taking my question and congrats on all the progress. Can you just elaborate a little bit more in terms of what you're seeing in terms of reimbursement?

Speaker #3: Yeah. Thanks, Ellie. Let me I'll start with the Tringulza question. We are seeing coverage to label. The label is very strong here, right? Greater than 500.

Speaker #5: I know you mentioned that you're seeing reimbursement for Tringulza, sorry, in patients with triglycerides over 500. But are you seeing any differences in how payers are treating the coverage of patients with triglycerides over 880 versus those over 500?

Speaker #3: It does not limit patients over 880. It does not limit a history of acute pancreatitis. So the conversations that we've had with payers and what we've seen from the early approvals through the medical exception process has all reflected the actual indication statement in the label, which is what we expected based on our payer research going into the launch.

Speaker #5: And then, just a second question: What are your expectations for Waylivra U.S. sales in polyneuropathy now after the cardiotransform data, given that much of the polyneuropathy patient population is mixed phenotype?

Speaker #3: of work for the HCPs, as expected, at launch to do these prior authorizations. To provide a letter of medical necessity, potentially, to justify the background therapies that the patient has been on and what their triglyceride levels are.

Speaker #5: Thanks.

Speaker #1: Yeah. Thanks, Ellie. Let me—I'll start with the Tringulza question. We are seeing coverage to label. The label is very strong here, right? Greater than 500.

Speaker #3: But that's all very consistent with what we expected the policies to represent. So I think things are on track, and we're very encouraged by the early interactions and discussions that we've had with payers.

Speaker #1: Does that limit patients over 880? It does not limit a history of acute pancreatitis. So, the conversations that we've had with payers and what we've seen from the early approvals through the medical exception process have all reflected the actual indication statement in the label, which is what we expected based on our payer research going into the launch.

Speaker #3: On the Wayne US side, demand continues to be strong for the hereditary polyneuropathy patient. The challenge that we are seeing on the Wayne US side is with the mixed phenotype patient, where Invutra has an indication for both polyneuropathy and cardiomyopathy.

Speaker #1: So it will take a little bit of work for the HCPs, as expected, at launch to do these prior authorizations. To provide a letter of medical necessity, potentially, to justify the background therapy that the patient has been on and what their triglyceride levels are.

Speaker #3: But otherwise, physicians are having very positive experience prescribing and treating these patients. And feedback has been very strong in terms of control of TTR and knockdown, control of polyneuropathy symptoms, payer access and coverage, and the ability to self-administer with an auto-injector.

Speaker #1: But that's all very consistent with what we expected the policies to represent. So I think things are on track, and we're very encouraged by the early interactions and discussions that we've had with payers.

Speaker #3: So we expect sales to continue in polyneuropathy and the teams continue to do a nice job.

Speaker #1: On the Wayne US side, demand continues to be strong for the hereditary polyneuropathy patient. The challenge that we are seeing on the Wayne US side is with the mixed phenotype patient, where Invutra has an indication for both polyneuropathy and cardiomyopathy.

Speaker #1: The next question comes from Gary Nockman of Canaccord Genuity. Please go ahead.

Speaker #6: Hi. Thanks, and good morning. So for SHTG, are you finding that most of these patients are already on some TG-lowering or lipid-lowering drugs? Are they switching to Tringulza or adding Tringulza on top of their other treatments?

Speaker #1: But otherwise, physicians are having very positive experience prescribing and treating these patients. And feedback has been very strong in terms of control of TTR and knockdown, control of polyneuropathy symptoms, payer access and coverage, and the ability to self-administer with an auto-injector.

Speaker #6: And are there any real true naive patients that are being put on drug at this point? And then just what are you hearing from physicians on Tringulza's profile as a monthly sub-queue?

Speaker #1: So we expect sales to continue in polyneuropathy and the teams continue to do a nice job.

Speaker #6: And has there been any real concerns with the elevated liver fat holding back prescribing at all? And how are you communicating that? Thanks.

Speaker #2: The next question comes from Gary Nockman of Canaccord Genuity. Please go ahead.

Speaker #6: Hi. Thanks. And good morning. So for SHTG, are you finding that most of these patients are already on some TG-lowering or lipid-lowering drugs? Are they switching to Tringulza or adding Tringulza on top of their other treatments?

Speaker #3: Yeah. Thanks, Gary. So the short answer to the first question is we're seeing a mix of patients. The majority of these patients obviously are high-risk SHTG patients.

Speaker #3: They're above 500. The majority of these patients have been on some sort of background therapy, which is very consistent with our core and core two trials.

Speaker #6: And are there any real true naive patients that are being put on drug at this point? And then just what are you hearing from physicians on Tringulza's profile as a monthly sub-Q?

Speaker #3: I mean, almost 100% of the patients were on some sort of fibrate or omega-3 or statin in the clinical trial. And that's consistent with how HCPs are using standard of care today and doing everything they can to try to get triglycerides lowered.

Speaker #6: And has there been any real concerns with the elevated liver fat holding back prescribing at all? And how are you communicating that? Thanks.

Speaker #3: Below 500 and get these patients out of the risk of acute pancreatitis, but have just been unable to do so. So the majority of these patients are on background standard of care therapy, and they are adding Tringulza to those patients in order to get the benefit of up to a 72% risk excuse me, reduction in triglycerides.

Speaker #1: Yeah. Thanks, Gary. So the short answer to the first question is we're seeing a mix of patients. The majority of these patients obviously are high-risk SHTG patients.

Speaker #1: They're above 500. The majority of these patients have been on some sort of background therapy, which is very consistent with our core and core two trials.

Speaker #3: And up to a 91% reduction in acute pancreatitis. So they're using it very consistent with the way that the clinical trial was designed and the way that HCPs have been treating these patients up to this time.

Speaker #1: I mean, almost 100% of the patients were on some sort of fibrate or omega-3 or statin in the clinical trial. And that's consistent with how HCPs are using standard of care today and doing everything they can to try to get triglycerides lowered.

Speaker #3: The profile is coming across very strong. First, I'll just mention the indication statement, having AP represented there. It really reflects the outcome of treating high triglycerides and what that means for patients and what that means for HCPs that are trying to treat these patients.

Speaker #1: Below 500 and get these patients out of the risk of acute pancreatitis, but have just been unable to do so. So the majority of these patients are on background standard of care therapy, and they are adding Tringulza to those patients in order to get the benefit of up to 72% risk excuse me, reduction in triglycerides.

Speaker #3: I didn't get them out of harm's way of acute pancreatitis. The monthly auto-injector is very well received. It's low dose. It's very easy to use.

Speaker #1: And up to a 91% reduction in acute pancreatitis. So they're using it very consistent with the way that the clinical trial was designed and the way that HCPs have been treating these patients up to this time.

Speaker #3: The patients can take it once a month. They don't have to try to figure out, is it month one or month two or month three?

Speaker #3: And we're finding that consistent with the FCS launch, adherence, and persistency in patients are starting and staying on and doing very well on the monthly administration with the auto-injector.

Speaker #1: The profile is coming across very strong. First, I'll just mention the indication statement, having AP represented there. It really reflects the outcome of treating high triglycerides and what that means for patients and what that means for HCPs that are trying to treat these patients and get them out of harm's way of acute pancreatitis.

Speaker #3: And for hepatic fat I'll turn it over to Brett.

Speaker #6: Yeah. Thanks, Hal. And Gary, thanks for the question. So we are we believe that the evidence that the effects on the liver fat small increases in liver fat we see is an on-target effect.

Speaker #1: The monthly auto-injector is very well received. It's low dose. It's very easy to use. The patients can take it once a month. They don't have to try to figure out, is it month one or month two or month three?

Speaker #6: It's very convincing. And prior to us presenting the data at National Lipid Association earlier this year, we didn't even have pushback at that time from HCPs on concerns over the small increases in liver fat, especially because there was no association with any clinical sequelae.

Speaker #1: And we're finding that, consistent with the FCS launch, adherence and persistency in patients are strong. Patients are starting, staying on, and doing very well with the monthly administration using the auto-injector.

Speaker #6: There were no clinical complications associated with the small increases in liver fat that we saw. That was further reinforced when we presented the NLA data, the data NLA, which we showed that with continued treatment, that the increase in liver fat was returning to baseline.

Speaker #1: And for hepatic fat I'll turn it over to Brett.

Speaker #4: Yeah. Thanks, Kyle. And Gary, thanks for your question. So we are we believe that the evidence that the effects on the liver fat small increases in liver fat we see is an on-target effect.

Speaker #6: Again, with long-term treatment, no association with clinical sequelae. So that was just reinforced there. And as we continued to evaluate patients in the long-term, even further long-term, open label extension, again, we're not seeing any emerging adverse events in the study.

Speaker #4: It's very convincing. And prior to us presenting the data at National Lipid Association earlier this year, we didn't even have pushback at that time from HCPs on concerns over the small increases in liver fat, especially because there was no association with any clinical sequelae.

Speaker #6: So no concerns on the HCP community. And that's been further reinforced with long-term data. Great. Thank you.

Speaker #4: There were no clinical complications associated with the small increases in liver fat that we saw. That was further reinforced when we presented the NLA data, the data NLA, which we showed that with continued treatment, that the increase in liver fat was returning to baseline.

Speaker #1: The next question comes from Moritz Reiter of Guggenheim Securities. Please go ahead.

Speaker #4: Again, with long-term treatment, no association with clinical sequelae. So that was just reinforced there. And as we continued to evaluate patients in the long-term, even further long-term, open label extension, again, we're not seeing any emerging adverse events in the study.

Speaker #7: Hi. This is Moritz on for Debjit. Thanks so much for taking our question. I have two questions. The first one on Tringulza. How, if at all, has the recent pezozuran data changed your outlook for Tringulza?

Speaker #7: And the second one on Horizon. What's your confidence in the trial and should Horizon disappoint? How are you thinking about your path to profit profitability?

Speaker #4: So no concerns on the HCP community, and that's been further reinforced with long-term data.

Speaker #7: Thank you so much.

Speaker #6: Yeah. So Moritz, thank you for the question. We believe we have based on everything we've seen so far, we continue to believe that we have a best-in-class medicine when you look at the totality of the data for the treatment of SHTG.

Speaker #6: Great. Thank you.

Speaker #2: The next question comes from Moritz Reiter of Guggenheim Securities. Please go ahead.

Speaker #7: Hi, this is Moritz. I'm here for Deborah. Thanks so much for taking our question. I have two questions. The first one on Tringulza: How, if at all, has the recent Prazosan data changed your outlook for Tringulza?

Speaker #6: And when you look at the triglyceride lowering, that Holly summarized in her prepared remarks and the overall reduction in acute pancreatitis along with safety and tolerability, and first mover advantage, also we have no concerns about competition.

Speaker #7: And the second one on Horizon. What's your confidence in the trial? And should Horizon disappoint? How are you thinking about your path to profit profitability?

Speaker #6: We continue to reiterate our peak product sales in the US of being $3 billion plus. So there was no surprises in any data that has emerged since we've launched.

Speaker #7: Thank you so much.

Speaker #4: Yeah. So Moritz, thank you for the question. We believe we have based on everything we've seen so far, we continue to believe that we have a best-in-class medicine when you look at the totality of the data for the treatment of SHTG.

Speaker #6: With respect to Horizon, our confidence remains continues to be the same, high. We believe that LPLLA is a cardiovascular risk factor, independent risk factor.

Speaker #4: And when you look at the triglyceride lowering, that highly summarized in her prepared remarks and the overall reduction in acute pancreatitis along with safety and tolerability, and first mover advantage, also we have no concerns about competition.

Speaker #6: The evidence is overwhelming. We have the right drug. The baseline demographics lays it all manuscript lays it all out on the powering assumptions, in that study.

Speaker #6: And the drug's been well tolerated. And we're looking forward to the results in the later this year. And then I'm sorry. The third part of the question was oh.

Speaker #4: We continue to reiterate our peak product sales in the US have been $3 billion-plus, so there were no surprises in any data that has emerged since we've launched.

Speaker #7: Just the should. Should the trial disappoint? What's the profitability?

Speaker #4: With respect to Horizon, our confidence remains high and continues to be the same. We believe that Lp(a) is a cardiovascular risk factor, an independent risk factor. The evidence is overwhelming.

Speaker #5: Yeah. Good morning. So I would say in the event that Helicarsen, phase three, were not to be positive, it would not have an impact on our 2026 financial guidance.

Speaker #4: We have the right drug. The baseline demographics—the manuscript lays it all out on the powering assumptions for that study. And the drug has been well tolerated.

Speaker #5: It would put some pressure on our ability to achieve our goal of cash flow breakeven in 2028. But I want to emphasize that's a very important goal for us at Ionis.

Speaker #4: And we're looking forward to the results in the later this year. And then I'm sorry. The third part of the question was oh.

Speaker #5: And we will work very, very hard to achieve that goal.

Speaker #6: Thank you, Moritz.

Speaker #7: Just to clarify, should the trial disappoint, what's the profitability?

Speaker #1: The next question comes from Mike Oles of Morgan Stanley. Please go ahead.

Speaker #5: Yeah. Good morning. So I would say in the event that Helicarsen, phase three, were not to be positive, it would not have an impact on our 2026 financial guidance.

Speaker #8: Good morning. Thanks for taking the question. Maybe a few just on Ion775, just curious if you can give us a sense of what data we might expect at the upcoming ESC meeting, maybe in terms of endpoints, level of follow-up, etc.

Speaker #5: It would put some pressure on our ability to achieve our goal of cash flow break-even in 2028. But I want to emphasize that's a very important goal for us at IONIS.

Speaker #8: there. And then maybe just secondly, as we think about timelines for this program, maybe you can share how you're thinking about that in terms of path to market, number of clinical studies, and is there ways to sort of shorten that, just given your experience with the core programs?

Speaker #5: And we will work very, very hard to achieve that goal.

Speaker #4: Thank you, Moritz.

Speaker #2: The next question comes from Mike Oles of Morgan Stanley. Please go ahead.

Speaker #8: Thanks.

Speaker #5: This is Holly. Thank you. The Ion775 data that we'll be sharing at ESC, it's year-long data. It's safety as well as our efficacy and activity data and our key biomarkers.

Speaker #6: Good morning. Thanks for taking the question. Maybe a few just on ION775, just curious if you can give us a sense of what data we might expect at the upcoming ESC meeting, maybe in terms of endpoints, level of follow-up, etc.

Speaker #5: So it should be a very interesting data set for everybody to view. In terms of where we're at, so we are in the phase two B study right now.

Speaker #6: there. And then maybe just secondly, as we think about timelines for this program, maybe you can share how you're thinking about that in terms of path to market, number of clinical studies, and is there ways to sort of shorten that, just given your experience with the core programs?

Speaker #5: Of course, we are using all of our previous learnings to accelerate the program as much as we can. We haven't discussed timing externally, but we are absolutely using everything that we've learned from our previous programs and data sets to apply to this program.

Speaker #6: Yeah. And just to add to that, Mike, so you'll see long-term data on triglycerides, in the mildly elevated triglyceride population, and the durability that 775 is offering as Holly mentioned in her prepared remarks.

Speaker #6: Thanks.

Speaker #5: This is Holly. Thank you. The ION775 data that we will be sharing at ESC is year-long data. It's safety as well as our efficacy and activity data, and our key biomarkers.

Speaker #6: This is at least a twice-a-year or even less frequent dosing opportunity. So it's a pure play on convenience. We don't believe that we can do much better than the efficacy that Tringulza is already presenting.

Speaker #5: So it should be a very interesting data set for everybody to view. In terms of where we're at, so we are in the phase two B study right now.

Speaker #5: Of course, we are using all of our previous learnings to accelerate the program as much as we can. We haven't discussed timing externally, but we are absolutely using everything that we've learned from our previous programs and data sets to apply to this program.

Speaker #6: I mean, it's a best-in-class efficacy profile. It's really allowing us to get to maybe twice a year, once a year dosing. And that's what we're going to focus on.

Speaker #4: Yeah. And just to add to that, Mike, you'll see the long-term data on triglycerides in the mildly elevated triglyceride population. And the durability that 775 is offering, as Holly mentioned in our prepared remarks, this is at least a twice-a-year or even less frequent dosing opportunity.

Speaker #6: And the data will show APOC3 reductions that support that conclusion, triglyceride reductions that support that conclusion as well as the good tolerability. And also just to add, the enrollment's going well for although it's early innings for the phase two B study, it's going well.

Speaker #6: And our focus is to get that study done so I could dose and move to phase three as quickly as possible, but it's still too early to put timelines on when we can get that done.

Speaker #4: So it's a pure play on convenience. We don't believe that we can do much better than the efficacy that Tringulza is already presenting. I mean, it's a best-in-class efficacy profile.

Speaker #8: Great. Thank you.

Speaker #4: It's really allowing us to get to maybe twice a year, once a year dosing. And that's what we're going to focus on. And the data will show APOC3 reductions that support that conclusion, triglyceride reductions that support that conclusion as well as the good tolerability.

Speaker #1: The next question comes from Yana Zhao of Wells Fargo Securities. Please go ahead.

Speaker #4: Great. Thanks for taking our questions. For SHTG, I was wondering based on the first few weeks of launch, how did that early momentum track with your internal expectation?

Speaker #4: And also, just to add, the enrollment is going well for although it's early innings for the phase two B study, it's going well. And our focus is to get that study done to select a dose and move to phase three as quickly as possible, but it's still too early to put timelines on when we can get that done.

Speaker #4: Especially in relationship to the full-year guidance. Apparently, you made that guidance without any firsthand experience of the launch. So just curious, are you do you think you're ahead of that internal expectation at this point of time or in line?

Speaker #6: Great. Thank you.

Speaker #2: The next question comes from Yana Zhao of Wells Fargo Securities. Please go ahead.

Speaker #4: And for cardiotransform, I was wondering is there a regulatory path for monotherapy? And could any of the data to be presented at ESC inform how you and AstraZeneca think about any potential regulatory path?

Speaker #8: Great, thanks for taking our questions. For SHTG, I was wondering—based on the first few weeks of launch, how did that early momentum track with your internal expectations?

Speaker #8: Especially in relationship to the full-year guidance. Apparently, you made that guidance without any firsthand experience of the launch. So just curious, are you do you think you're ahead of that internal expectation at this point of time or in line?

Speaker #4: Thank you.

Speaker #6: Thanks, Yana. And I'll take the first the second question first, and then I'll hand it over to Kyle. To talk about how the SHTG is tracking with respect to guidance and so on.

Speaker #6: So we and AstraZeneca continue to review the data from the cardiotransform studies a lot of data. We're preparing to present at ESC. We're preparing to publish.

Speaker #8: And for cardiotransform, I was wondering is there a regulatory path for monotherapy? And could any of the data to be presented at ESC inform how you and AstraZeneca think about the any potential regulatory path?

Speaker #6: We have several presentations at ESC. Including the cardiotransform study, the combination subgroup, as well as the meta-analysis study that is being conducted by an independent group of academic physicians.

Speaker #8: Thank you.

Speaker #4: Thank you, Yana. I'll take the second question first, and then I'll hand it over to Kyle to talk about how SHTG is tracking with respect to guidance, and so on.

Speaker #6: As far as regulatory path, AstraZeneca is weighing all their options, Yana. They're still going through the data. There's a lot to process there. So there's nothing new to report with that.

Speaker #4: So we and AstraZeneca continue to review the data from the cardiotransform studies a lot of data. We're preparing to present at ESC. We're preparing to publish.

Speaker #6: And the data at ESC, I think, will support all the conclusions we've made already, which is very clear that in the monogroup that was on monotherapy at baseline, so no tafamidis at baseline, the efficacy in the composite primary endpoint as well as the secondary endpoints are in line with the silencer class.

Speaker #4: We have several presentations at ESC. Including the cardiotransform study, the combination subgroup, as well as a meta-analysis study that is being conducted by an independent group of academic physicians.

Speaker #4: As far as regulatory path, AstraZeneca is weighing all their options, Yana. And they're still going through the data. There's a lot to process there.

Speaker #6: There was no benefit in the combination group. And you'll see that data in quite detail at the ESC meeting. Kyle? Yeah. Thanks, Yana. And I'll say internally, we are absolutely meeting the expectations of the launch here, keeping in mind that we're only four or five weeks into this.

Speaker #4: So there's nothing new to report with that. And the data at ESC, I think, will support all the conclusions we've made already, which is very clear that in the mono group.

Speaker #6: So it's very early. The key priorities right out of the gate, obviously, is to get drug into channel. We did that within one week, both the 50 and 80 milligram doses were in channel, a very, very quickly.

Speaker #4: Was on monotherapy at baseline, so no tofersen at baseline. The efficacy in the composite primary endpoint as well as the secondary endpoints are in line with the silencer class.

Speaker #6: Allowing the prescriptions that were coming in early, if approved by the payer, to be able to go out directly to patients and get patients on drug very quickly.

Speaker #4: There was no benefit in the combination group, and you'll see that data in quite detail at the ESC meeting. Kyle?

Speaker #6: So a lot of this is operational at the very beginning. And based on the launches of Tringulza and FCS and Donzera and HAE, we had a really good experience recently of launching drugs and making sure that we did this expeditiously and effectively.

Speaker #3: Yeah. Thanks, Yana. And I'll say internally, we are absolutely meeting the expectations of the launch here. Keeping in mind that we're only four or five weeks into this.

Speaker #6: And it's exactly what we've done with SHTG. So I'm very pleased with the team's execution there. The other components, things around training, for example, training of the field teams, approval of materials, deployment of content, those types of things went extremely well.

Speaker #3: So, it's very early. The key priorities right out of the gate, obviously, are to get drug into channel. We did that within one week. Both the 50 and 80 milligram doses were in channel.

Speaker #3: A very, very quickly. Allowing the prescriptions that were coming in early, if approved by the payer, to be able to go out directly to patients and get patients on drug very quickly.

Speaker #6: Our omnichannel capabilities, our operating exactly as planned. So we've been able to give notice about the approval to tens of thousands of HCPs that see patients with high triglycerides.

Speaker #3: So a lot of this is operational at the very beginning. And based on the launches of Tringulza and FCS and Donzera and HAE, we had a really good experience recently of launching drugs and making sure that we did this expeditiously and effectively.

Speaker #6: So building awareness and making sure that there's an understanding that there's a product now available to treat those patients. Payer engagement and patient services are the other two areas that I would highlight, which have both gone very well.

Speaker #3: And it's exactly what we've done with SHTG. So I'm very pleased with the team's execution there. The other components, things around training, for example, training of the field teams, approval of materials, deployment of content, those types of things went extremely well.

Speaker #6: So operationally, I'm very pleased with the team and we're off to a very good start with the launch. In terms of full-year guidance, 100 to 110 million, we are still confident in that based on the FCS performance that we saw earlier in the year.

Speaker #3: Our omnichannel capabilities are operating exactly as planned. So we've been able to give notice about the approval to tens of thousands of HCPs that see patients with high triglycerides.

Speaker #6: And based on the early signs and signals that we're seeing, combined with the very strong label that we achieved for Tringulza and SHTG.

Speaker #3: So building awareness and making sure that there's an understanding that there's a product now available to treat those patients. Payer engagement and patient services are the other two areas that I would highlight, which have both gone very well.

Speaker #4: Great to hear. Thanks for all the cover.

Speaker #1: The next question comes from Yarin Warver of TD Cowan. Please go ahead.

Speaker #6: Great. Thanks so much. And congrats on the progress. Maybe Kyle, two questions for you commercially on SHTG. One of the questions we've been getting is do you think there's going to be sort of an initial pent-up demand or bolus or some clinics already kind of triaging patients to get treated with Tringulza now that it's approved?

Speaker #3: So operationally, I'm very pleased with the team and we're off to a very good start with the launch. In terms of full-year guidance, the 100 to 110 million, we are still confident in that based on the FCS performance that we saw earlier in the year.

Speaker #3: And based on the early signs and signals that we're seeing, combined with the very strong label that we achieved for Tringulza and SHTG.

Speaker #6: And then secondly, for Donzera, I mean, you're seeing very nice kind of quarter-over-quarter growth. You mentioned obviously it's a switch market. What sort of is the main competitor at this point?

Speaker #8: Great to hear. Thanks for all the cover.

Speaker #2: The next question comes from Yarin Warver of TD Cowan. Please go ahead.

Speaker #6: And how are you what are you seeing in terms of demand? Thank you. Yeah. Thanks for the questions. In terms of pent-up demand, we believe this is going to be a gradual build and a moderate build over time.

Speaker #4: Great. Thanks so much. And congrats on the progress. Maybe Kyle, two questions for you commercially on SHTG. One of the questions we've been getting is do you think there's going to be sort of an initial pent-up demand or bolus or some clinics already kind of triaging patients to get treated with Tringulza now that it's approved?

Speaker #6: For a couple of reasons. Number one, this is a new mechanism and a new treatment. And it takes some time to educate the HCPs.

Speaker #6: Number two, we've got to get those patients into the clinic to see these HCPs. So we've got to drive that awareness and interest through the patient.

Speaker #4: And then secondly, for Donzera, I mean, you're seeing very nice kind of quarter-over-quarter growth. You mentioned obviously it's a switch market. What sort of is the main competitor at this point?

Speaker #6: So that they're motivated to get into these clinics and be treated. And then the third component is the payer access piece that I discussed earlier, right?

Speaker #6: We've got medical exception process here early on as we're gaining the utilization management criteria with payers. So it'll take a little bit of time for that to build and grow.

Speaker #4: And how are you what are you seeing in terms of demand? Thank you.

Speaker #5: Yeah. Thanks for the questions. In terms of pent-up demand, we believe this is going to be a gradual build and a moderate build over time.

Speaker #6: I expect that to happen through the back half of this year. And then 2027 is where we will really see the launch begin to build and pick up as HCPs gain more experience and more patients begin to come in and be treated for SHTG.

Speaker #5: For a couple of reasons. Number one, this is a new mechanism and a new treatment, and it takes some time to educate the HCPs.

Speaker #5: Number two, we've got to get those patients into the clinic to see these HCPs. So we've got to drive that awareness and interest through the patient.

Speaker #6: On the Donzera side, I couldn't be more pleased with how the team is performing and how we are building the momentum. Q2, we did 26 million dollars in revenue.

Speaker #5: So that they're motivated to get into these clinics and be treated. And then the third component is the payer access piece that I discussed earlier, right?

Speaker #5: We've got the medical exception process here early on, as we're gaining the utilization management criteria with payers. So it'll take a little bit of time for that to build and grow.

Speaker #6: It's up 63% over Q1. This is less than one year in the market. We've got meaningful share of a market that is a switch market.

Speaker #6: We're seeing switches. We're also seeing patients that are being treated with on-demand only therapies be started on Donzera and also naive patients. But as you would expect, there are multiple therapies in the class.

Speaker #5: I expect that to happen through the back half of this year. And then 2027 is where we will really see the launch begin to build and pick up as HCPs gain more experience and more patients begin to come in and be treated for SHTG.

Speaker #6: And they have different profiles. And what we know from the switch data is that some patients have an efficacy challenge. Some have a tolerability challenge.

Speaker #5: On the Donzera side, I couldn't be more pleased with how the team is performing and how we are building the momentum. Q2, we did 26 million dollars in revenue.

Speaker #6: And some have an experience in duration of treatment issue, right? Where they're having to take the drug too frequently. So it depends on which drug it is.

Speaker #5: It's up 63% over Q1. This is less than one year in the market. We've got meaningful share of a market that is a switch market.

Speaker #6: But we're seeing switches from all of the prophylactic therapies out there. And HCPs are having very positive experiences prescribing. And they're coming back to use the drug more and more, which we're very encouraged by.

Speaker #5: We're seeing switches. We're also seeing patients who are being treated with on-demand only therapies being started on Donzera, and also naïve patients. But as you would expect, there are multiple therapies in the class.

Speaker #1: The next question comes from Agnes Tawari of Jefferies. Please go ahead.

Speaker #5: And they have different profiles. And what we know from the switch data is that some patients have an efficacy challenge. Some have a tolerability challenge.

Speaker #7: Okay. This is Manoj on for Agnes. Just one from our end. Do you expect GTS 102 to demonstrate a meaningful efficacy trend in the upcoming angel man tradeout?

Speaker #5: And some have an experience in duration of treatment issue, right? Where they're having to take the drug too frequently. So it depends on which drug it is.

Speaker #7: And how should we think about the potential read-through from the data to expectations for ionis 582? Thanks.

Speaker #5: But we're seeing switches from all of the prophylactic therapies out there. And HCPs are having very positive experiences prescribing. And they're coming back to use the drug more and more, which we're very encouraged by.

Speaker #8: Can you repeat the question, please? We didn't quite get that.

Speaker #7: For the angel man's upcoming readout for GTX 102, how should we think about the read-through from that data to your program?

Speaker #2: The next question comes from Akis Tawari of Jefferies. Please go ahead.

Speaker #8: Yeah, yeah.

Speaker #1: Yep.

Speaker #2: Yeah. This is Holly. I'd be happy to take that. So the autogenic stator readout, we're expecting that later this year. That will teach us a couple of things.

Speaker #6: Hey. This is Manoj. For August. Just one from our end. Do you expect GTS 102 to demonstrate a meaningful efficacy trend in the upcoming Angelman tradeout?

Speaker #2: One of the big things that we're looking for from that is to understand the placebo effect that the patient population will have. That's not something that we know from this.

Speaker #6: And how should we think about the potential read-through from the data to expectations for IONIS-582? Thanks.

Speaker #2: So we are looking to do that. In terms of the read-through to our program for the autogenic state itself, you have to remember that those are very different molecules.

Speaker #7: Can you repeat the question, please? We didn't quite get that.

Speaker #2: So they're dosing at a much lower dose than we're dosing. So we hope that they have positive effects that are encouraging for the community.

Speaker #6: For the Angelman's upcoming readout for GTX 102, how should we think about the read-through from that data to your program?

Speaker #2: However, if they don't, it'll likely be because they're dosing lower than we are for our study.

Speaker #7: Yeah, yeah.

Speaker #1: Yep. Yeah. This is Holly. I'd be happy to take that. So the autogenic stator readout, we're expecting that later this year. That will teach us a couple of things.

Speaker #8: Yeah. And I'll just add to that that our research organization has done a very nice job benchmarking Obie Anderson with ion 582 with other molecules that are out there that are in development.

Speaker #1: One of the big things that we're looking for from that is to understand the placebo effect that the patient population will have. That's not something that we know from this.

Speaker #1: So we are looking to do that. In terms of the read-through to our program for the autogenic state itself, you have to remember that those are very different molecules.

Speaker #8: And we don't see any potency advantages of any other molecule compared to ion 582. So we have a highly potent molecule. And as Holly said, we've been able to dose to the maximum dose that we've set out to dose to drive efficacy as an 80 milligram quarterly dose.

Speaker #1: So they're dosing at a much lower dose than we're dosing. So we hope that they have positive effects that are encouraging for the community.

Speaker #1: However, if they don't, it'll likely be because that they're dosing lower than we are for our study.

Speaker #7: Yeah. And I'll just add to that that our research organization has done a very nice job benchmarking Obie Anderson with ION 582 with other molecules that are out there that are in development.

Speaker #8: So we're looking forward to emerging data and we're looking forward to reading out our study next year.

Speaker #7: Thanks. That's really helpful.

Speaker #1: The next question comes from Salvine Richter of Goldman Sachs. Please go ahead.

Speaker #7: And we don't see any potency advantages of any other molecule compared to ION 582. So we have a highly potent molecule. And as Holly said, we've been able to dose to the maximum dose that we've set out to dose to drive efficacy as an 80 milligram quarterly dose.

Speaker #2: Thanks for taking our question. This is Tommy on for Salvine. And just two on Tringulza. So in FCS, maybe some more color on the impact from switches from Arrowhead and on the capture of new starts.

Speaker #2: If you're seeing any and on SHTG, maybe if you could lean more into what you're seeing from the primary care side. Thank you.

Speaker #7: So looking forward to emerging data and we're looking forward to reading out our study next year.

Speaker #6: Yeah. Thanks, Tommy. We've seen no meaningful impact from the competition in FCS. Q2 was by far our strongest demand quarter. And the highest quarter that we've had for new patient starts.

Speaker #8: That's really helpful.

Speaker #2: The next question comes from Salvine Richter of Goldman Sachs. Please go ahead.

Speaker #6: The profile of Tringulza is being very well received by HCPs. HCPs that are using Tringulza for the first time are looking to come back to it.

Speaker #1: Thanks for taking our question. This is Tommy on for Salvine. And just two on Tringulza. So, in FCS, maybe some more color on the impact from switches from Arrowhead and on the capture of new starts, if you're seeing any.

Speaker #6: And when they see the triglyceride lowering, and the ability to self-administer, with the auto-injector, the profile is stacking up very, very strong in terms of the way that they need to treat these patients and the way that the patients feel and are doing on treatment once they get initiated.

Speaker #1: And on SHTG, maybe if you could lean more into what you're seeing from the primary care side. Thank you.

Speaker #5: Yeah. Thanks, Tommy. We've seen no meaningful impact from the competition in FCS. Q2. By far our strongest demand quarter. And the highest quarter that we've had for new patient starts.

Speaker #6: On the primary care side of things, part of the audience of the 20,000 HCPs that we have targeted that are treating these SHTG patients at high risk, also are from the PCP audience.

Speaker #5: The profile of Tringulza is being very well received. By HCPs. HCPs that are using Tringulza for the first time are looking to come back to it.

Speaker #6: So they are seeing these patients. And I think the predominant prescriptions we're going to get are going to be from cardiology, endocrinology, and lipidology.

Speaker #5: And when they see the triglyceride lowering, and the ability to self-administer, with the auto-injector, the profile is stacking up very, very strong in terms of the way that they need to treat these patients and the way that the patients feel and are doing on treatment once they get initiated.

Speaker #6: But I just think it's important to note that PCPs are seeing these patients. And they're willing to prescribe. And they're interested in trying to treat these patients on their own because they've been trying to do so with standard of care with fibrates omega-3, statins, etc., and just have been unsuccessful up to this point.

Speaker #5: On the primary care side of things, part of the audience of the 20,000 HCPs that we have—SHTG patients at high risk—also are from the PCP audience.

Speaker #6: So we will continue the very broad awareness and disease education to all specialties that are seeing these patients. And early on, we've got very positive indicators across the board.

Speaker #5: So they are seeing these patients, and I think the predominant prescriptions we're going to get are going to be from cardiology, endocrinology, and lipidology.

Speaker #8: Thanks, Tommy.

Speaker #1: The next question comes from Luca Icey of RBC. Please go ahead.

Speaker #5: But I just think it's important to note that PCPs are seeing these patients. And they're willing to prescribe. And they're interested in trying to treat these patients on their own because they've been trying to do so with standard of care with fibrates omega-3, statins, etc.

Speaker #6: Oh, great. Thanks so much for taking my question. Congrats on the progress. Maybe Kyle, one more for you. On the launch of severe health producer edema, obviously clear enthusiasm here from the KOL community to prescribe a drug.

Speaker #5: And just have been unsuccessful up to this point. So we will continue the very broad awareness and disease education to all specialties that are seeing these patients.

Speaker #6: However, we have heard from a couple of docs that one of the barriers is that there's no dedicated ICD-10 code specifically for severe heart failure edema.

Speaker #6: So doc needs to use codes for related conditions like hyperkalememia syndrome or maybe hyperglyceridemia. And so that can sometimes create some barriers, some confusions to get the drug reimbursed.

Speaker #5: And early on, we've got very positive indicators across the board.

Speaker #7: Thanks, Tommy.

Speaker #2: The next question comes from Luca Icey of RBC. Please go ahead.

Speaker #6: Is that consistent with what you've been hearing? And if so, can you talk about how you're planning to address that? And then maybe second for CTR cardiomyopathy, Brett, if I can circle back on a prior question.

Speaker #5: Oh, great. Thanks so much for taking my question. Congrats on the progress. Maybe, Kyle, one more for you. On the launch of severe high triglyceridemia, there's obviously clear enthusiasm here from the KOL community to prescribe the drug.

Speaker #6: You mentioned at ESC, you will present this meta-analysis done by an independent group of physicians. Can maybe just expand a little bit more on that?

Speaker #5: However, what we've heard from a couple of docs who wanted a barrier is that there's no dedicated ICD-10 code specifically for severe high triglyceridemia.

Speaker #6: What's the purpose of that analysis? And how should you think about the implication of that analysis for the broader field? Thanks so much.

Speaker #5: So doc needs to use codes for related conditions like hyperkalememia syndrome or maybe hyperglyceridemia. And so that can sometimes create some barriers, some confusions to get the drug reimbursed.

Speaker #4: Yeah. Thanks, Luca. On the ICD-10 code side, I'll start by saying that has been on our radar for quite some time. And it's something that we are looking for opportunities to help the community come up with an ICD-10 code that they can use to explicitly reference SHTG.

Speaker #5: Is that consistent with what you've been hearing? Again, if so, can you talk about how you're planning to address that? And then maybe second for CTR cardiomyopathy, Brett, if I can circle back on a prior question, you mentioned at ESC, you will present this meta-analysis done by an independent group of physicians.

Speaker #4: So that work is ongoing. With the agencies and we'll see what we can do in order to help that happen. But in terms of reimbursement, there are other things that they can use to justify the appropriate use of the drug and get reimbursement.

Speaker #5: Maybe just expand a little bit more on that. What's the purpose of that analysis? And how should you think about the implication of that analysis for the broader field?

Speaker #5: Thanks so much.

Speaker #4: First is the labeled indication. Second is to support that labeled indication with the patient's medical history and reference the drugs that those patients are being treated on, as well as the triglyceride levels that the patients still exhibit even though that they're on those medications.

Speaker #4: Yeah. Thanks, Luca. On the ICD-10 code side, I'll start by saying that has been on our radar for quite some time, and it's something that we are looking for opportunities to help the community come up with—an ICD-10 code that they can use to explicitly reference SHTG.

Speaker #4: So doing a prior authorization, including a letter of medical necessity, is pretty standard for a specialty product like this at launch. And we're working with the different HCPs in order to make sure they understand what's required in order to do that and also supporting them in a compliant way so that they can do that successfully.

Speaker #4: So that work is ongoing with the agencies, and we'll see what we can do in order to get reimbursement. There are other things that they can use to justify the appropriate use of the drug and get reimbursement.

Speaker #7: And Luca, I'm going to ask Holly to take the question back. Expanding on the meta-analysis at ESC.

Speaker #4: First is the labeled indication. Second is to support that labeled indication with the patient's medical history and reference the drugs that those patients are being treated on, as well as the triglyceride levels that the patients still exhibit even though that they're on those medications.

Speaker #2: Yep. So the meta-analysis is really focused on the silencer class and understanding the totality of data within that class, including our new cardiotransform data.

Speaker #2: And comparing them both as monotherapies as well as on top of the stabilizers.

Speaker #4: So, doing a prior authorization, including a letter of medical necessity, is pretty standard for a specialty product like this at launch. And we're working with the different HCPs in order to make sure they understand what's required in order to do that.

Speaker #7: That's the main presentation is going to be comparing those two studies and as single agents as well as combination.

Speaker #4: And also supporting them in a compliant way, so that they can do that successfully.

Speaker #6: Got it. Thanks so much, guys.

Speaker #3: And Luca, I'm going to ask Holly to take the question back. Expanding on the meta-analysis at ESC.

Speaker #1: The next question will come from Jessica Fai of JPMorgan. Please go ahead.

Speaker #1: Yep. So, the meta-analysis is really focused on the silencer class and understanding the totality of data within that class, including our new CardioTransform data.

Speaker #5: Hey, guys. Good morning. I was curious about ION337 for Gravet. Can you help us think about when we might see the part one data from the phase one, two?

Speaker #1: And comparing them both as monotherapies as well as on top of the stabilizers.

Speaker #5: And just given the long lead time for Zoriva Nursen, how might 337 differentiate? Thank you.

Speaker #3: That's the main presentation—it's going to be comparing those two studies as single agents as well as in combination.

Speaker #3: Yeah. I'm happy to take that one. So for 337, we just started dosing. So it's too early to talk about timelines, but we are there's a lot of enthusiasm from the community, the KOLs know Ionis and know our technology.

Speaker #5: Got it. Thanks so much, guys.

Speaker #2: The next question will come from Jessica Fai of JP Morgan. Please go ahead.

Speaker #3: And our we're excited to get that moving quickly as is the community. In terms of differentiation, because we're using our new NMA technology, it's more potent than the MO chemistry, our previous chemistry that we used for splice modulation.

Speaker #6: Hey, guys. Good morning. I was curious about ION 337 for Gravet. Can you help us think about when we might see the part one data from the Phase 1/2?

Speaker #3: So you get increased potency and then allows you to spread out your dosing interval and increase your efficacy.

Speaker #6: And just given the long lead time for Zoriva Nursen, how might 337 differentiate? Thank you. Yeah, I'm happy to take that one. So for 337, we just started dosing.

Speaker #7: And thanks, Jess. I think we have time for one more question.

Speaker #6: So it's too early to talk about timelines, but we are there's a lot of enthusiasm from the community, the KOLs know IONIS and know our technology.

Speaker #1: All right. Last question comes from Eric Joseph of City. Please go ahead.

Speaker #7: Hi. Thanks for taking the questions. Just thinking about the upcoming core OLE data at ESC, maybe just a little bit of expectation setting there.

Speaker #6: And our we're excited to get that moving quickly as is the community. In terms of differentiation, because we're using our new NMA technology, it's more potent than the MO chemistry, our previous chemistry that we used for splice modulation.

Speaker #7: What incremental endpoints in addition to the NLA presentation are of interest, or would you have us focus on there? To what extent, I guess, is ongoing AP event rate something that you're tracking in the OLE portion?

Speaker #6: So you get increased potency and that allows you to spread out your dosing interval and increase your efficacy. Thank you.

Speaker #3: And thanks, Jess. I think we have time for one more question.

Speaker #7: And then just perhaps a clarifying question on the strategy with 775. Is the goal here predominantly to be a convenience playover triangle in SHTG, or is there an expansion opportunity in moderate HTG that you think is worth pursuing?

Speaker #2: Our last question comes from Eric Joseph of Citi. Please go ahead.

Speaker #7: Hi. Thanks for taking the questions. Just thinking about the upcoming core OLE data at ESC, maybe just a little bit of expectation setting there.

Speaker #7: And if so, what would a TPP look like there? Thanks. Yeah. Thanks, Eric. I'll ask Holly to talk a little bit about what we're planning to present at ESC on the long-term data on core and core two.

Speaker #7: What incremental endpoints in addition to the NLA presentation are of interest or would you have us focus on there? To what extent, I guess, is ongoing AP event rate something that you're tracking in the OLE portion?

Speaker #7: I'll take 775. So the goal is primarily we're primarily focused right now on severe hypertriglyceridemia. 775 as a follow-on molecule for this indication. And it isn't primarily a convenience play.

Speaker #7: And then just perhaps a clarifying question on the strategy with 775. Is the goal here predominantly to be a convenience play over trend goals in SHTG, or is there an expansion opportunity in moderate HTG that you think is worth pursuing?

Speaker #7: I think I mentioned earlier that the efficacy and tolerability, safety profile of triangles and SHTG is difficult to beat. So we'll strive to do that, but it's really a convenience play that we think that we can dose this drug twice a year, maybe once per year based on our phase one data.

Speaker #7: And if so, what would a TPP look like there? Thanks.

Speaker #3: Yeah. Thanks, Eric. I'll ask Holly to talk a little bit about what we're planning to present at ESC on the long-term data on CORE and CORE 2.

Speaker #7: And that phase one data will be presented at ESC. And I think it'll be clear how durable 775 is. We'll always consider other indications, but primarily and we haven't laid out we have not established our phase three plan yet.

Speaker #3: I'll take 775. So, right now, the goal is we're primarily focused on severe hypertriglyceridemia. 775 is a follow-on molecule for this indication, and it isn't primarily a convenience play.

Speaker #7: We're still working through that. It needs to be we need more phase two data before we can really make those decisions. But it's really primarily focused on SHTG.

Speaker #3: I think I mentioned earlier that the efficacy and tolerability, safety profile of TRIGAL and SHTG is difficult to beat. So we'll strive to do that.

Speaker #7: And Holly, what can we expect on the long-term data for core two at ESC?

Speaker #2: Yep. This is looking at one year into the OLE. So of course, we'll be looking at triglyceride levels as well as full safety data.

Speaker #3: But it's really a convenience play—we think that we can dose this drug twice a year, maybe once per year, based on our phase 1 data.

Speaker #2: And all of the key biomarker is looking at remnant cholesterol, APOC3, non-HDL, all of those various markers.

Speaker #3: And that phase one data will be presented at ESC. And I think it'll be clear how durable 775 is. We'll always consider other indications, but primarily and we haven't laid out we have not established our phase three plan yet.

Speaker #7: Yeah. It's very exciting long-term data. On the durability of efficacy as well as lack of any emerging adverse events or anything. On the safety side.

Speaker #3: We're still working through that. It needs to be we need more phase two data before we can really make those decisions. But it's really primarily focused on SHTG.

Speaker #7: So thanks for the question, Eric. Thank everybody for joining us today for participating in our call. We really are looking forward to an exciting second half of the year for Ionis.

Speaker #3: And Holly, what can we expect on the long-term data for core two at ESC?

Speaker #1: Yep. This is looking at one year into the OLE. So, of course, we'll be looking at triglyceride levels as well as full safety data.

Speaker #7: And we look forward to sharing our progress along the way. Until then, thanks, everybody. Have a great day.

Speaker #1: And all of the key biomarker is looking at remnant ant cholesterol, APOC3, non-HDL, all of those various markers.

Speaker #3: Yeah. It's very exciting long-term data. On the durability of efficacy as well as lack of any emerging adverse events or anything. On the safety side.

Speaker #3: So thanks for the question, Eric. Thank everybody for joining us today. For participating in our call. We really are looking forward to an exciting second half of the year for IONIS.

Speaker #3: And we look forward to sharing our progress along the way. Until then, thanks everybody and have a great day.