Q3 2025 Ionis Pharmaceuticals Inc Earnings Call

Good morning, and welcome to the Ion <unk> third quarter 2025 financial results Conference call.

Remind you this call is being recorded at this time I would like to turn the conference over to Mr. Wade Walke Senior Vice President of Investor Relations.

Paul Please begin sir.

Thank you Chuck.

Before we begin I encourage everyone to go to the investors section of <unk> website.

The tables, we will be discussing today, including a reconciliation of GAAP to non-GAAP financials, we believe GAAP financial results better represent the economics of our business. How we manage our business. We have also posted slides on our website that accompany today's call with me on the call. This morning are Brent <unk>, our Chief Executive Officer.

Richard Geary, our Chief Development Officer, Alan <unk>, our Chief Global product strategy Officer, and Beth Hougen, our Chief Financial Officer.

Also joining us are Eugene Schneider, Chief clinical development Officer, and Eric Swayze Executive Vice President of research will join us for the Q&A portion of the call.

I would like to draw your attention to slide three which contains our forward looking language statement. During this call we will be making forward looking statements that are based on our current expectations and beliefs. These statements are subject to certain risks and uncertainties and our actual results may differ materially.

I encourage you to consult the risk factors contained in our SEC filings for additional detail with that I'll turn the call over to Brett.

Thanks, Wade and good morning, everyone and thank you for joining us on today's call.

The third quarter was a watershed moment for <unk> as we made important progress advancing first and best in class medicines for several serious diseases, including in our core focus areas of neurology and cardio metabolic diseases.

Our first independent launch for <unk>.

Only FDA approved treatment for familial cargo Micronesia syndrome, or FCS continues to build strong momentum there.

This performance reflects for Ingalls was compelling clinical profile strong launch execution and the significant unmet need that we are addressing.

Based on this performance and confidence in our continued success across the business. We are raising our 2025 financial guidance, including <unk> revenues, which Beth will review in more detail shortly.

<unk> also recently received European approval and we are pleased that our partner <unk> expects to begin bringing this transformative medicine to patients across Europe in the fourth quarter.

In August the FDA approved <unk> Zara for hereditary angioedema are HLA, marking our second independent launch.

This is an important milestone for people living with HIV and for Iona I'm, especially proud of the launch execution by our commercial team, which Kyle will further highlight in a few moments.

And in September we reported positive top line results from two pivotal programs from our wholly owned pipeline.

Both of which were groundbreaking in their own right <unk> and severe hypertrichosis Redeemer rsh TG showed highly significant reductions in triglycerides and became the first medicine ever to show a significant reduction in acute pancreatitis in this population.

And in Neurology yoga nurse and showed the first ever disease modifying effect in Alexander disease, a rare and often fatal neurologic disease.

These results reinforce the strength of our science and position I owners for two additional independent launches next year.

Together these two programs along with <unk> and <unk> Zara represents significant breakthroughs for patients and the potential for multibillion dollar revenue right on us.

And complementing our rich wholly owned pipeline as our partner pipeline, which continues to progress very well.

By the end of 2027, we anticipate four key launches from our partnered pipeline targeting both rare and highly prevalent life threatening diseases.

Brett Monia: Through your patience and the potential for multi-billion dollar revenue for Ionis. In complementing our rich wholly owned pipeline is our partner pipeline, which continues to progress very well. By the end of 2027, we anticipate four key launches from our partnered pipeline targeting both rare and highly prevalent life-threatening diseases. We expect these partner programs will further expand the impact of Ionis Discovered Medicines and meaningfully increase total revenue for Ionis. With strong momentum across our business, including our first two independent launches underway in advancing wholly owned late-stage pipeline and a robust partnered portfolio, Ionis is well positioned to deliver transformative medicines for patients year after year, driving sustained growth. I'll turn the call over to Richard.

We expect these partnered programs will further expand the impacted by owners discovered medicines and meaningfully increased total revenue for eye on us.

With a strong momentum across our business, including our first two independent launches underway and advancing wholly owned late stage pipeline and a robust partnered portfolio I honest is well positioned to deliver transformative medicines for patients year after year driving sustained growth and with that I'll turn the call over to Rick.

Sure.

Well, thank you Brad.

Making excellent progress across our pipeline reinforcing <unk> ability to deliver on our mission.

Bringing transformational medicines to patients for years to come.

Just last month, we reported positive top line results from the phase III core and core two studies of <unk> in people with S. H T G, who had triglyceride levels substantially higher than 500 milligram per deciliter, despite being on standard of care in lipid lowering therapies at baseline.

Richard Geary: Thank you, Brett. We're making excellent progress across our pipeline, reinforcing Ionis Pharmaceuticals' ability to deliver on our mission of bringing transformational medicines to patients for years to come. Just last month, we reported positive top-line results from the phase 3 Q4 and Q2 studies of olezarsen in people with severe hypertriglyceridemia who had triglyceride levels substantially higher than 500 milligrams per deciliter, despite being on standard of care lipid-lowering therapies at baseline, putting them at risk of life-threatening acute pancreatitis. In these pivotal studies, olezarsen demonstrated highly statistically significant and clinically meaningful mean reductions of up to 72% in placebo-adjusted fasting triglycerides at six months, the primary endpoint of these studies. In these studies, olezarsen also significantly reduced acute pancreatitis events, making it the first and only treatment to achieve this positive outcome in people with severe hypertriglyceridemia.

With the strong momentum of our business, including our first 2 independent launches underway, advancing wholly-owned late-stage pipeline, and a robust partnered portfolio, I believe this is well-positioned to deliver transformative medicines for patients year after year, driving sustained growth. And with that, I'll turn the call over to Richard.

Thank you, Brad.

Putting them at risk of life threatening acute pancreatitis in these pivotal studies all assumption demonstrated highly statistically significant and clinically meaningful mean reductions of up to 72% in placebo adjusted fasting triglycerides at six months.

We're making excellent progress across our pipeline. Reinforcing our ability to deliver on our mission of bringing transformational medicines to patients for years to come.

The primary endpoint of these studies.

This last month we reported positive Topline results from the phase 3 core and Core 2 studies of all the sarsen and people with shtg who had triglyceride levels substantially higher than 500 milligram per deciliter, despite being on standard of care, lipid, lowering therapies at Baseline.

In these studies <unk> also significantly reduced acute pulmonary tightened <unk> thinking of the first and only treatment to achieve this positive outcome in people with S. H T G I.

<unk> achieved a highly statistically significant and 85% reduction in adjudicated acute pancreatitis events.

Putting them at risk of life-threatening acute pancreatitis in these pivotal studies Allosaurus and demonstrated. Highly statistically, significant and clinically meaningful mean, reductions of up to 72% in Placebo, adjusted fasting triglycerides at 6 months.

The primary endpoint of these studies.

It's important to remember that the main goal of Triglyceride management NSX T. G is to prevent these 80 events and <unk> is the first medicine to demonstrate it can do just that.

Richard Geary: Olezarsen achieved a highly statistically significant 85% reduction in adjudicated acute pancreatitis events. It's important to remember that the main goal of triglyceride management in severe hypertriglyceridemia is to prevent these acute pancreatitis events, and olezarsen is the first medicine to demonstrate it can do just that. We believe these unprecedented results position olezarsen to meet the substantial unmet needs of people with severe hypertriglyceridemia, a large patient population in great need for more effective triglyceride lowering to reduce the risk of potentially fatal acute pancreatitis. In terms of next steps, we're looking forward to presenting additional data from the Q4 and Q2 studies at the American Heart Association on November 8th. Following that, we are on track to submit our sNDA in the U.S. by the end of the year, with additional global filings expected next year.

In these studies Allosaurus and also significantly reduced acute. Pancreatitis events making it. The first and only treatment to achieve this positive outcome in people with shtg.

We believe these unprecedented results position <unk> to meet the substantial unmet needs of people with us hte, a large patient population in great need for more effective triglyceride lowering.

Colasour and achieved a highly statistically significant 85% reduction in adjudicated acute pancreatitis events.

To reduce the risk of potentially fatal acute pancreatitis in.

In terms of next steps, we're looking forward to presenting additional data from the core and core two studies at IHA on November eight.

It's important to remember that the main goal of triglyceride management and shtg is to prevent these AP events and ossur as the first medicine to demonstrate, it can do just that.

Following that we are on track to submit our NDA in the U S. By the end of the year with additional global filings expected next year.

we believe these unprecedented results, positional as arson to meet the substantial unmet needs of people with shtg, a large patient population in great, need for more effective triglyceride lowering

And as Kyle highlighted.

To reduce the risk of potentially fatal acute pancreatitis.

Launch preparations are already underway and we are moving with urgency as we look to deliver all of its awesome to people with <unk> next year.

In terms of next steps, we're looking forward to presenting additional data from the core and Core 2 studies at AHA on November 8th.

Turning our attention to <unk>.

A medicine to treat Alexander disease, an ultra rare Luca dystrophy profoundly impacts patients and families who today have no approved disease modifying therapies.

Richard Geary: As Kyle will highlight, launch preparations are already underway, and we are moving with urgency as we look to deliver olezarsen to people with severe hypertriglyceridemia next year. Turning our attention to Zilganirsa, our medicine to treat Alexander disease, an ultra-rare leukodystrophy that profoundly impacts patients and families who today have no approved disease-modifying therapies. With the positive phase 3 results in hand, we are on track for another independent launch next year, and we expect this to be the first of numerous additional independent launches from our leading neurology pipeline. In our phase 3 studies, Zilganirsa achieved statistically significant and clinically meaningful stabilization on the primary endpoint of gait speed. This is an assessment of gross motor function as measured by the 10-meter walk test. At week 61, Zilganirsa showed a 33% mean benefit in gait speed versus control, with a favorable safety and tolerability profile.

Following that we are on track to submit our snda in the US by the end of the year with additional Global filings expected next year.

And as Kyle will highlight.

With the positive phase III results in hand, we are on track for another independent launch next year.

Launch preparations are already underway, and we are moving with urgency as we look to deliver Ossur to people with SHTG next year.

And we expect this to be the first of numerous additional independent launches from our leading neurology pipeline.

In our phase III studies, <unk> achieved statistically significant and clinically meaningful stabilization on the primary endpoint of gait speed.

Turning our attention to zilon our medicine to treat Alexander Disease an ultra rare. Luca droy. The profoundly impacts patients and families. Who today have no approved disease, modifying Therapies?

This is an assessment of gross motor function as measured by the 10 meter walk test at week 61, silver nurse and showed a 33% mean benefit and gait speed versus control.

With the positive Phase 3 results in hand, we are on track for another independent launch next year, and we expect this to be the first of numerous additional independent launches from our leading neurology pipeline.

With a favorable safety and Tolerability profile <unk>.

<unk> also demonstrated consistent benefit across key secondary endpoints.

In our phase 3 studies, Zelda nurse and achieved statistically significant and clinically meaningful stabilisation on the primary endpoint of gait speed.

These results represent the first time, an investigational medicine has shown a positive disease modifying impact Alexander disease.

We plan to submit a new drug application to the FDA in the first quarter of 2026, and we are also initiating an expanded access program in the U S.

This is an assessment of gross motor function as measured by the 10-meter walk test. At week 61, Silgan showed a 33% mean benefit in gait speed versus control.

Richard Geary: Zilganirsa also demonstrated consistent benefit across key secondary endpoints. These results represent the first time an investigational medicine has shown a positive disease-modifying impact in Alexander disease. We plan to submit a new drug application to the FDA in the first quarter of 2026, and we are also initiating an expanded access program in the U.S. Turning to ION582, our investigational medicine for Angelman syndrome, the newest addition to our late-stage pipeline. Angelman syndrome is a serious, rare neurodevelopmental disorder that causes profound and lifelong physical and cognitive impairments estimated to affect more than 100,000 people. Earlier this month, at our Innovation Day, we shared additional 12 and 18-month data from the long-term extension portion of the HALOS study. Results from this study showed consistent and durable improvement on expressive communication over 18 months, exceeding what is seen in natural history while maintaining a favorable safety and tolerability profile.

Turning to eye on Friday to our investigational medicine for Angelman syndrome. The newest addition to our late stage pipeline.

<unk> syndrome is a serious rare neurodevelopmental disorder.

With a favorable safety and tolerability profile, Zila nurse and also demonstrated consistent benefit across key, secondary endpoints and these results represent the first time an investigational medicine has shown a positive disease, modifying impact in Alexander disease.

Causes profound.

We plan to submit a new drug application to the FDA and the first quarter of 2026.

And lifelong physical and cognitive impairments estimated to affect more than 100000 people.

And we are also initiating an expanded access program in the US.

Earlier this month at our innovation day, we shared at 12 and 18 month data from the long term extension portion of the Halo study.

<unk> from this study showed consistent and durable improvement on expressive communication over 18 months exceeding what is seen in natural history.

While maintaining a favorable safety and tolerability profile.

It causes profound and lifelong physical and cognitive impairments, estimated to affect more than 100,000 people.

Improvements were also observed across multiple other functional domains, including cognition and motor function.

Earlier this month at our Innovation Day, we shared digital 12- and 18-month data from the long-term extension portion of the Halo study.

Suggesting meaningful disease modifying potential for ion five five to eight two.

As a reminder.

Results from this study showed consistent and durable Improvement on expressive communication over 18 months exceeding. What is seen in Natural History?

Primary endpoint in our phase III reveal study is expressive communication, reflecting what families have reported matters most to them.

Richard Geary: Improvements were also observed across multiple other functional domains, including cognition and motor function, suggesting meaningful disease-modifying potential for ION582. As a reminder, the primary endpoint in our phase 3 REVEAL study is expressive communication, reflecting what families have reported matters most to them. Just last month, the FDA granted ION582 breakthrough therapy designation, recognizing the encouraging results from the phase 1 to HALOS study and the significant unmet need. Enrollment in the phase 3 registration study is progressing well, and we remain on track to be fully enrolled next year with data in 2027. With multiple data readouts and regulatory milestones expected this year and next, our advancing pipeline underscores the strength of our science and our commitment to addressing unmet needs in people with serious diseases. With that, I'll turn the call over to Kyle.

While maintaining a favorable safety and tolerability profile.

And just last month, the FDA granted <unk> $5 eight to breakthrough therapy designation, recognizing the encouraging results from the phase one two halo study and the significant unmet need.

Improvements were also observed across multiple other functional domains, including cognition and motor function, suggesting meaningful disease-modifying potential for ION 52.582.

Enrollment in the phase III registration study is progressing well and we remain on track to be fully enrolled next year with data in 2027.

As a reminder, the primary endpoint in our phase 3 reveal study is expressive communication reflecting what families have reported matters most to them.

With multiple data Readouts and regulatory milestones expected this year and next our advancing pipeline underscores the strength of our science and our commitment to addressing unmet need and people with serious diseases.

And just last month, the FDA granted ION582 breakthrough therapy designation, recognizing the encouraging results from the Phase 1 Halo study and the significant unmet need.

With that I'll turn the call over to Kyle.

Enrollment in the phase 3, registration study is progressing. Well and we remain on track to be fully enrolled next year with data in 2027.

Yes.

Thank you Richard.

With our first independent launch gaining momentum our second now underway and two more anticipated next year. Our commercial team is focused on flawless execution to bring these important medicines to patients in.

In the third quarter <unk> continued to exhibit strong momentum as we reported $32 million and net product sales, reflecting a nearly 70% increase in revenues per quarter.

With multiple data readouts and Regulatory Milestones expected this year. And next our advancing pipeline, underscores, the science, and our commitment to addressing unmet need in people with serious diseases.

Brett Monia: Thank you, Richard. With our first independent launch gaining momentum, a second now underway, and two more anticipated next year, our commercial team is focused on flawless execution to bring these important medicines to patients. In the third quarter, Tringola continued to exhibit strong momentum as we reported $32 million in net product sales, reflecting a nearly 70% increase in revenues quarter over quarter. Our patient identification initiatives are proving effective. The breadth and depth of unique physicians prescribing Tringola continued to expand through the third quarter, underscoring the positive experience of both clinicians and patients. This demand also spans a broad mix of specialties, with cardiologists and endocrinologists representing nearly 70% of prescribers, and lipidologists and internal medicine providers making up the balance. This favorable provider mix will support awareness and familiarity when we expand into the broader SHTG patient population next year, assuming approval.

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

Thank you, Richard.

Our patient identification initiatives are proving effective.

Breadth and depth of unique physicians prescribing for Ingalls up continued to expand through the third quarter underscoring the positive experience of both clinicians and patients.

With our first independent launch gaining momentum, a second is now underway, and two more are anticipated next year. Our commercial team is focused on flawless execution to bring these important medicines to patients.

This demand also spans a broad mix of specialties with cardiologists endocrinologists, representing nearly 70% of prescribers and lipid <unk> internal medicine providers, making up the balance this favorable provider mix will support awareness and familiarity when we expand into the broader <unk> patient population next.

In the third quarter tranga, continued to exhibit strong momentum. As we reported 32 million in net product sales, reflecting a nearly 70% increase in revenues quarter over quarter.

Our patient identification, initiatives are proving effective. The breadth and depth of unique Physicians, prescribing tring, golza continued to expand through the third quarter underscoring, the positive experience of both clinicians and patients.

Year, assuming approval.

Access and coverage have also remained strong.

To date, the coverage mix for patients Entre goelzer as approximately 60% commercial and 40% government.

This demand also spans a broad mix of specialties, with cardiologists and endocrinologists representing nearly 70% of prescribers, and lipidologists and internal medicine providers making up the balance.

Importantly, both clinically diagnosed and genetically confirmed patients have continued to obtain coverage through a growing number of formal policies or via the medical exception process.

Brett Monia: Access and coverage have also remained strong. To date, the coverage mix for patients on Tringola is approximately 60% commercial and 40% government. Importantly, both clinically diagnosed and genetically confirmed patients have continued to obtain coverage through a growing number of formal policies or via the medical exception process. We're proud of Tringola's early momentum, but we know we're still in the early innings. The vast majority of the estimated 3,000 people living with familial chylomicronemia syndrome in the U.S. remain unidentified. As a result, we're continuing to focus on our patient finding efforts and HCP education. Our customer-facing team has reached over 3,000 physicians, and over 30,000 HCPs have been targeted through our omnichannel capabilities, further increasing awareness of familial chylomicronemia syndrome, expanding patient identification, and educating on the potential benefits of Tringola treatment.

This favorable provider mix will support awareness and familiarity. When we expand into the broader SHTG patient population next year, assuming approval.

We're proud of turn goals as early momentum, but we know we're still in the early innings. The vast majority of the estimated 3000 people living with FCS in the U S remain on identified as a result, we're continuing to focus on our patient finding efforts in HCP education or.

Access and coverage have also remained strong.

To date, the coverage mix for patients on Tris is approximately 60% commercial and 40% government.

Our customer facing team has reached over 3000 physicians and over 30000 Hcp's had been targeted through our omni channel capabilities further increasing awareness of FCS expanding patient identification and educating on the potential benefits of <unk> treatment.

Importantly, both clinically diagnosed and genetically confirmed patients have continued to obtain coverage through a growing number of formal policies or via the medical exception process.

Backed by an experienced and high performing team, we are well positioned to continue to take advantage of our first mover position to bring <unk> to patients in need.

We're proud of TR goals as early momentum, but we know, we're still in the early Innings. The vast majority of the estimated 3,000 people living with FCS in, the US, remain unidentified, as a result, we're continuing to focus on our patient, finding efforts in hcp education.

Building on our early success in FCS we are preparing for a launch in a severe hyper triglyceride EMEA patient population.

<unk> represents a large patient population many of whom struggle to manage their triglyceride levels with current treatments in the U S alone more than 1 million people have high risk SHT G defined as individuals with triglyceride levels above 880 milligrams per deciliter are above 500 milligrams per deciliter with a history of acute.

Brett Monia: Backed by an experienced and high-performing team, we are well positioned to continue to take advantage of our first mover position to bring Tringola to patients in need. Building on our early success in familial chylomicronemia syndrome, we are preparing for a launch in the severe hypertriglyceridemia patient population. SHTG represents a large patient population, many of whom struggle to manage their triglyceride levels with current treatments. In the U.S. alone, more than 1 million people have high-risk SHTG, defined as individuals with triglyceride levels above 880 milligrams per deciliter or above 500 milligrams per deciliter with a history of acute pancreatitis or other comorbidities. With a significant first mover advantage and groundbreaking positive phase 3 data in hand, as Richard just outlined, we believe olezarsen is well positioned to address the unmet needs of patients with severe hypertriglyceridemia.

Our customer facing team has reached over 3,00 Physicians and over 30,000 hcps. Have been targeted through our Omni Channel capabilities further, increasing, awareness of FCS expanding patient identification and educating on the potential benefits of Ting golsa treatment.

Backed by an experienced in high performing team. We are well positioned to continue to take advantage of our first mover position to bring tring goals at a patients in need.

Building on our early success in FCS, we are preparing for a launch in the severe hyper triglyceridemia patient population.

Pancreatitis or other comorbidities.

With a significant first mover advantage and groundbreaking positive phase III data in hand, as Richard just outlined we believe <unk> is well positioned to address unmet needs of patients with severe hyper triglyceride EMEA.

Shtg represents a large patient population, many of whom struggle to manage their triglyceride levels with current treatments.

Our commercial team is making excellent progress as we prepare for an expected launch next year.

To unlock the potential of <unk> and SHT G. We plan to initially target approximately 20000 hcp's in the U S who are high volume treaters of high risk <unk> patients and expand this outreach even further via our omnichannel capabilities.

In the us alone, more than 1 million. People, have high risk, shtg defined as individuals with triglyceride levels of 880 milligrams per deciliter or above 500 milligrams per deciliter, with a history of acute pancreatitis or other comorbidities.

Brett Monia: Our commercial team is making excellent progress as we prepare for an expected launch next year. To unlock the potential of olezarsen in SHTG, we plan to initially target approximately 20,000 HCPs in the U.S. who are high-volume treaters of high-risk SHTG patients and expand this outreach even further via our omnichannel capabilities. Our commercial strategy leverages the strong foundation we have built with healthcare providers already prescribing Tringola, many of whom manage SHTG patients. At the same time, we are broadening our reach to additional prescribers who treat SHTG patients. To support this effort, we are expanding awareness through targeted disease education and continued investment in our commercial infrastructure. With key field leadership now in place, we plan to scale the Tringola field force to approximately 200 representatives ahead of launch. At the same time, we have begun engaging payers to ensure broad patient access at launch.

With a significant first, mover advantage and groundbreaking positive, phase 3 data in hand, as Richard just outlined, we believe as ours and is, well, positioned to address, the unmet needs of patients with severe hypertriglyceridemia.

Our commercial strategy Leverages. The strong foundation, we have built with health care providers already prescribing tringali.

Our commercial team is making excellent progress as we prepare for an expected launch next year.

Many of whom managed <unk> patients at the same time, we are broadening our reach to additional prescribers, who treat <unk> patients.

To support this effort, we are expanding awareness through targeted disease education and continued investment in our commercial infrastructure with.

Of high-risk, shtg patients and expand this Outreach. Even further via our Omni Channel capabilities.

With key field leadership now in place we plan to scale the <unk> field force to approximately 200 Representatives ahead of launch.

Our commercial strategy, leverages the strong Foundation. We have built with Healthcare Providers already prescribing tringa. Many of whom managed shtg patients.

At the same time, we have begun engaging payers to ensure broad patient access at launch.

At the same time, we are broadening our reach to additional prescribers who treat shtg patients.

We believe there is strong recognition of the value in treating SHT G. Given the potential to reduce the risk of life threatening triglyceride induced acute pancreatitis at the costs associated.

To support this effort, we are expanding awareness through targeted disease education and continuing to invest in our commercial infrastructure.

With treating these patients.

With key field leadership. Now in place, we plan to scale the tring goals of Field Force to approximately 200 Representatives ahead of launch.

Now turning to Don's era, the approval of <unk> Zara marked a major milestone for eye on us and our team is energized and focused on executing a successful launch.

Brett Monia: We believe there is strong recognition of the value in treating SHTG, given the potential to reduce the risk of life-threatening triglyceride-induced acute pancreatitis and the cost associated with treating these patients. Now turning to Donsera, the approval of Donsera marked a major milestone for Ionis Pharmaceuticals, and our team is energized and focused on executing a successful launch. We built a top-tier commercial organization with deep experience in allergy and immunology, including in HAE. Within 10 days of approval, we shipped our first prescriptions, and the first patients self-administered their initial dose. We're pleased to see strong early adoption of Donsera, with patients switching from prior prophylactic or on-demand therapies, as well as treatment-naive patients starting on Donsera. The initial feedback from both physicians and patients has been very encouraging, with clear early excitement around Donsera. Notably, we are already seeing repeat prescribers. The U.S.

at the same time, we have begun engaging payers to ensure broad patient access at launch

We've built a top tier commercial organization with deep experience in allergy and immunology, including an 8-K.

Within 10 days of approval, we shipped our first prescriptions in the first patients self administer their initial dose.

we believe there is strong recognition of the value in treating shtg, given the potential to reduce the risk of life-threatening triglyceride induced acute pancreatitis at the cost associated with, treating these patients

We're pleased to see strong early adoption of <unk> Zara with patient switching from prior prophylactic or on demand therapies as well as treatment naive patients starting on <unk> and.

Now, turning to Dawn, zero, the approval of dawn zero, marked a major milestone for ionis and our team is energized and focused on executing a successful launch.

And the initial feedback from both physicians and patients has been very encouraging with clear early excitement around <unk> Zara, notably we are already seeing repeat prescribers.

We built a top tier commercial organization with deep experience and Allergy and Immunology, including an Hae.

Within 10 days of approval, we shipped our first prescriptions and the first patient self-administered. Their initial dose.

The U S prophylactic HVAC market is well established yet many patients remain dissatisfied with their current therapies.

20% of patients switch treatments each year, highlighting the ongoing need for better treatment options.

We're pleased to see strong early adoption of Don Zahra, with patients switching from prior prophylactic or on-demand therapies, as well as treatment-naive patients starting on Don Zahra.

Educating patients and physicians and supporting transition existing therapies will take time, we believe <unk> Zara with its differentiated profile and focus launch strategy is well positioned to meet this unmet need.

And the initial feedback from both physicians and patients has been very encouraging, with clear early excitement around Don Zahra.

Brett Monia: prophylactic HAE market is well established, yet many patients remain dissatisfied with their current therapies. Approximately 20% of patients switch treatments each year, highlighting the ongoing need for better treatment options. While educating patients and physicians and supporting transition from existing therapies will take time, we believe Donsera, with its differentiated profile and focused launch strategy, is well positioned to meet this unmet need. As with Tringola and familial chylomicronemia syndrome, we are committed to providing appropriate and comprehensive support to the HAE community, including ensuring broad and timely access for patients who need Donsera. We've established differentiated patient assistance and financial support programs. We are offering a free trial program, which allows patients in collaboration with their healthcare providers to determine if Donsera is the right fit for them. For eligible commercially insured patients, out-of-pocket costs can be reduced to as little as $0.

Notably, we are already seeing repeat prescribers.

The US prophylactic he Market, as well as established yet. Many patients remain dissatisfied with their current Therapies.

As with <unk> and FCS, we are committed to providing appropriate and comprehensive support to the AG community, including extremely broad and timely access for patients who need <unk> Zara.

Approximately 20% of patients switch, treatments each year. Highlighting the ongoing need for better treatment options.

We have established differentiated patient assistance and financial support programs, we are offering a free trial program, which allows patients in collaboration with their health care providers to determine if don's era is the right fit for them.

While educating patients and physicians and supporting the transition from existing therapies will take time, we believe Don Zahra, with its differentiated profile and focused launch strategy, is well positioned to meet this unmet need.

For eligible commercially insured patients out of pocket costs can be reduced to as little as zero dollars.

With this foundation in place we are confident in the anticipated trajectory of <unk> Zara as we work to transform the treatment landscape for patients with HMA.

As with tring goals and FCS, we are committed to providing appropriate and comprehensive support to the he Community, including ensuring Broad and timely access for patients who need Don Zahra.

Now turning to Zillow Gunnerson Alexander disease.

<unk> could deliver the first meaningful advance for patients and caregivers, where there are currently no approved disease modifying treatments. This program represents another important opportunity to extend our commercial capabilities.

We've established differentiated patient assistance and financial support programs. We are offering a free trial program which allows patients and collaboration with their Healthcare Providers, to determine if donza is the right fit for them.

Brett Monia: With this foundation in place, we are confident in the anticipated trajectory of Donsera as we work to transform the treatment landscape for patients with HAE. Now turning to Zilganirsa for Alexander disease, Zilganirsa could deliver the first meaningful advance for patients and caregivers where there are currently no approved disease-modifying treatments. This program represents another important opportunity to extend our commercial capabilities. We will build on Ionis Pharmaceuticals' longstanding partnerships with the neurology community and patient advocacy groups to support awareness, diagnosis, and access. At launch, our focus will be on ensuring continued access for clinical trial participants to Zilganirsa, expediting access for diagnosed patients, and improving identification of new patients, including enhanced genetic screening. Additionally, we will be working to ensure treatment availability at appropriately equipped centers.

For eligible commercially insured patients. Out-of-pocket costs can be reduced to as little as 0.

We will build on I honest has long standing partnerships with the neurology community and patient advocacy groups to support awareness diagnosis and access.

With this foundation in place, we are confident in the anticipated trajectory of Don Zahra as we work to transform the treatment landscape for patients with HAE.

Now, turning to Zila Nurse in for Alexander disease.

At launch our focus will be on ensuring continued access for clinical trial participants to Zillow gunnerson.

Expediting access for diagnose patients and improving identification of new patients, including enhanced genetic screening.

Zila Nursing could deliver the first meaningful advance for patients and caregivers where there are currently no approved disease-modifying treatments. This program represents another important opportunity to extend our commercial capabilities.

Additionally, we will be working to ensure treatment availability at appropriately equipped centers.

We will build on ionis long-standing Partnerships with the neurology community and patient, advocacy groups to support awareness, diagnosis and access.

With preparations well underway, we are confident that <unk> can provide a first in class disease modifying treatment option for patients and caregivers and opens the door to further strengthen our foundation as we advance our leading neurology pipeline.

At launch, our Focus will be on ensuring continued access for clinical trial, participants to Zila nursing.

Expediting access for diagnosed patients and improving. Identification of new patients including enhanced genetic screening.

Our experienced commercial organization is already delivering strong results as reflected in the early momentum of both <unk> and <unk> Zara building on the success, we remain focused on maximizing the full potential of these therapies, while preparing to execute two additional launches by the end of next year expanding I honest has reached to even more patients.

Brett Monia: With preparations well underway, we are confident that Zilganirsa can provide a first-in-class disease-modifying treatment option for patients and caregivers and opens the door to further strengthen our foundation as we advance our leading neurology pipeline. Our experienced commercial organization is already delivering strong results, as reflected in the early momentum of both Tringola and Donsera. Building on this success, we remain focused on maximizing the full potential of these therapies while preparing to execute two additional launches by the end of next year, expanding Ionis Pharmaceuticals' reach to even more patients in need of our medicines. With that, I will now turn it over to Beth.

Additionally, we will be working to ensure treatment availability at appropriately equipped centers.

With preparations. Well underway. We are confident that. Zila. Nursing can provide a first in class disease, modifying treatment option for patients and caregivers and opens the door to further. Strengthen our foundation, as we advance our leading neurology pipeline,

In need of our medicines with that I'll now turn it over to Beth.

We delivered another strong quarter, driven by continued commercial execution and disciplined financial management.

Our experienced commercial organization is already delivering strong results as reflected in the early momentum of both. Tran Goa and danzo.

Enables us to raise our financial guidance once again.

Our results reflect accelerating revenue growth with strong contributions from our marketed medicines and sustained progress across our pipeline.

Elizabeth Hougen: Kyle, we delivered another strong quarter driven by continued commercial execution and disciplined financial management, which enables us to raise our financial guidance once again. Our results reflect accelerating revenue growth with strong contributions from our marketed medicines and sustained progress across our pipeline. We remain focused on executing our strategy, advancing our late-stage portfolio, and maintaining the financial strength that enables us to invest in future growth. In the third quarter, we generated $157 million in revenue, representing a 17% increase year over year. For the first nine months of this year, revenue totaled $740 million, an increase of 55% compared with the prior year. As you heard from Kyle, the Tringola launch continues to perform exceptionally well. We earned $32 million in product sales, representing a nearly 70% increase over the second quarter.

Building on this success, we remain focused on maximizing the full potential of these therapies while preparing to execute two additional launches by the end of next year. Expanding Ionis has reached even more patients in need of our medicines. With that, I'll now turn it over to Beth.

We remain focused on executing our strategy advancing our late stage portfolio and maintaining the financial strength and enables us to invest in future growth.

In the third quarter, we generated $157 million in revenue, representing a 17% increase year over year.

We delivered another strong quarter driven by continued commercial execution, and disciplined financial management, which enables us to raise our financial guidance once again.

Our results reflect accelerating revenue growth with strong contributions from our marketed medicines and sustained progress in our pipeline.

For the first nine months of this year revenue totaled $740 million, an increase of 55% compared with the prior year.

As you heard from Kyle of the <unk> launch continues to perform exceptionally well.

Portfolio and maintaining the financial strength and enables us to invest in future growth.

Earned $32 million in product sales, representing a nearly 70% increase over the second quarter.

In the third quarter, we generated $157 million in revenue, representing a 17% increase year-over-year.

Royalty revenues increased by approximately 13% to $76 million into third quarter anchored by meaningful contributions from both <unk> and Nossa and <unk> App.

For the first 9 months of this year Revenue totaled, 740 million in increase of 55% compared with the prior year.

As planned total non-GAAP operating expenses year to date.

As you heard from Kyle, the Trango launch continues to perform exceptionally well.

9% year over year, highlighting our commitment to disciplined investment and driving operating leverage.

Elizabeth Hougen: Royalty revenues increased by approximately 13% to $76 million in the third quarter, anchored by meaningful contributions from both Spinraza and Wainua. As planned, total non-GAAP operating expenses year to date increased 9% year over year, highlighting our commitment to disciplined investment and driving operating leverage. Our sales and marketing expenses increased year over year, driven by our investments in the U.S. launch of Tringola and Donsera. R&D expenses decreased year over year, as several of our late-stage studies recently concluded. Importantly, we continued to strategically fund our advancing pipeline with more than two-thirds of our total R&D expenses funding our late-stage programs. Based on this continued strong performance and fourth quarter outlook, we are once again increasing our 2025 financial guidance, our third consecutive increase this year.

We are in 32 million in product sales, representing a nearly 70% increase over the second quarter.

Our sales and marketing expenses increased year over year, driven by our investments in the U S launch of <unk> and <unk>.

Royalty revenues increased by approximately 13% to 76 million in the third quarter, anchored by meaningful contributions, from both spinraza, and Wayne Nua.

R&D expenses decreased year over year at several of our late stage studies recently concluded.

Currently we continued to strategically advancing pipeline with them.

As planned, total non-gaap operating expenses year to date increased 9% year-over-year, highlighting, our commitment, to disciplined investment and driving operating Leverage.

More than two thirds of our total R&D expenses funding our late stage programs.

Based on the continued strong performance and fourth quarter outlook. We are once again, increasing our 2025 financial guidance, our third consecutive increase this year.

Our sales and marketing expenses increased year-over-year, driven by our investments in the U.S. launch of tring, goza, and danzer.

R&D expenses. Decreased year-over-year as several of our late stage studies. Recently concluded.

Now expect to generate between $875 million and $900 million in total revenue for the year, an increase of $50 million versus our prior guidance.

Importantly, we continue to strategically fund our advancing pipeline with more than two-thirds of our total R&D expenses. Our late-stage programs,

Our guidance reflects meaningful contributions from our commercial portfolio, including continued strong performance of shingles. We now anticipate tangles that product sales of between 85 and $95 million for the full year.

Elizabeth Hougen: We now expect to generate between $875 million and $900 million in total revenue for the year, an increase of $50 million versus our prior guidance. Our guidance reflects meaningful contributions from our commercial portfolio, including continued strong performance of Tringola. We now anticipate Tringola product sales between $85 million and $95 million for the full year, also an increase from prior guidance. Given the timing of approval, we expect Donsera will provide a modest revenue contribution this year, with a greater impact beginning next year. We now expect an operating loss between $275 million and $300 million for the full year. This improvement includes our planned acceleration in investments to support commercial preparations for olezarsen and Zilganirsa following the strong phase 3 data and anticipated launches next year.

Based on this continued strong performance and fourth-quarter outlook, we are once again increasing our 2025 financial guidance. This marks our third consecutive increase this year.

So an increase from prior guidance.

Given the timing of approval, we expect on Derek will provide a minus strategy contribution this year, but the greater impact beginning next year.

We now expect to generate between $875 million and $900 million in total revenue for the year, an increase of $50 million versus our prior guidance.

We now expect an operating loss between 275 and $300 million for the full year.

This improvement includes our planned acceleration in investments to support commercial preparations for <unk> and silicon or thin following the strong phase III data and anticipated launches next year.

Our guidance reflects meaningful contributions from our commercial portfolio, including continued strong performance of tring goza. We now anticipate tring goals of product sales between 85 and 95 million for the full year. Also, an increase from prior guidance.

Given the timing of approval, we expect on zero will provide a modest Revenue contribution this year with a greater impact beginning next year.

Additionally, we now expect to end the year with a cash balance of more than $2 $1 billion, highlighting our strong balance sheet that will support continued investments to drive accelerating growth.

Our third quarter results demonstrate strong execution across our business.

With two product launches now under way and more on the horizon.

Elizabeth Hougen: Additionally, we now expect to end the year with a cash balance of more than $2.1 billion, highlighting our strong balance sheet that will support continued investment to drive accelerating growth. Our third quarter results demonstrate strong execution across our business. With two product launches now underway and more on the horizon, Ionis Pharmaceuticals is well positioned to deliver transformative medicines to patients in need and achieve our goal of cash flow break even by 2028, driving long-term value creation. I'll turn the call back over to Brett.

We now expect an operating loss between 20075 and 300 million dollars for the full year. This Improvement, includes our planned acceleration and Investments to support commercial preparations for Ozark and Zila. Nursing following the strong phase 3 data and anticipated launches next year.

This is well positioned to deliver transformative.

<unk> medicines to patients in need and achieve our goal of cash flow breakeven by 2028, driving long term value creation.

Additionally, we now expect to end the year with a cash balance of more than $2.1 billion, highlighting our strong balance sheet that will support continued investment to drive accelerating growth.

That I will turn the call back over to Frank Thanks Beth.

Our third quarter results demonstrate strong execution across our business.

The third quarter was marked by strong execution and accelerating momentum across our business with two independent launches underway.

<unk> pipeline progress and key regulatory milestones achieved we are delivering on our strategy.

The commercial organization continues to perform very well.

Brett Monia: Thanks, Beth. The third quarter was marked by strong execution and accelerating momentum across our business. With two independent launches underway, continued pipeline progress, and key regulatory milestones achieved, we are delivering on our strategy. The commercial organization continues to perform very well. The Tringola launch is strong, and the approval of Donsera for HAE marked another important milestone, with encouraging early feedback from physicians and patients. Positive phase 3 results for olezarsen in severe hypertriglyceridemia and Zilganirsa in Alexander disease are paving the way for two additional independent launches next year. Together, these achievements strengthen our foundation for long-term growth. With a deep pipeline, outstanding execution, and a clear path to achieve cash flow break even in 2028, Ionis Pharmaceuticals is well positioned to deliver transformative medicines for patients and accelerating value creation for shareholders.

<unk> launch is strong.

And the approval of <unk> zero for <unk> marks another important milestone with encouraging early feedback from physicians and patients.

With two product launches now underway and more on the horizon, Ionis is well positioned to deliver transformative medicines to patients in need, with a goal of cash flow break-even by 2028, driving long-term value creation. I will turn the call back over to Brett. Thanks, Beth. The third quarter was marked by strong execution and accelerating momentum across our business.

And positive phase III results for <unk> S. H T G in cylinders and Alexander disease are paving the way for two additional independent launches next year.

With two independent launches underway, we continue to pipeline progress and key regulatory milestones are achievable. We are delivering on our strategy.

Together these achievements strengthen our foundation for long term growth with a deep pipeline outstanding execution, and a clear path to achieve cash flow breakeven in 2028.

The commercial organization continues to perform very well.

The changing goals of launch is strong.

And the approval of Don Zahra for HAE marked another important milestone, with encouraging early feedback from physicians and patients.

<unk> is well positioned to deliver transformative medicines for patients and accelerating value creation for shareholders.

In positive Phase 3 results for asarone, SHTG, and Zilan in Alexander disease are paving the way for two additional independent launches next year.

Now before we move to the Q&A I'd like to take a moment to recognize and thank Richard Geary for his tremendous impact on <unk> over the past 30 years.

Together, these achievements strengthen our foundation for long-term growth.

With his retirement at the end of the at the end of this year. This will be his last earnings call with US Richard has been a driving force behind our innovation, leading dozens of development programs in guiding six transformative medicines through regulatory or regulatory approvals and to patients.

With a deep pipeline, outstanding execution, and a clear path to achieve cash flow break-even in 2028.

Brett Monia: Now, before I move to the Q&A, I'd like to take a moment to recognize and thank Richard Geary for his tremendous impact on Ionis Pharmaceuticals over the past 30 years. With his retirement at the end of this year, this will be his last earnings call with us. Richard has been a driving force behind our innovation, leading dozens of development programs and guiding six transformative medicines through regulatory approvals and to patients. His leadership, vision, and unwavering commitment to patients have been instrumental in shaping Ionis Pharmaceuticals into the company we are today. On behalf of the entire Ionis Pharmaceuticals team, I want to thank Richard for his remarkable contributions and his dedication to improving the lives of patients around the world. With that, we'll now open the call up for questions. Chuck?

Ionis is well positioned to deliver transformative medicines for patients and accelerate value creation for shareholders.

Now.

His leadership vision and unwavering commitment to patients who have been instrumental in shaping <unk> into the company we are today.

Before I move to the Q&A, I'd like to take a moment to recognize and thank Richard, Gary for his tremendous impact. On my own is over the past 30 years.

On behalf of the entire IR team I want to thank Richard for his remarkable contributions and his dedication to improving the lives of patients around the world and with that we'll now open the call up for questions Chuck.

With his retirement, at the end of this, at the end of this year, this will be his last earnings call with with us. Richard has been a driving force behind our Innovation, leading dozens of De development programs and guiding 6. Transformative medicines through regulatory regulatory approvals and to patients.

Thank you we will now begin the question and answer session.

To ask a question you May Press Star then one on your Touchtone phone.

His leadership vision and unwavering commitment to patients have been instrumental in shaping Ionis into the company we are today.

If youre using a speakerphone please pick up your handset before pressing the keys.

If at any time. Your question has been addressed and you would like to withdraw your question. Please press Star then two.

Operator: Thank you. We will now begin the question and answer session. To ask a question, you may press star one on your touch-tone phone. If you're using a speakerphone, please pick up your handset before pressing the key. If at any time your question has been addressed and you would like to withdraw your question, please press star, then two. At this time, we'll take our first question. Excuse me. We'll come from Ms. Jessica Fye with JP Morgan. Please go ahead.

Dedication to improving the lives of patients around the world. And with that, we'll now open the call up for questions, Chuck.

And at this time, we will take our first question.

Excuse me will come from MS. Jessica Fye with Jpmorgan. Please go ahead.

Thank you. We will now begin the question and answer session.

To ask a question, you may press star, then 1, on your touchtone phone.

Hey, guys. Good morning, Thanks for taking our question I was hoping you could talk a little bit about how we should think about the shape of the launch curve for <unk> S. H T G and I guess, what do you mean by that is kind of like in terms of the physicians, you're targeting and the number of patients they cover.

If you're using a speaker-phone, please pick up your handset before pressing the keys.

if at any time your question has been addressed and you would like to withdraw your question, please press star then 2

And at this time, we will take our first question.

[Analyst 1]: Hey, guys. Good morning. Thanks for taking our question. I was hoping you could talk a little bit about how we should best think about the shape of the launch curve for all the surgeons in STDs. What I mean by that is in terms of the physicians you're targeting and the number of patients they cover, do you perceive that there's pent-up demand or almost like a warehouse effect where you could see rapid adoption the way we have in this obviously much, much smaller familial chylomicronemia syndrome setting? If not, what is the right way to think about the shape of that ramp? Thank you.

Excuse me, will come from Miss Jessica fee with JP Morgan. Please go ahead.

Sure.

Do you perceive that there's.

Pent up demand or almost like a warehouse effect, where you could see rapid adoption. The way we have and this obviously much much smaller Fcs setting.

Or if not what is the right way to think about the shape of that ramp. Thank you.

Yes. Thanks, Jess this is Kyle it's a great question first I'll just mentioned that.

There is strong interest in trying to expand the use of <unk>.

And interest to use <unk> in the <unk> patient population Thats, an ongoing question that we get from Hcp's as we're interacting with them today.

Brett Monia: Yeah. Thanks, Jess. This is Kyle. It's a great question. First, I'll just mention that there's strong interest in trying to expand the use of Tringola and interest to use olezarsen in the SHTG patient population. It's an ongoing question that we get from HCPs as we're interacting with them today. Our current target population of HCPs is about 3,000 that we're reaching with our existing sales force. We're going to expand that to reach approximately 20,000 HCPs. Those 20,000 HCPs are covering approximately 360,000 patients that have SHTG. Some of those are high-risk patients, meaning above 880 or above 500 with a history of acute pancreatitis. Many of those patients are currently on standard of care treatments, so they're on fibrates and fish oils and statins and PCSK9s and other background therapies.

Hey guys. Good morning. Thanks for taking our question. I was hoping you could talk a little bit about how we should best think about the shape of the launch curve, for Asar, in shtg. And I guess what I mean by that is kind of like in terms of the, you know, Physicians you're targeting. And then the number of patients, they cover, you know, do you perceive that there's uh, you know, pent-up demand or almost like a warehouse effect where you could see you rapid adoption the way we have in this obviously much much smaller FCS setting, um, or or if not, you know, what is the right way to think about the shape of that ramp? Thank you.

Our current target population of Hcp's has about 3000 that we're reaching with our existing sales force.

Going to expand that to reach approximately 20000 Hcp's. Those 20000 hcp's are covering approximately 360000.

Patients that have <unk>. Some of those are high risk patients, meaning above 80 to 80 or above 500 with a history of AP.

Yeah, thanks, Jess. Uh, this is Kyle, um, it's a great question. Um, first I'll just uh, mention that that, uh, there's strong interest in uh, trying to expand the use of uh tring Gola um, and and interest to use as arson in the shtg patient population. It's an ongoing question that we get from hcps as we're interacting with them today.

Many of those patients are currently on standard of care treatments. So they are on five rates and fish oils and status and Pcf's guides and other background therapies. So what we are expecting is that those patients are on standard of care treatment and theyre not getting to goal today.

Um, our current Target population of hcps is about 3,000 that were reaching with our existing sales force. Um, we're going to expand that to reach approximately 20,000 hcps.

There will be interest in using <unk> in that population based on the phase III data that we generated in core and core too.

Those 20,000 HCPs are covering approximately 360,000 patients that have SHTG. Some of those are high-risk patients, meaning 880 or above, or 500 with a history of AP.

That will be the beachhead in which we will approach this and we expect we expect strong uptake based on the interest and what we've learned about the market thus far.

Brett Monia: What we are expecting is that if those patients are on standard of care treatment and they're not getting to goal today, there will be interest in using olezarsen in that population, you know, based on the phase 3 data that we generated in Q4 and Q2. That will be the beachhead in which we will approach this, and you know, we expect strong uptake based on the interest and what we've learned about the market thus far.

Thank you.

The next question will come from Gena Wang with Barclays. Please go ahead.

Thank you for taking my questions. So maybe I'll also ask one is all of safran corn.

Um, many of those patients are currently on standard of care. Treatments. So they're on 5 rates and fish oils and statins and pcsk9 and other background therapies. So, what we are expecting is that, uh, if those patients are on standard of care treatment and they're not getting to goal today, uh, that, uh, there will be interest in using as arson and not population. You know, based on the phase 3 data that we generated in core and Core 2

Yes.

Thanks, you will have update at HPE, we already have a topline data.

So that's, that will be the beach head in which, uh, we will approach this. And, uh, you know, we expect, we expect strong uptake based on, uh, the interest in what we've learned about the market thus far.

[Analyst 1]: Thank you.

Anything that would be concerning regarding see acute pancreatitis events.

Operator: The next question will come from Gina Wang with Barclays. Please go ahead.

Thank you.

[Analyst 2]: Thank you for taking my question. Maybe I will also ask one, is all the surgeons Q4 and Q2 data, since you will have updated AHA, we already have a top-line data. Anything that will be concerning regarding, say, the acute pancreatitis events? You know, if it's a, I know the rate ratio is super impressive, but you know, you did have approved two studies. Would that be anything we should pay attention to? Would that be well balanced between the Q1 and Q2 regarding the acute pancreatitis events and also any other things we should pay attention to? That was one question. The second, high level, I know you give a peak revenue potential for Donsera, over $500 million. Do you have a view regarding, say, all the surgeons and also Alexander's disease?

I know the renovations is super impressive.

The next question will come from Jina Hwang with Barclays. Please go ahead.

But you did have a pud two studies with Debbie anything will be.

Thank you for taking my questions. So maybe I will also ask, is all Assassin corn CU data.

We should be paying attention to what that would be well balanced between the core noncore to regarding that acute pancreatitis events and also any any other things we should pay attention to so that was one question in a second.

High level.

I know you gave.

Peak revenue potential for.

Zara over 500 million do you have a view regarding all of Safran and also Alexandre.

Steve.

Okay.

Let's try it does three questions, let's try to go through them quickly, but thank you. So I'll start with the IHA presentation, and I'll turn it over to Kyle for Dawn Zier and Alexander disease. So we're very much looking forward to presenting the detailed data.

American Heart Association in a prestigious late breaking.

Brett Monia: Okay. Let's try to—there's three questions. Let's try to go through them quickly, but thank you. I'll start with the AHA presentation, then I'll turn it over to Kyle for Donsera and Alexander's disease. We're very much looking forward to presenting the detailed data at American Heart Association in a prestigious, late-breaking, clinical trial session on November 8. Nothing to be concerned about. The AP data is groundbreaking. I think that people are going to really be impressed when we share the detailed data on the AP outcome, including how rapid the protection is against acute pancreatitis and how durable those effects are. Remember, this was a pre-specified statistical plan analysis of Q1 and Q2 purposefully because we wanted to ensure the maximum powering for a positive outcome, which was proven to be a very, very smart thing to do.

Uh, since you will have updated. Aha, you. We already have a Topline data, um, anything that will be concerning, uh, regarding say, the acute pancreatitis events, you know, if it's a, I, I know the rate ratio is a super impressive, uh, but you know, you did have approved, 2 studies, uh, would that be anything will be, you know? Uh, we should be paying attention to, would that be well, balanced between the core and The Core 2 regarding the, uh, acute pancreatitis events, and also any, any other things we should be paying attention to. So, uh, that was 1 question and the second, um, high level. Um, I know you give a peak Revenue, uh, potential for uh, don Zahra. Uh, over 500 million. Uh, do you have a view regarding see, all Assassin, and also Alexander, uh, disease.

Clinical trials session on November eight.

Nothing nothing nothing.

Nothing to be concerned about the AP data is is groundbreaking.

And I think that people are going to really be impressed when we shared a detailed data on that on the AP.

Including the repeated how rapid the protection is against acute pancreatitis and how durable those effects are.

Remember this was a pre specified statistical plan analysis of core and core to purposefully because.

We want to ensure.

The maximum empowering for a positive outcome, which was proven to be very very smart thing to do.

Core <unk> two have been published on the based on demographics and what you see in the baseline demographics as that.

There is a higher triglyceride median amount in core versus core too and that reflect that will reflect a few pancreatitis events. In this study two that youll see all of that data.

Um, okay, uh let's let's try to 3 questions. You know, let's try to go through them quickly, but thank you. Um, so I'll, I'll start with the AHA presentation. Then I'll turn it over to Kyle for done zero in Alexander disease. So, um, we're very much looking forward to presenting the detailed data, um, at American Heart Association in a prestigious late-breaking, um, uh, clinical trial session at on November 8th. Um, no. Don't don't nothing to be concerned about. Uh, the AP data is is uh, groundbreaking, um, and, and I think that people are going to really be impressed when we share the details data on that, on the AP, um, outcome including uh, the rapid, how rapid the protection is against acute pancreatitis and and how durable those effects are. Um, remember this was a prespecified, uh, statistical plan, analysis of core and Core 2 purpose because, um, we want to ensure that the, the, um, the maximum powering for the

Brett Monia: Q1 and Q2 have been published on the baseline demographics, and what you see in the baseline demographics is that there's a higher triglyceride median amount in Q1 versus Q2. That will reflect acute pancreatitis events in the study too. You'll see all that data at the AHA, and there's nothing else to be concerned about. We're very much looking forward to it. Again, groundbreaking results in the AHA will be a great venue. We're also encouraged with where we are in the review process for a publication. No guarantees, but we're hoping for a simultaneous publication with the presentation, if we can get that done. All the details that we can't get to in the presentation will be in the publication. Stay tuned for all that. Looking forward to it. Touch on Donsera and Alexander? Yeah. I'll just touch on peak sales for each of the programs.

At the IHA and there's nothing else to be concerned about we're very much looking forward to it.

Again brown brick groundbreaking results in the ALJ will be.

A great venue, we're also encouraged that.

And with.

Where we are in the review process for publication no guarantees, but we're hoping for a simultaneous publication.

With the presentation.

If we can get that done and then all the details that we can't get through in the presentation will be in your publication. So stay tuned for all that looking forward to it.

Touch on Dawn Zier, and Alexander I'll, just touch on the peak sales for each of the programs. So peak sales for Don's areas, you referenced are expected to be greater than $500 million.

Proven to be very, very smart thing uh to do. Um, core and Core 2, um, have been published on their ba, the Baseline demographics. And what you see in the Baseline demographics, is that, um, there's a higher triglyceride, uh, median, uh, amount in core versus Core 2 in in that reflect, that will reflect a few pancreatitis events in the study too, but you'll see all that data at at the AHA. And there's nothing else to be concerned about. We're very much looking forward to it. Um, again, Brown groundbreaking results and the AHA will be, um, a great venue. We're also encouraged that

For <unk>, our first anticipated blockbuster launch, we're expecting to be greater than $1 billion and for Alexander's disease is greater than $100 million are the expectations.

Brett Monia: Peak sales for Donsera, as you referenced, are expected to be greater than $500 million. For all the surgeons, our first anticipated blockbuster launch, we're expecting to be greater than $1 billion. For Alexander's disease, it is greater than $100 million are the expectations.

Thank you very much.

The next question will come from Mike <unk> with Morgan Stanley. Please go ahead.

With, um, where we are in the review process for a publication no guarantees. But we're hoping for a simultaneous publication, um, with the presentation, um, um, if we can get that done and then all the details that we can't get to in the presentation, will be in the publication, so stay tuned for all that. Looking forward to it, uh, touch on Don's there and and Alexander. Yeah, I'll just touch on uh, Peak sales for each of the programs. So Peak sales for donz as you referenced or expected to be greater than 500 million.

Good morning, and thanks for taking the question, maybe just a follow up on <unk> S. H D G.

Right.

Just curious if you have any updated thoughts on pricing I know this is an area where you're doing some extra work. So just curious if there's anything there to share.

[Analyst 2]: Thank you very much.

For all Lazarus and our first anticipated Blockbuster uh launched. We are expecting to be greater than 1 billion dollars and for Alexander's disease uh is greater than 100 million dollars are the expectations.

Thank you very much.

Operator: The next question will come from Mike Youls with Morgan Stanley. Please go ahead.

When we might expect a little bit more clarity on the pricing question. Thank you.

[Analyst 3]: Good morning, and thanks for taking the question. Maybe just a follow-up on all the surgeons in STDs. Just curious if you have any updated thoughts on pricing. I know this is an area where you're doing some extra work, so just curious if there's anything there to share, or if not, you know, when we might expect a little bit more clarity on the pricing question. Thank you.

The next question will come from Mike yours with Morgan Stanley. Please go ahead.

Yes. Thanks, Mike This is Karl again.

The work is ongoing and we do have the corn Corps two data the essence data and we've got a lot of work to go through with our.

Information related to ER visits hospitalization rates.

Number needed to treat which is some information that will come out at <unk> as well, so theres still a lot for us to to pull together.

Brett Monia: Yeah. Thanks, Mike. This is Kyle again. The work is ongoing. We do have the Q1 and Q2 data, the ESSENCE data, and we've got a lot of work to go through with our information related to visits, hospitalization rates, a number needed to treat, which is some information that will come out at the AHA as well. There is still a lot for us to pull together. The research will kick off, and we expect to have additional information next year for us to be able to make some decisions around in terms of final pricing recommendation.

Uh, good morning, and thanks for taking the question. Maybe just a, a follow-up on Ozark and shtg. Uh, just curious if you have any updated thoughts on pricing. I know this is an area where you're doing some extra work. So just curious if there's anything there to to share or if not, you know, when we might expect a little bit more clarity on on the pricing question. Thank you.

The research will will kick off and we expect to have additional information next year for us to be able to make some decisions around in terms of final pricing recommendation.

I think what some early signals continue to tell us and is consistent with the research that we've done in the past is that this is a market of greater than 3 million patients in that payers are going to look at this market in terms of their total exposure to potentially covering <unk> and an <unk> indication of greater than 500.

Brett Monia: I think what some early signals continue to tell us and is consistent with research that we've done in the past is that this is a market of greater than 3 million patients and that payers are going to look at this market in terms of their total exposure to potentially covering all the surgeons in an STDs indication of greater than 500 milligrams per deciliter patient population. We are still doing that work, and we will announce the final price upon the approval of the STDs indication, similar to how we've done with the FCS indication as well as the HAE indication for Donsera.

<unk> milligrams per deciliter Ah patient population. So we're still doing that work and we will announce the final price upon the approval of the <unk> indication similar to how we've done with the FCS indication as well as the <unk> indication for <unk> Zara.

Great. Thank you.

The next question will come from newer Werber TD Cowen. Please go ahead.

Yeah, thanks Mike. Uh, this is Kile again. Um, the work is ongoing, we do have the core and Core 2 Data, the essence data. Um, and we've got a lot of work to go through with our um, information related to uh, ER visits hospitalization rates, uh, number needed to treat, which is some information that will come out at aha as well. So there's still a lot for us to uh to pull together. Um, the the research will uh will kick off and we expect to have additional information next year for us to be able to make some decisions around in terms of final pricing recommendation. Um, I think what some early signals continue to tell us and is consistent with uh research that we've done in the past is that this is a market of greater than 3 million patients. And that pay payers are going to look at this market in terms of their total exposure, uh, to potentially covering all Lazarus and and and an shtg indication of greater than 500, uh milligrams per deciliter a patient population.

Great. Thanks, so much congrats on a really nice quarter and Oh, hopefully should be very good next year as well.

Couple of questions number one just for H, a when you're looking at when we're looking at the data should we be expecting that it's the reduction in AP is going to be principally in patients with a history of AP or is there a chance that you're going to show potentially of prevention of new events in patients that did not have a pea events in the past.

[Analyst 3]: Great. Thank you.

So, we’re still doing that work, and we will announce the final price upon the approval of the SATG indication, similar to how we've done with the FCS indication, as well as the HE indication for Donzero.

Great. Thank you.

Operator: The next question will come from Jeroen Worber with P.D. Cowen. Please go ahead.

[Analyst 4]: Great. Thanks so much. Congrats on a really nice quarter, and hopefully, this should be very good next year as well. A couple of questions. Number one, just for AHA, when you're looking at when we're looking at the data, should we be expecting that the reduction in acute pancreatitis is going to be principally in patients with a history of acute pancreatitis, or is there a chance that you're going to show potentially a prevention of new events in patients that did not have acute pancreatitis events in the past? Secondly, some of the other companies in the hereditary angioedema space are actually beginning to talk that there's considerably more patients in the U.S. market. I think some are mentioning as many as 11,000 patients and 75% on prophylaxis. I know you're mentioning 7,000. Maybe can you help us kind of maybe understand the difference a little bit?

The next question will come from your line of PD Cohen. Please go ahead.

And then secondly, some of the other companies in the space are actually beginning to talk that there is considerably more patients in the U S market. There I think someone mentioned and as many as 11000 patients and 75% on prophylaxis.

You're mentioning 7000, maybe can you can you help us maybe understand the difference a little bit. Thank you.

Great. Thanks so much, congrats on a really nice quarter now. Hopefully it should be very good next year as well. Um couple of questions number 1 just for aha when you're looking at when we're looking at the data, should we be expecting that? It's the reduction in AP is going to be principally in patients with a history of AP. Or is there a chance that you're going to show potentially a prevention of new events in patients that are did not have AP events in the past?

Sure your own. Thank you for the question Paul will address.

Market research and the prevalence of <unk> in the U S.

Regarding H E E.

H American Heart Association meeting.

<unk>.

So again I don't want to get ahead of the details your own but what else what I can say is this.

[Analyst 4]: Thank you.

Brett Monia: Sure, Jeroen. Thank you for the question. Kyle will address the market research and the prevalence in hereditary angioedema (HAE) in the U.S. Regarding HAE, I mean, American Heart Association meaning AHA. I don't want to get ahead of the details, Jeroen, but what I can say is this. All of the research that has been done over the decades has indicated that the higher the triglycerides, the more acute pancreatitis (AP) events that you're going to get in a study, and that's exactly what we've seen in our study. The higher the triglycerides, the more AP events you're going to get in the study. That will correspond to the data that we present at AHA, which is going to be in the patients not only with AP above 880, also consistent with research. If you've had an AP prior event, your chances of having another one is higher.

And then secondly you know, some of the other companies in the Hae space are actually beginning to talk that um, there's considerably more patients in the US market. They're I think some are mentioning as many as 11,000 patients and uh, 75% on prophylaxis. Um, I know you're mentioning 7,000 maybe can you can you help us? Kind of maybe understand the difference a little bit. Thank you.

All of the research has been done over the decades has indicated that the higher the triglycerides the more AP events that youre going to get in.

In our study and that's exactly what we've seen in our studies show the higher the triglycerides, the more IP events youre going to get in the study and that will.

Will correspond to the data that we presented IHA or does it going to be in.

Patients not only with.

<unk>.

AP above AAV also consistent with research if you've had an AP prior vendor chances of having another one is higher so that is consistent with the data that we will present a J. So you can see a lot of you're going to see more events in the high risk patient population as you would expect there's no surprises here and that's actually very comforting because that means that all the work that we've done.

Done all the research we've done it is holding up and triglycerides are driving these events.

Brett Monia: That is consistent with the data that we will present at AHA. You're going to see more events in the high-risk patient population, as you would expect. There's no surprises there. That's actually very comforting because that means that all the work that we've done, all the research we've done, it's holding up, and triglycerides are driving these AP events. Kyle? Yeah. In terms of the prevalence in the U.S., we're still working off of the 7,000 estimated patients in the U.S. That's the information that we've documented and been able to work from up to this point. You've referenced that about 75% of those patients are on a current prophylactic therapy today. This is a switch market, and that's really the market that we're focused on, moving patients over that could potentially do better on a therapy with a profile like Donsera.

Yes in terms of the prevalence in the United States, We're still working off of the 7000 estimated patients in the U S.

The information that we've documented and be able to work from up to this point.

You referenced that about 75% of those patients are on a current prophylactic therapy today and so this is a switch market and thats really the market that we're focused on is moving patients over that could be doing and potentially do better on.

Consistent with research. If you've had an AP prior event, your chances of having another 1 is higher. So that is consistent with the data that we will present. Aha. So you're going to see a lot of you're going to see more events in the high risk patient population as you would expect. So there's no surprises there and that's actually very comforting because that means that all the work that we've done, all the research, we've done is holding up and triglycerides are driving these AP events.

On a therapy with the profile like <unk> Zara and there are some patients that were on demand therapy patients only that have added done zero up to this point and we will also get newly diagnosed patients as you're referencing but I'm.

I'm not aware of an 11000 number we're still working off of the 7000 population that has been addressable up to this point.

Brett Monia: There are some patients that were on-demand therapy patients only that have added Donsera up to this point. We'll also get newly diagnosed patients, as you're referencing. I'm not aware of an 11,000 number. We're still working off of the 7,000 population that has been addressable up to this point. Jeroen, I'd like to come back to your first question too. At one point I didn't make that I think is very important is to remember that the AP data that we have generated in Q1 and Q2 is after only 12 months of treatment, right? When you think about a cardiovascular outcome trial, when you're looking at outcome data, it's years of treatment. This is only 12 months. We expect there to be even more AP events eventually in all segments of the STDs population with longer-term observation, longer-term treatment.

Your own I'd like to come back to your first question too.

One point I didn't make that I think is very important is to remember that the data that we have generated in core and core to us. After only 12 months of treatment right. So when you think about a cardiovascular outcome trial when you're looking at outcomes data. Its years of treatment. This is only 12 months. So we expect there'll be.

Okay. Yeah, in terms of the the prevalence in the United States. So we're still working off of the 7,000 estimated patients in the US. That's uh, the information that we've documented and be able to work from up to this point. Um, you've referenced that about 75% of those patients are on a current prophylactic therapy today and so this is a switch market and that's really the market that we're focused on is moving patients over. That could be doing potentially do better on uh on a on a therapy with a profile like Don zero and uh there are some patients that were on demand therapy patients, only that have added Don Zahra up to this point and uh, we'll also get newly diagnosed patients as your referencing. But um, yeah, we're I'm not aware of an 11,000 number. We're still working off of the 7,000 population that has been addressable up to this point.

Even more AP events eventually in all segments of the population with longer term.

Observation longer term treatment.

This is a relatively short study, which is major makes our results even more remarkable.

The next question will come from Gary Nachman with Raymond James. Please go ahead.

Thanks, and congrats on all the progress.

Brett Monia: This is a relatively short study, which makes our results even more remarkable.

So <unk> accelerated really nicely in the third quarter, where most of those additional FCS patients coming from so how many physicians are prescribing right now and maybe describe the percent genetics versus clinical that are diagnosed and based on your full year guidance you had that acceleration slowing.

And in your own, I'd like to come back to your first question too. Um, you know, at 1 point I I didn't make that I think is very important is to remember that the AP data that we have generated in core and Core 2 is after only 12 months of treatment, right? So you know, when you think about a cardiovascular outcome trial when you're looking at outcome data, it's years of treatment, this is only 12 months. So um we expect there to be even more AP events. Eventually in all segments of the fhcg population with longer term um observation longer term treatment. So this is a relatively short study which is makes our results even more remarkable.

Operator: The next question will come from Gary Nockman with Raymond James. Please go ahead.

[Analyst 5]: Thanks, and congrats on all the progress. Tringola accelerated really nicely in the third quarter. Where are most of those additional FCS patients coming from? How many physicians are prescribing right now? Maybe describe the % genetic versus clinical that are diagnosed. Based on your full-year guidance, you had that acceleration slowing a bit in the fourth quarter. Is there any good reason for that? Could you explain that? On the all the surgeons filing for severe high trigs, any chance you can get a priority review for it, especially if it's going to be lowering the cost of the drug significantly? You're still working through that, but it would be a significant drop. I don't know if that's an argument that could be made to get it on the market sooner. Thank you.

The next question will come from Gary knockmany.

A bit in the fourth quarter is there any good reason for that could you explain that.

And then just on the <unk> filing for severe high trigger any chance you can get a priority review for it.

Especially if it's going to be lowering the cost of the drive significantly I mean, youre still working through that but it would be a significant drop so I don't know if thats an argument that could be made to get it on the market sooner. Thank you.

Thanks and congrats on all the progress. Uh, so Trula accelerated really nicely in the third quarter, where are most of those additional FCS patients coming from. So how many Physicians are prescribing right now and maybe describe the percent genetics versus clinical that are diagnosed and and based on your full year guidance, you have that acceleration slowing a bit in the fourth quarter. Um, is there any good reasons for that? Could you explain that?

Gary I will take the second question first and Carl can address the.

Your question about your Ingalls.

So our.

Our assumptions right now or is a standard review supplemental NDA by the end of the year 10 month review. However, we will do we will.

We'll pursue all avenues to potentially bring this medicine to the market as quickly as possible.

Brett Monia: Gary, I'll take the second question first, and then Kyle could address your question about Tringola. Our assumptions right now are a standard review, supplemental NDA by the end of the year, 10-month review. However, we will pursue all avenues to potentially bring this medicine to the market as quickly as possible. Stay tuned for that. Right now, we're assuming a 10-month review. We don't see any reason why it couldn't be considered for other paths forward with regulators. In terms of the FCS patient population, there are a couple of things that we've been doing. Number one is identification of patients, and you move them through the diagnosis and then the prescription. We focused on those highest prescribing STDs physicians, the first 3,000 that we've been working through throughout the balance of this year.

Um, and then, just on the Asar since filing. For Severe High Triggs, any chance you can get a priority review for it? Especially if it's going to be lowering the cost of the drug significantly. I mean, you're still working through that, but it would be a significant drop. So I don't know if that's an argument that could be made to get it on the market sooner. Thank you.

So stay tuned for that but right now we're assuming a 10 month review and we don't see any reason why it couldnt be considered for other.

Are there other paths forward with regulators yes.

Yes in terms of the FCS patient population there are a couple of things that we've been doing number one is identification of patients and then you'd move them through the diagnosis and then.

Prescription.

We focused on those highest prescribing SHT G physicians.

<unk> 3000 rate that we've been working through throughout the balance of this year.

Um, Gary, I'll take the second question. Um, first and Kyle could address the, um, you know, the, your question about tring goals that. Um, so, um, our assumptions right now are is a standard review, supplemental NDA by the end of the year, 10 months review. However, we will do, uh, we, we will pursue all avenues to potentially bring this medicine to the market as quickly as possible. Um, so stay tuned for that, but right now, we're assuming at 10 months review, we don't see any reason why it couldn't be considered for for other, you know, other other paths uh forward with regulators.

Also supplemented that with some of our marketing and our omnichannel capabilities to drive more disease state awareness and understanding about the need to treat patients with high triglycerides and specifically.

How to assess and diagnose Fcs.

The clinical scoring tools, either north America, or FCS, scoring tool or the mulan criteria are.

Brett Monia: We've also supplemented that with some of our marketing and our omnichannel capabilities to drive more disease state awareness and an understanding about the need to treat patients with high triglycerides and specifically how to assess and diagnose FCS. The clinical scoring tools, either the North America FCS scoring tool or the MULAN criteria, are also driving the clinical diagnosis ability for these HCPs. They're looking for these patients. They know these patients are in need. They want to get them out of harm's way of acute pancreatitis, and they're using the available tools and resources to either clinically confirm or genetically confirm these patients. The other thing I'll mention is on the payer dynamics, the policies are getting put in place to where it's a streamlined process for HCPs to be able to prescribe once they've made the diagnosis for FCS.

Are also driving the clinical diagnosis ability for these hcp's. So theyre looking for these patients. They know these patients are in need they want to get them out of harm's way of acute pancreatitis and theyre using the available tools and resources to either clinically confirm or genetically confirmed these patients.

Yeah. In terms of the FCS uh, patient population, there are a couple of things that we've been doing. Uh number 1 is, is identification of patients and you've moved them through the diagnosis and then uh, the prescription, um, we focused on those highest prescribing. Uh, shtg Physicians. The, the first 3,000, right. That we've been working through throughout the balance of this year, um, and we've also supplemented that with some of our marketing and our Omni Channel capabilities to drive more disease, data, awareness. And an understanding about, uh, the need to treat patients with high.

The other thing I'll mention is on the payer dynamics the policies are getting put in place.

Where it's a streamlined process for HCP to be able to prescribe once they've made the diagnosis for FCS So I won't get into specific numbers around hcp's or the split between genetic and clinical confirmation.

What's going well as disease education is improving the awareness of the need to treat continues to go up and.

<unk> is performing very well when hcp's are using it and they're looking for more appropriate patients in order to treat with shrink goals because of the performance of the drug.

Brett Monia: I won't get into specific numbers around HCPs or the split between genetic and clinical confirmation. What's going well is disease education is improving. The awareness of the need to treat continues to go up. Tringola is performing very well when HCPs are using it, and they're looking for more appropriate patients in order to treat with Tringola because of the performance of the drug.

Q4 <unk>.

For Q4.

It's.

Don't want to say, it's a slowdown we took a look at a couple of things. One thing is is the duration. It's 10 weeks as opposed to 13 weeks because we've got the holidays in there.

And also we don't know the seasonality yet if there is some implications here at the end of the year. Because this is our first full year of the <unk>.

[Analyst 5]: Q4?

Brett Monia: For Q4, I don't want to say it's a slowdown. We took a look at a couple of things. One thing is the duration. It's 10 weeks as opposed to 13 weeks because we've got the holidays in there. Also, we don't know the seasonality yet, if there's some implications here at the end of the year because this is our first full year of the Tringola launch. We're just making sure that we're taking into account some of the unknowns as we're considering the guidance for the quarter.

Improving the awareness of the need to treat continues to go up. And the trend goes as performing very well when HCPs are using it and they're looking for more appropriate patients in order to treat with Tran Gosa because of the performance of the drug.

<unk> launch so we're just making sure that we're taking into account some of the unknowns as we are considering the guidance for the quarter.

Okay.

Alright, great. Thank you and best of luck to you Richard on your retirement.

Okay.

Thank you.

The next question will come from Jason <unk> with Bank of America. Please go ahead.

Hey, guys.

Thanks for taking my questions just two for me.

[Analyst 5]: All right. Great. Thank you. Best of luck to you, Richard, on your retirement.

Q4, oh, for Q4. Um, it's, uh, I don't want to say it's a slowdown. We took a look at a couple of things. One thing is, uh, is the duration; it's 10 weeks as opposed to 13 weeks because we've got the holidays in there. Um, and then also, we don't know the seasonality yet if there's some implications here at the end of the year because this is our first full year of, uh, of the Trinica launch. So, you know, we're just making sure that, uh, we're taking into account some of the unknowns as, uh, as we're considering the guidance for the quarter.

I had a cardio transform next year I just wonder.

Get your latest thoughts.

[Analyst 3]: Thank you.

All right. Great, thank you. And, uh, best of luck to you, Richard, on your retirement.

How do you maybe maximize the benefit of.

Operator: The next question will come from Jason Gerberi with Bank of America. Please go ahead.

The data in combination with the famine if it.

If it hits that.

[Analyst 5]: Hey, guys. Thanks for taking my questions. Just two for me. I had a cardio transform next year. I just want to get your latest thoughts. How do you maybe maximize the benefit of the data in combination with Tafamidis if it hits stats to the disproportionate benefit of Epler and Tersen and that there isn't sort of a free-riding effect that happens for your competitor as it pertains to sort of the validated benefit of the silencers and stabilizers together? That's question one. Then just question two, into AHA and the update on NNT. Just wondering if you can contextualize, you know, as we think about the NNT both in the all-comer and the high-risk group.

Question will come from Jason jerary with Bank of America? Please go ahead.

Two the disproportionate benefit of Epsilon person and that there isn't sort of a free riding effect that happens for your competitor as it pertains to sort of the validated benefit of silence <unk> and stabilizers together.

Hey guys. Uh, thanks for taking my questions. Um, there's 2 for me, uh, ahead of cardio transform next year. I just want to, you know, get your latest thoughts.

So that's question one and then just a question too.

And to a J and the update on M T.

Wondering if you can contextualize.

As we think about the <unk> both in the all comer and the high risk group.

<unk>.

If obviously the <unk> is more compelling than the high risk group, but that's a small proportion of the overall population.

How how do you maybe maximize the benefit, um, of of the data in combination with the famine? As if it if it hits stats um, to the disproportionate benefit of eplanters. And and that there isn't sort of a free riding effect that happens for your competitor as it pertains to sort of the validated you know benefit of

How important that is that to the overall kind of value proposition in the eyes of payers in your from your perspective.

Thanks, Thanks, Jason.

On cardio transform.

[Analyst 5]: You know, if obviously the NNT is more compelling in the high-risk group, but that's a small proportion of the overall population, how important that is to the overall kind of value proposition in the eyes of payers from your perspective?

As you know.

The largest study ever conducted in.

GTR cardiomyopathy by far and we will have the largest.

The amount of data.

For combination usage as well as monotherapy usage in the study.

Brett Monia: Thanks, Jason. You know, on CardioTransform, as you know, it's the largest study ever conducted in TTR cardiomyopathy, I mean, by far. We will have the largest amount of data for combination usage as well as monotherapy usage in this study. The combination usage is a key secondary endpoint in the statistical plan for CardioTransform as well. You know how important, how valuable that will be once we launch eplontersen in TTR cardiomyopathy is to be seen, to be determined. Obviously, the mechanisms are highly complementary in theory, and we expect to see added benefit over monotherapy in the study, but that remains to be seen and proven. If anyone is going to be able to show a benefit of combination usage and for that to drive value and resulting in driving value for the commercial opportunity for eplontersen, it'll be this program.

Of of silencers and stabilizers together. Uh, and so this question 1, and then just question 2, um, into Aha. And in the update on nnt, just wondering if you can contextualize, um, you know, as we think about the nnt, both in the all Comer and the high-risk group um, you know if if obviously the nnt is more compelling in the higher risk group but that's a small proportion of the overall population, uh, how important that is, is that to the overall kind of, uh, value proposition in the eyes of payers and your, from your perspective.

And.

The combination usage is a key secondary endpoint in the statistical plan for cardio transform and.

Well so.

How important how valuable that will be.

Once we launch <unk> in GTR cardiomyopathy is to be seen to be determined obviously the mechanisms are highly complementary in theory, and we expect to see added benefit over over monotherapy study with that remains to be seen and proven but if anyone is going to be able to show.

A benefit of combination usage.

And for that to drive value and resulting in driving value for the commercial opportunity for <unk> and it'll be it'll be this program I don't want to comment on whether that provides.

<unk> for other competitor programs and those sorts of things we're focused on at one person and we think we have the right trial design the right drug and we're very much looking forward to the data in the second half.

Um, thanks, thanks Jason. Um, you know, on cardio transform, um, as you know, uh, it's the largest study ever conducted, um, in TTR cardiomyopathy. I mean by far and we will have the largest, uh, amount of data, um, for combination usage as well as monotherapy usage in the study. Um, and, um, you know, the, the combination usage is a key, secondary endpoint in the statistical plan for a cardio transform and, um, as as as well. So, you know how important, um, how valuable that will be. Uh, once we launched e-pilen person in, in, uh, TTR code of myopathy, is to be seen to be determined. Obviously, the mechanisms are highly complimentary in theory, and we expect to see added benefit over over monotherapy in the study with that. Remains to be seen and proven. But if anyone is going to be able to show

Over the next year.

We will be sharing some data on anti indifferent subgroup populations and SHT G. IHA and if we can get a simultaneous publication as well I think the results are going to be strikingly positive in both groups or all the subgroups that we've looked at.

Brett Monia: I don't want to comment on whether that provides tailwinds for other competitor programs, those sorts of things. We're focused on eplontersen, and we think we have the right trial design, we have the right drug, and we're very much looking forward to the data in the second half of next year. We will be sharing some data on NNT in different subgroup populations in STDs at the American Heart Association, and if we can get a simultaneous publication as well. I think the results are going to be strikingly positive in both groups or in all the subgroups that we've looked at. I don't want to get ahead of that data at this time, Jason. As far as the value for payers, I'll leave it to Kyle to comment on that. Yeah.

But I don't want to get ahead of that data at this time.

Jason as far as the value for Payors or maybe the Kyle can comment, yes, I want to comment on the totality of the data and the evidence is stacking up for core and core to and how that will will be interpreted by the payers rate reductions in triglyceride levels to the magnitude that we're seeing of up to 72% for example.

On top of standard of care.

These are patients that are being treated already that arent getting to goal that aren't getting out of harm's way.

Brett Monia: I want to comment on the totality of the data and how the evidence is stacking up for Q1 and Q2 and how that will be interpreted by the payers, right? Reductions in triglyceride levels to the magnitude that we're seeing of up to 72%, for example, on top of standard of care. These are patients that are being treated already that aren't getting to goal, that aren't getting out of harm's way of acute pancreatitis on the current standard. By adding olezarsen, you're seeing significant reductions in triglycerides. An 85% reduction in acute pancreatitis is really incredible to see. Payers, I think, will react accordingly when they see that data. Hospitalizations and visit data, the NNT data will just add value and will complement that. It'll talk about some of the subpopulations.

Um, a benefit of combination usage, um, and and for that to drive value and and resulting in driving value for, you know, the commercial opportunity for e-pilen tours. And it'll be, it'll be this program. I don't want to comment on whether that provides, um, you know, Tailwind for other competitor programs. And those sorts of things we're focused on on Atlantic, and we think we have the right trial design, we have the right drug. And we're very much looking forward to the data in the second half of of, of, of the next year. Um, we will be sharing some data on nnt in different subgroup populations in shtg at Aha. And and if we can get a simultaneous publication as well, I think um the results are are are going to be strikingly positive in both groups or all the subgroups that we've looked at. But I don't want to get ahead of that data at this time as um, um, Jason as far as the value for payers, I'll, I'll leave it to Kyle to comment on that.

Of AP on the current standard and by adding.

<unk> youre seeing significant reductions in triglycerides, and 85% reduction in acute pancreatitis.

<unk>.

It's really incredible to see and payers I think we'll we'll react accordingly, when they see that data hospitalizations and ER visit data. The <unk> data will just add value and will complement that it will talk about some of the sub populations, but overall I think the quality in the totality.

Yeah, I would I want to comment on the totality of the data and and how the the evidence is stacking up for core and Core 2 and how that will will be interpreted by the payers, right? Reductions in triglyceride levels to the magnitude that we're seeing of up to 72%, for example, on top of standard of care. Uh so these are patients that are being treated already that aren't getting to goal that aren't getting out of Harm's Way um, of AP on the current standard and by adding a Lazarus and you're seeing significant reductions in triglycerides

The data here is what's going to drive payer engagement and <unk>.

<unk> reimbursement here keep in mind that the focus here is to prevent a first AP attack from ever occurring.

Hcp's.

Stand that the guidelines represent that and hep's or trying to treat to goal and they just can't with the current existing therapies that are out there. The other thing that I'll mention is these are fasting triglyceride levels and youre going to have post granule spikes in these patients.

Brett Monia: Overall, I think that the quality and the totality of the data here is what's going to drive payer engagement and effective reimbursement here. Keep in mind that the focus here is to prevent a first AP attack from ever occurring. HCPs understand that. The guidelines represent that. HCPs are trying to treat to goal, and they just can't with the current existing therapies that are out there. The other thing that I'll mention is these are fasting triglyceride levels, and you're going to have postprandial spikes in these patients, you know, even if they are between 500 and 880, that increases their risk of having an acute pancreatitis event. That whole story and the comprehensive nature of the data that I just talked through, I think, is going to be the value story and the proposition for the payers. Thanks, guys.

Even if they are between 580 <unk> that increases their risk of having an acute pancreatitis events, so that whole story and the comprehensive nature of the data that I. Just just talked through I think is going to be the value sorry in the proposition for the payers.

Thanks, guys.

The next question will come from <unk> with Wells Fargo Securities. Please go ahead.

Oh, great. Thanks for taking our questions and congrats on the quarter.

Maybe a couple of questions one on <unk> launch one.

We knew.

Totality of the data here is what's going to drive uh payer engagement and and uh you know effective reimbursement here. Keep in mind that the the focus here is to is to prevent a first AP attack from ever occurring and uh hcp's understand that the guidelines represent that and hcps are trying to treat the goal. And they just can't with the current existing therapies that are out there. The other thing that I'll mention is these are fasting triglyceride levels and you're going to have postprandial spikes in these patients. Uh, you know, even if they are between 500 and 880, that increases their risk of having an acute pancreatitis event, so that whole story and that the comprehensive nature of the data that I just uh just talked through, I think is going to be the value. Sorry in the proposition for the payers

Can you give.

Operator: The next question will come from Yunenzu with Wells Fargo Securities. Please go ahead.

Thanks guys.

A little more color on the early prescription for Zara.

Are these from switching patients who are newly diagnosed patients and switching patients any pattern of the previous therapy.

[Analyst 2]: Oh, great. Thanks for taking our questions and congrats on the quarter. Maybe a couple of questions, one on Donsera launch, one on Wainua. Can you give a little more color on the early prescriptions for Donsera? Are these from switching patients or newly diagnosed patients? If it's switching patients, any pattern of the previous therapy? For Wainua, there's also a sizable bump in the polyneuropathy revenue. Looks like 25%. Is that due to the growing of the market via newly diagnosed patients, or is that reflecting you taking share? Any updated metrics like new-to-brand numbers? Thank you.

The next question will come from Yunnan zoo with Wells Fargo Securities. Please go ahead.

Four we knew.

There's also a sizable bump.

In in the Polyneuropathy revenue.

It looks like 25%.

Is that due to the growing of the market via newly diagnosed patients or is that reflecting you taking share.

And any updated metrics like new to brand numbers. Thank you.

Oh, great. Thanks for taking our questions and congrats on the quarter, uh, may, maybe a a couple of questions 1 on donera launch when on uh, renua. Um, can you give more a little more color on the early prescriptions for for down Zahra? Um, are you from um, switching patients or newly diagnosed patients? And if it's switching patients to any pattern of the previous therapy, um, for we knew, uh, uh, there's also a sizeable bump, uh,

I'll start with the <unk> Zara launch first it's going very well as were highlighted in the opening comments, both HCP and payers that feedback has been very positive.

Commercial team has executed extremely well getting product in the channel getting the first prescriptions and getting those patients on to treatment and.

In the partner, opsy Revenue. Uh, looks like 25%, um, is that due to the growing of the market via newly diagnosed patients? Or is that reflecting? Uh you taking share? Um, and any updated metrics uh, like new to Brand numbers. Thank you.

Brett Monia: Yeah. I'll start with the Donsera launch. First, it's going very well, as were highlighted in the opening comments. Both HCPs and payers, the feedback has been very positive. The commercial team has executed extremely well, getting product into channel, getting the first prescriptions in, getting those patients onto treatment, and patients self-administering with Donsera. The launch is going very well. It's very early, right? I mean, the PDUFA was August 21. We're a month or so into this launch. I don't want to provide too many details or specifics at this point in time, but I'll just share with you that the receptivity by HCPs has been very strong.

In patient self administering with Don Zara. So the launch is going very well, it's very early right I mean, the <unk> was August 21st.

Our month to month or so into this launch so I don't want to provide too many details or specifics.

At this point in time, but I'll just share with you that.

The receptivity by Hcp's has been very strong the profile of the drug the data to support it the label and specifically the switch data.

Has been very valuable so that they can understand that they can move these patients over safely and effectively and get them started on dawn Zara and have a positive experience there using our ion us every step of patient support program.

Brett Monia: The profile of the drug, the data to support it, the label, and specifically the switch data has been very valuable so that they can understand that they can move these patients over safely and effectively and get them started on Donsera and have a positive experience there using our Ionis EveryStep patient support program. I think all signals are very positive. We are seeing switches from all of the currently approved prophylactic treatments. We're seeing Donsera added to on-demand treatments where patients weren't on a prophylactic treatment. We're seeing newly diagnosed patients as well. I won't get into the details on the splits, but all signals are very positive so far with the early signs of the launch. The bump in Wainua revenue? Yeah. The bump in Wainua revenue, again, this is a growth market.

I think all signals are very positive we are seeing switches from all of the currently approved prophylactic treatments we're seeing.

<unk> added two on demand treatments, where patients werent on a prophylactic treatment and then we're <unk>.

The donza launch. Um first it's going very well as we're highlighted in the the opening comments. Uh, both hcps and payers the feedback has been very positive, uh, the commercial team has executed extremely well getting product into Channel. Getting the first prescriptions in getting those patients, uh, onto treatment, um, in patients, self-administering, uh, with Don Zahra. So, the, the launch is going very well. It's very early, right? I mean, the Padua was August 21st, uh, you know, we're, you know, a month month or so into this launch. So I, I don't want to provide too many details or specifics um, at this point in time, but but I'll just share with you that um, the receptivity by hcps has been very strong, the profile of the drug, the data to support it. The label and uh specifically the switch data um has been very valuable so that they can understand that they can move these patients over safely and effectively and get them started on Don Zahra and have a positive experience there.

Seeing newly diagnosed patients as well so I won't get into the details on the splits but all signals are very positive so far with the early signs of the launch.

The bump in <unk>.

Revenue, yes, the bumping window of revenue again. So this is a growth market and as we've said all along it's about new patient identification and Thats predominantly where the demand is coming from in the third quarter for <unk>.

The product's performing very well in terms of quality of life improvements.

Uh, using our ionis every step of patient support program. So I think all signals are very positive. We are seeing switches from, uh, all of the currently approved prophylactic treatments. Uh, we're seeing, uh, donza added to On Demand treatments, where patients weren't on a prophylactic treatment and then, uh, you know, we're seeing newly diagnosed patients as well. So I won't get into the details on the splits. But, uh, all signals are very positive so far with the early signs of the launch.

Access is going very strong in terms of coverage the majority of patients paying zero dollars out of pocket.

In the bumping way newa.

Brett Monia: As we've said all along, it's about new patient identification, and that's predominantly where the demand is coming from in the third quarter for Wainua. The product's performing very well in terms of quality of life improvements. Access is going very strong in terms of coverage. The majority of patients paying $0 out of pocket. We do expect continued growth with the identification of new patients, especially in the centers of excellence where these amyloidosis centers are using Wainua very broadly for the polyneuropathy indication. I think we just continue to be encouraged by AstraZeneca's execution around the launch and their focus on the program.

We do expect continued growth with the identification of new patients, especially in the centers of excellence.

These amyloidosis centers.

<unk> are using way new up very broadly for the Polyneuropathy indication and.

We just continue to be encouraged by Astrazeneca is execution around the launch and their focus on the program.

Great. Thank you.

The next question will come from mouse military with William Blair. Please go ahead.

Hi, Thanks for taking the question first off congratulations to Richard on his retirement thoroughly deserved.

The question is on hepatic fat fraction deiter in the KOL studies and if you can comment on that and if it was said I've just been getting some questions considering you've got.

Operator: Great. Thank you. The next question will come from Mallesminter with William Blair. Please go ahead.

Yeah, the bumping Way, new Revenue again. So this is a growth market. And, uh, you know, as we've said all along it's it's about new patient identification. And that's predominantly where, uh, the demand is coming from uh, in the third quarter for way newa. Um, the products performing very well, uh, in terms of quality of life, um, improvements, um, access is going very strong in terms of coverage. The majority of patients paying zero dollar out of pocket. Um, you know, we do expect uh, continued growth, uh, with the identification of new patients, uh, especially in the centers of excellence. Uh, where these amaly dosis centers are, uh, are using way newa, very broadly for the poly neuropathy indication. And, uh, I I think we just continue to be encouraged by astroica execution, around the launch and their focus on the program.

Great. Thank you.

Robust serum triglyceride reductions there whether you something it might be three months it will differ at any one time and it's accumulating there.

[Analyst 2]: Hi. Thanks for taking the question. First off, congratulations to Richard on his retirement, thoroughly deserved. The question is on hepatic fat fraction data in the core studies and if you can comment on that and if we'll see it. I've just been getting some questions considering you've got, you know, robust serum triglyceride reductions there, whether you're shunting, you know, maybe too much to the liver at any one time and it's accumulating there. I'm also acutely aware that you have the Waylivra data presented that actually showed reductions in hepatic fat fraction. Any sort of color on that metric would be helpful. Thanks.

The next question will come from mentor with William Blair. Please go ahead.

Sorry, acutely aware that you have to widely for data presented that actually showed reductions in hepatic fat fraction. So any sort of color on that metric would be helpful. Thanks.

Hi. Thanks for taking the question. Uh, first off. Congratulations to uh Richard on his retirement thoroughly deserved. Um

Yeah, Myles I don't want to get ahead of the IHA presentation, because that is a secondary endpoint. So it will be it will be covered in the presentation and publication.

The question is on hepatic fat fraction data in in the core studies, and if you can comment on that and if we'll see it, I've just been getting some questions. Considering you've got, you know,

So we're going to present.

We're going to do a deep dive a J on the primary endpoint of triglyceride lowering including both doses through 12 months time courses and those that kind of thing you will see the durability of triglyceride reductions you'll see details on the acute pancreatitis, which is a secondary endpoint and youll see all the data.

Brett Monia: Yeah. Miles, I don't want to get ahead of the AHA presentation because, you know, that is a secondary endpoint, so it will be covered in the presentation and publication. We're going to present, we're going to do a deep dive at AHA on the primary endpoint of triglyceride lowering, including both doses through 12 months, time courses, that kind of thing. You'll see the durability of triglyceride reductions. You'll see details on the acute pancreatitis, which is a secondary endpoint. You'll see all the data listed out on all the secondary endpoints, including hepatic fat fraction. We'll also talk a little bit about the NNT that we touched on in the earlier question. I don't want to get ahead of that. We're just a couple of weeks away from AHA, and let's just leave it there.

The white live for a data presented that actually showed reductions in HPAT fractions. So, any sort of color on that metric would be helpful. Thanks.

Listed out.

All of the secondary endpoints, including hepatic fat.

That traction will also talk a little bit about the <unk> that we touched on earlier in the earlier question. So I don't want to get ahead of that.

A couple of weeks away from a J.

Let's just leave it there.

Alright. Thanks.

The next question will come from Luca <unk> with RBC. Please go ahead.

Oh, great. Thanks, so much for taking my question and then Richard Congrats on a fantastic run them all the best in your next chapter there.

Maybe if I can circle back on severe Hopkins with readymade, Kyle and Beth.

[Analyst 2]: No worries. Thanks.

Yeah, miles. I don't want to get ahead of the a presentation because, you know, that is a secondary endpoint so it'll be, it will be covered in the presentation in, uh, in publication. Um, uh, so yeah, we're going to present. Um, we're going to do a deep dive at AA on the primary endpoint of triglyceride lowering, um, including both doses through 12 months time courses. And those, that kind of thing, you'll see the durability of triglyceride reductions. You'll see, um, details on the acute pancreatitis, which is a secondary endpoint. And you'll see all the data, you know, listed out on all the secondary endpoints, including the padic uh, of that fraction. We'll also talk a little bit about the nnt that we touched on Earl in the earlier question. So I don't want to get ahead of that. Let's let's just, we're just a couple of weeks away from Aha and let's just leave it there.

Operator: The next question will come from Luca Esse with RBC. Please go ahead.

You have obviously $2 billion plus peak revenue Romney opportunity for drug.

No worries. Thanks.

[Analyst 6]: Great. Thanks so much for taking my question. Richard, congrats on a fantastic run and all the best on your next chapter there. Maybe if I can circle back on severe high triglyceridemia, Kyle and Beth, you have obviously a billion-dollar-plus peak revenue opportunity for the drug. Is that conservative? The reason why I'm asking is because if the TAM is truly a million patients and the price is $20,000 per patient, which seems consistent with your commentary, that only implies like 5% penetration at peak, which again feels a little conservative to me. I would love to hear you talk about some of the assumptions that went into that $1 billion-plus number that you have articulated.

Is that conservative.

The next question will come from Luca. I see we have RBC; please go ahead.

The reason why Im asking is because of the Tam is truly a million patients. The price is $20000 of patients seem consistent with your commentary.

Holding pliers like 5% penetration of peak, which again feels a little conservative to me So love to two.

Oh great, thanks so much for taking my question and then Richard uh, congrats on a fantastic run and all the best on your next chapter there. Um, maybe if I can Circle back on, severe hot triggers for addmia, Kyle and Beth. Uh,

To hear you talk about some of the assumptions that went into that $1 billion plus number that you have articulated and then maybe sticking on severe heartburn, but what's the latest.

Thinking on whether youre going to file just the 80 milligram, which is obviously the same dose approved and FCS versus filing both the safety and the 80 milligram to give docs more options to kind of tailored to dose the patients any call Dan much appreciate it. Thanks, so much okay. Thanks, Luke I'll take the easy question.

You have obviously a billion dollar plus Peak, revenue revenue opportunity for the drug to that conservative. The reason why I'm asking is because if the Tam is truly a million patients, the price is $20,000 for patients, which seem consistent with your commentary that poll implies like 5% penetration of peak, which again feels a little conservative to me. So we would love to

[Analyst 6]: Maybe sticking on severe high triglyceridemia, what's the latest thinking on whether you're going to file just the 80 milligram, which is obviously the same dose approved in familial chylomicronemia syndrome versus filing both the 50 and the 80 milligram to give docs more options to kind of tailor the dose based on the needs of the patients? Any call there, much appreciated. Thanks so much.

We're filing on both doses.

to hear you talk about some of the assumptions that went into that 1 billion dollar plus uh number that you have articulated and then maybe sticking on severe heart disease. What's the latest uh,

Both doses, but great.

And we believe that dosing flexibility in the hands of cardiologists endocrinologists lipid specialists will be very well received once we get to the market.

So that's that and with respect to them.

Brett Monia: Thanks, Luca. I'll take the easy question. We're filing on both doses. Both doses look great. We believe that dosing flexibility in the hands of cardiologists, endocrinologists, and lipid specialists will be very well received once we get to the market. With respect to peak sales, Luca, I mean, you know, I keep referencing that this is a prevalent patient population, right? Greater than 3 million patients. The high-risk STDs patients, you've got approximately a million of that you were just referencing as well. I think we still have some unknowns here around the payer dynamics. We also have some unknowns around pricing dynamics in order to factor into these assumptions. You know, what we felt comfortable with, I think, going into this and have been consistent all along is greater than $1 billion in peak sales is where we've landed up to this point.

Sales, yes Luca.

I keep referencing.

Prevalent patient population right greater than 3 million patients to high risk <unk>.

Patients you've got approximately $1 million of that.

You were just referencing as well.

I think we still have some unknowns here around the payer dynamics. We also have some unknowns around pricing dynamics in order to factor entities. These assumptions, what we felt comfortable with I think going into this and have been consistent all along is greater than $1 billion in peak sales is where we've landed up to this.

Point, we're continuing to assess the market we've got a lot of good learnings from FCS as well in terms of how the launch trajectory is gone here.

Thinking on whether you're going to file, just the 80 milligram which is obviously the same bill as the proof in FCS versus filing. Both the 50 and the 80 milligram to give, uh, you know, docs more options to kind of tailor the dose based on the need of the patient. Any call their much appreciated. Thanks so much, thanks. L, I'll take the easy question. We're, we're we're filing on both doses. Um, both doses. Look great. Um, and, uh, we believe that dosing flexibility in the hands of cardiologists endocrinologists with it. Specialists will be very well received once we get to the market. So that's that and, um, with respect to, um, speak sales. Yeah, Luca, I mean, you know, I, I keep referencing the, this is a, it's a prevalent patient population, right? Greater than 3 million patients, the high risk shtg patients. You've got approximately a million of that, that you were just referencing as well. Um, I I think we still have some unknowns here.

Doing more market research to understand.

And payer and patient perceptions.

Around the <unk> marketplace, and we will provide updated information as we learn more and feel more comfortable and confident with the way the information come together, but yes.

Brett Monia: We're continuing to assess the market. We've got a lot of good learnings from FCS as well in terms of how the launch trajectory has gone here. We're doing more market research to understand HCP and payer and patient perceptions around the STDs marketplace. We will provide updated information as we learn more and feel more comfortable and confident with the way the information comes together. Yeah, it's greater than $1 billion is where we feel comfortable today.

Yes, it's greater than a $1 billion is where we feel comfortable today.

Hi, Thanks, so much guys.

Your next question will come from Jay Olson with Oppenheimer. Please go ahead.

Oh, Hey, congrats on all the progress and I'll add my best wishes to Richard as well.

Beth I know you commented a little bit about this on your opening remarks, but with your strong balance sheet could you share your priorities for capital allocation, especially with regards to any.

[Analyst 6]: Thanks so much, guys.

Uh, the payer Dynamics, we also have, uh, some unknowns around pricing Dynamics. Uh, in order to factor into these, uh, these assumptions. You know what, we felt comfortable with, I think going into into this, uh, and have been consistent all along, is greater than a billion in Peak sales, is where we've landed up to this point. Uh, we're continuing to assess the market. We've got a lot of good learnings from FCS, as well. In terms of how the launch trajectory has gone here. Uh, we're doing more market research to understand, uh, hcp and, and payer, and patient perceptions, um, around the shtg marketplace and uh, you know, we will provide, uh, you know, updated information as as we learn more and feel more comfortable and confident with uh with the way, the information comes together but um yeah, it's greater than a billion dollars is where we feel comfortable today.

Operator: The next question will come from Jay Olson with Oppenheimer. Please go ahead.

I thanks so much, guys.

[Analyst 4]: Oh, hey, congrats on all the progress. I'll add my best wishes to Richard as well. Beth, I know you commented a little bit about this in your opening remarks, but with your strong balance sheet, could you share your priorities for capital allocation, especially with regards to any external versus internal investments? Thank you.

External versus internal investments. Thank you.

The next question will come from J. Olsen with Oppenheimer. Please go ahead.

Sure happy to.

We do have a strong balance sheet very healthy cash balance.

And that in effect with the increased guidance that will that will maintain that and as we go into next year and it continued to execute on these launches as well as the <unk> silica in Harrison launches next year.

Oh hey. Congrats on all the progress, and I'll add my best wishes to Richard as well. Um, Beth, I know you commented a little bit about this in your opening remarks, but with your strong balance sheet, could you share your priorities for capital allocation, especially with regards to any

Elizabeth Hougen: We're happy to. We do have a strong balance sheet, very healthy cash balance, and expect with the increased guidance that we'll maintain that as we go into next year and continue to execute on these launches as well as the Zilganirsa launches next year. Our top priority for capital allocation is for internal growth. We think that there's tremendous opportunity in our pipeline and behind these existing marketed products and the ones coming to market here shortly. We will continue to prioritize growth for capital allocation. We'll do that with discipline as we've done historically. That's where you should expect to see us using our balance sheet.

Um, external versus internal investments. Thank you.

Our capital our top priority for capital allocation is for our internal growth, we think that that there's tremendous opportunity in our pipeline and behind these existing marketed products and the mines coming to market here shortly so.

We will continue to prioritize growth.

Our capital allocation, we will do that with discipline as we've done historically.

Where you should expect to see us.

Using our balance sheet.

Great. Thank you.

I think we have time for one more question.

Our last question for the day will come from Mitchell Kapoor with H C. Wainwright. Please go ahead.

Hey, Thanks for taking the questions just wanted to ask.

With an impressive 90% rolling into the open label extension and the <unk> trials can you name some of the more prevalent dropout reasons.

[Analyst 4]: Great. Thank you. I think we have time for one more question.

For Capital allocations, we'll do that with discipline as we've done historically. Um, but that's what you where you should expect to see us. Um, uh, using our balance sheet.

Great. Thank you.

Operator: Our last question for the day will come from Mitchell Kapoor with H.C. Wainwright. Please go ahead.

I think we have time for one more question.

Whether there is any reasons that we should be cautious going into a launch because of some of those.

[Analyst 4]: Hey, thanks for taking the questions. Just wanted to ask, with an impressive 90% rolling into the open-label extension in the STDs trials, can you name some of the more prevalent dropout reasons and whether there's any, you know, reasons that we should be cautious going into a launch because of some of those?

Our last question for the day will come from Mitchell. Kapoor with HC Wayne Wright. Please go ahead.

Thanks Mitch.

Richard and ask answer the final question.

This earth.

Earnings call.

Any any any reasons to be concerned with dropouts in the core core two studies Richard anything you want to highlight.

Yeah. So.

Brett Monia: Thanks, Mitch. I'm going to let Richard answer the final question of this earnings call. Any reasons to be concerned with dropouts in the Q1 and Q2 studies? Richard, anything you want to highlight?

First I would say the dropout rate was about half what we expected from the beginning very well tolerated medicine.

Hey, thanks for taking the questions. Uh, just wanted to ask, uh, with an impressive, 90% rolling into the open label extension. Um, in the shtg trials, can you name some of the more prevalent Dropout reasons? And, uh, whether there's any, you know, reasons that we should be cautious going into a launch? Uh, because of some of those

There isn't actually any one.

Yes, you bet that led to discontinuation.

Eugene Schneider: Yeah. First, I would say the dropout rate was about half what we expected from the beginning. Very well tolerated medicine. There isn't actually any one issue that led to discontinuations. They varied across the study. Some of them had to do with personal reasons, moves, vacations, different things that needed to be taken care of, pregnancies, etc. I can't point to a main reason. For that reason, I'm very bullish on this medicine in terms of its tolerability and safety.

Thanks Mitch. And I'm going to let Richard and ask answer the final question of this um earnings call. Um uh any any any any reasons to be concerned with dropouts in the core Core 2 studies, Richard, anything you want to highlight

They varied across the study some of them had to do with personal reasons moves vacations different things that needed to be taken care of pregnancies Petra.

But there were so I can't point to like a main reason.

Yeah, so um first I would say the dropout rate was about half what we expected from the beginning. Very well, tolerated medicine.

And for that reason I'm very bullish on this medicine in terms of its tolerability and safety.

Great excellent. Thank you all very much and congrats Richard.

Thanks, Richard Thanks, Mitch Thanks.

Um, I would, there isn't actually any one issue that led to discontinuation. They varied across the study. Some of them had to do with personal reasons, moves, vacations, different things that needed to be taken care of, pregnancies, etc.

Thanks, everybody for joining us and participating on our call today.

We really do look forward to building on the remarkable momentum that we've achieved this year, so far and for and for years to come and sharing additional updates along the way.

[Analyst 4]: Great. Excellent. Thank you all very much. Congrats, Richard.

Um, but there were, and so, I can't point to like, a main reason. And for that reason, I'm very bullish on this medicine, in terms of its tolerability and safety.

Just as a reminder.

Brett Monia: Thanks, Richard. Thanks, Mitch. Thanks, everybody, for joining us and participating in our call today. We really do look forward to building on the remarkable momentum that we've achieved this year so far and for years to come and sharing additional updates along the way. Just as a reminder, the detailed data from the landmark phase 3 Q1 and Q2 studies for olezarsen will be presented during a late-breaking session on November 8th at the American Heart Association. We encourage you to listen in to our webcast. Until then, thanks for participating, and everybody have a great day.

The detailed data from the landmark phase III <unk> studies for <unk> and will be presented.

Great, excellent. Thank you all very much and congrats, Richard.

For <unk> will be presented during a late breaking session on November eight.

We encourage you to listen in to our webcast until then thanks for participating and everybody have a great day.

Thanks Richard. Thanks Mitch. Um, thanks everybody for joining us. Uh, in participating in our call today, we really do look forward to building on on the remarkable momentum that we've achieved this year so far and for and for years to come and sharing additional um updates along the way.

The conference has now goodbye thank.

Thank you for attending today's presentation you may now disconnect.

Operator: The conference is now concluded.

Just as a reminder uh the detailed data from The Landmark phase 3 core and core to studies for Oz, arson. Uh we'll be presented uh in essay for shg will be presented during a late breaking session on November 8th. At aha, we encourage you to listen in to our webcast until then uh thanks for participating and everybody have a great day.

[Analyst 2]: Goodbye.

Operator: Thank you for attending today's presentation. You may now disconnect.

The conference is now, goodbye.

Thank you for attending today's presentation. You may now disconnect.