Q4 2025 Arrowhead Pharmaceuticals Inc Earnings Call

Speaker #1: I will now hand the conference call over to Vince Anzalone, Vice President of Investor Relations for Arrowhead. Please go ahead.

Speaker #1: Vince.

Vince Anzalone: Thank you, Andrew. Good afternoon, and thank you for joining us today to discuss Arrowhead's results for its 2025 fiscal year ended 30 September 2025. With us today for management are President and CEO, Dr. Chris Anzalone, who will provide an overview; Bruce Given, Outgoing Chief Medical Scientist, who will provide an overview of the REDEMPLO FDA approval; Andy Davis, Senior Vice President and Head of the Global Cardiometabolic Franchise, who will provide an update on commercialization activities; Dr.

Speaker #2: Good afternoon, and thank you for joining us today to discuss Arrowhead's results for its fiscal year 2025, which ended September 30, 2025. With us today from management are President and CEO Dr. Christopher Anzalone, who will provide an overview; Bruce Given, outgoing Chief Medical Scientist, who will provide an overview of the Redemplo FDA approval; Andy Davis, Senior Vice President and Head of the Global Cardiometabolic Franchise, who will provide an update on commercialization activities; Dr. James Hamilton, Chief Medical Officer and Head of R&D, who will discuss our development programs; and Dan Apel, Chief Financial Officer, who will review the financials.

Operator: James Hamilton, Chief Medical Officer and Head of R&D, who will discuss our development programs, and Dan Apel, Chief Financial Officer, who will review the financials. Following management's prepared remarks, we will open up the call to questions. Before we begin, I would like to remind you that comments made during today's call contain certain forward-looking statements within the meaning of Section 27A of the Securities Act of 1933 and Section 21E of the Securities Exchange Act of 1934. All statements other than statements of historical fact are forward-looking statements and are subject to numerous risks and uncertainties that could cause actual results that differ materially from those expressed in any forward-looking statements. For further details concerning these risks and uncertainties, please refer to our SEC filings, including our most recent annual report on Form 10-K and our quarterly reports on Form 10-Q.

James Hamilton, Chief Medical Officer and Head of R&D, who will discuss our development programs, and Dan Apel, Chief Financial Officer, who will review the financials. Following management's prepared remarks, we will open up the call to questions. Before we begin, I would like to remind you that comments made during today's call contain certain forward-looking statements within the meaning of Section 27A of the Securities Act of 1933 and Section 21E of the Securities Exchange Act of 1934.

Speaker #2: Following management's prepared remarks, we will open up the call to questions. Before we begin, I would like to remind you that comments made during today's call contain certain forward-looking statements within the meaning of Section 27A of the Securities Act of 1933 and Section 1934.

Speaker #2: Following management's prepared remarks, we will open up the call to questions. Before we begin, I would like to remind you that comments made during today's call contain certain forward-looking statements within the meeting of Section 27A of the Securities Act of 1933 and Section 21E of the Securities Exchange Act of All statements are forward-looking statements, and are other than statements of historical fact subject to numerous risks and uncertainties that could cause actual results to differ materially from those expressed in any forward-looking statements.

All statements other than statements of historical fact are forward-looking statements and are subject to numerous risks and uncertainties that could cause actual results that differ materially from those expressed in any forward-looking statements. For further details concerning these risks and uncertainties, please refer to our SEC filings, including our most recent annual report on Form 10-K and our quarterly reports on Form 10-Q. I'd now like to turn the call over to Chris Anzalone, President and CEO of the company. Chris, thanks,

Speaker #2: Concerning these risks and uncertainties, please refer to our SEC filings, including our most recent annual report on Form 10-K and our quarterly reports on Form 10-Q.

Speaker #2: I'd now like to turn the call over to Christopher Anzalone, President and CEO of the

Operator: I'd now like to turn the call over to Chris Anzalone, President and CEO of the company. Chris, thanks, Vince. Good afternoon, everyone, and thank you for joining us today. Before we begin, I'd like to announce that this will be Bruce Given's final earnings call. He has been a valuable member of the Arrowhead team for almost 15 years. He will continue to help Arrowhead as a trusted advisor, but now that REDEMPLO has received its first FDA approval, he will be stepping back from day-to-day operational responsibilities, and hopefully he can finally enjoy his time in retirement, or in his re-retirement, which is probably more accurate. His contributions to Arrowhead's success, both current and future, have been critical, and we owe him a heartfelt thank you.

Speaker #3: Thanks,

Speaker #3: Vince: Good afternoon, everyone, and thank you for joining us today.

Chris Anzalone: Vince. Good afternoon, everyone, and thank you for joining us today. Before we begin, I'd like to announce that this will be Bruce Given's final earnings call. He has been a valuable member of the Arrowhead team for almost 15 years. He will continue to help Arrowhead as a trusted advisor, but now that REDEMPLO has received its first FDA approval, he will be stepping back from day-to-day operational responsibilities, and hopefully he can finally enjoy his time in retirement, or in his re-retirement, which is probably more accurate. His contributions to Arrowhead's success, both current and future, have been critical, and we owe him a heartfelt thank you.

Speaker #2: Before we begin, I'd like to announce that this is Chris. The ARROWHEAD team has had Bruce Given as our earnings advisor for almost 15 years. Now that Redemplo has received its first FDA approval, he'll be stepping back from day-to-day operational responsibilities. However, he will continue to help ARROWHEAD as a trusted call.

Speaker #2: in his re-retirement, which is probably more accurate. His contributions to ARROWHEAD's success, both current and future, have been from Bruce, who will discuss the Redemplo FDA approval, which he came back to ARROWHEAD in out-of-retirement to help He's been a valuable member of the you.

Operator: Later in the call, you will hear from Bruce, who will discuss the REDEMPLO FDA approval, which he came back to Arrowhead in and out of retirement to help us get across the finish line. Bruce leaves us in a strong position with a very strong group of leaders across the organization. As you all know, James Hamilton has already assumed much of Bruce's prior responsibilities as Chief Medical Officer and Head of R&D. Thank you again, Bruce, for getting us to today, and thank you, James, for taking us into the next chapter for Arrowhead. Let's now turn to our business and what progress we've made during the recent period. This has been a very busy and enormously productive last few months. The most impactful change is the FDA approval of REDEMPLO.

Later in the call, you will hear from Bruce, who will discuss the REDEMPLO FDA approval, which he came back to Arrowhead in and out of retirement to help us get across the finish line. Bruce leaves us in a strong position with a very strong group of leaders across the organization. As you all know, James Hamilton has already assumed much of Bruce's prior responsibilities as Chief Medical Officer and Head of R&D. Thank you again, Bruce, for getting us to today, and thank you, James, for taking us into the next chapter for Arrowhead. Let's now turn to our business and what progress we've made during the recent period.

Speaker #2: Very strong group of leaders across the organization. As you all know, James Hamilton has a line. Bruce leaves us in a strong position with a already assumed much of Bruce's prior responsibilities as Chief Medical Officer and Head of R&D.

This has been a very busy and enormously productive last few months. The most impactful change is the FDA approval of REDEMPLO. On 18 November 2024, we announced that the FDA approved REDEMPLO, indicated as an adjunct to diet to reduce triglycerides in adults with familial chylomicronemia syndrome, or FCS. FCS is a severe, rare disease with an estimated 6,500 people in the United States living with genetic or clinical FCS, characterized by triglyceride levels that can be 10 to 100 times higher than normal, leading to a substantially higher risk of developing acute, recurrent, and potentially fatal pancreatitis.

Operator: On 18 November 2024, we announced that the FDA approved REDEMPLO, indicated as an adjunct to diet to reduce triglycerides in adults with familial chylomicronemia syndrome, or FCS. FCS is a severe, rare disease with an estimated 6,500 people in the United States living with genetic or clinical FCS, characterized by triglyceride levels that can be 10 to 100 times higher than normal, leading to a substantially higher risk of developing acute, recurrent, and potentially fatal pancreatitis. This is Arrowhead Pharmaceuticals' first FDA-approved medicine, marking a major milestone for the company as it transitions into commercial stage. REDEMPLO is the first and only FDA-approved siRNA medicine for people living with FCS, and can be self-administered at home with a simple subcutaneous injection once every three months.

Speaker #2: severe rare disease with an estimated 6,500 people in the United Later in the call, you will hear So thank you again, Bruce, for getting us to today, and thank States living with genetic or clinical FCS characterized by 100 times higher than normal, triglyceride levels that can be 10 to leading to a substantially higher risk of developing acute, recurrent, and potentially fatal pancreatitis.

Speaker #2: This is ARROWHEAD's first FDA-approved medicine, marking a major milestone for the company as it transitions into the commercial stage. Redemplo is the first and only FDA-approved siRNA medicine for people living with FCS and can be self-administered at home with a simple subcutaneous injection once every three months.

This is Arrowhead Pharmaceuticals' first FDA-approved medicine, marking a major milestone for the company as it transitions into commercial stage. REDEMPLO is the first and only FDA-approved siRNA medicine for people living with FCS, and can be self-administered at home with a simple subcutaneous injection once every three months. REDEMPLO is the first and only FDA-approved medicine to be backed by adequate and well-controlled studies that include patients with genetically diagnosed and clinically diagnosed FCS.

Speaker #2: Redemplo is the first and only FDA-approved medicine to be backed by adequate and well-controlled studies that include patients with genetically FCS. After many months of preparation, our commercial team was able to hit the ground running, and I'm happy to report that we have drug in channel a mere week after diagnosis and clinical diagnosis following approval.

Operator: REDEMPLO is the first and only FDA-approved medicine to be backed by adequate and well-controlled studies that include patients with genetically diagnosed and clinically diagnosed FCS. After many months of preparation, our commercial team was able to hit the ground running, and I'm happy to report that we had drug in channel a mere week after approval. We also launched Rely on REDEMPLO, a patient support program providing support services and resources for patients at each stage of the treatment journey with REDEMPLO, including financial assistance options for eligible patients. In addition, we also announced the one REDEMPLO pricing model that creates one consistent price across current and potential future indications. This is important. We are committed to sustainable innovation, and this requires rational drug pricing according to the value a medicine—excuse me—according to the value a medicine offers to patients and healthcare systems.

After many months of preparation, our commercial team was able to hit the ground running, and I'm happy to report that we had drug in channel a mere week after approval. We also launched Rely on REDEMPLO, a patient support program providing support services and resources for patients at each stage of the treatment journey with REDEMPLO, including financial assistance options for eligible patients. In addition, we also announced the one REDEMPLO pricing model that creates one consistent price across current and potential future indications. This is important.

Speaker #2: We also launched Rely on Redemplo, a patient support program providing support services and resources for patients at each stage of the treatment journey with Redemplo, including financial assistance options for eligible patients.

Speaker #2: In addition, we also announced the One one consistent price across current and potential future indications. This is important. We are committed to sustainable innovation, and this requires a rational drug pricing according to the value of a medicine according to a value—excuse me—according to the value a medicine offers to patients and Redemplo pricing model that creates healthcare systems.

We are committed to sustainable innovation, and this requires rational drug pricing according to the value a medicine—excuse me—according to the value a medicine offers to patients and healthcare systems. It also means that we will not ask different patients to pay different amounts for the same drug based solely on what disease they've been diagnosed with. REDEMPLO is a pancreatitis drug, and when we think about pricing, we look to those patient populations who are at greatest risk of acute TG-related pancreatitis. The patients we are serving now are also those at greatest risk of pancreatitis, people with FCS.

Speaker #2: It also means that we will not ask different patients to pay different amounts for the same drug based solely on the disease they've been diagnosed with.

Operator: It also means that we will not ask different patients to pay different amounts for the same drug based solely on what disease they've been diagnosed with. REDEMPLO is a pancreatitis drug, and when we think about pricing, we look to those patient populations who are at greatest risk of acute TG-related pancreatitis. The patients we are serving now are also those at greatest risk of pancreatitis, people with FCS. This includes those with a defined set of mutations, as well as those who share the same level of chylomicronemia and symptoms, but with more heterogeneous and often less well-characterized genetic backgrounds, who we refer to as clinically defined or phenotypic FCS. The broader patient population with substantially increased risk of acute pancreatitis are those with persistent chylomicronemia, meaning fasting triglycerides greater than 880mg/dL.

Speaker #2: Redemplo is a pancreatitis drug, and when we think about pricing, we look to those patient populations who are at greatest risk of acute TG-related patients we are serving now are also those pancreatitis.

Speaker #2: At greatest risk of pancreatitis are people with FCS. This includes those with a defined set of mutations, as well as those who share the same symptoms but with more heterogeneous and often less well-characterized genetic backgrounds, who we refer to as clinically defined or phenotypic FCS.

This includes those with a defined set of mutations, as well as those who share the same level of chylomicronemia and symptoms, but with more heterogeneous and often less well-characterized genetic backgrounds, who we refer to as clinically defined or phenotypic FCS. The broader patient population with substantially increased risk of acute pancreatitis are those with persistent chylomicronemia, meaning fasting triglycerides greater than 880mg/dL.

Speaker #2: The broader patient population with substantially increased risk of acute pancreatitis, or those with persistent calorimicronemia, meaning fasting triglycerides greater than 880 milligrams per deciliter.

Speaker #2: We believe the One Redemplo pricing model has these patients in mind, and the $60,000 annual WAC price is designed to provide real value to patients and healthcare systems in this population.

Operator: We believe there are approximately 750,000 of these patients in the US, and while they often have less day-to-day symptoms than FCS patients, they are clearly at high risk for acute pancreatitis. The one REDEMPLO pricing model has these patients in mind, and the $60,000 annual WAC price is designed to provide real value to patients and healthcare systems in this population. Our SHAFTS-3 and SHAFTS-4 phase three studies are designed to support an SNDA in this population, and while those studies are ongoing and we are actively serving the FCS population, we will have time to help payers properly appreciate REDEMPLO's value, and payers will have time to plan and budget for its possible eventual adoption pending regulatory review and approval. Outside REDEMPLO, we have also made good progress with two other pipeline programs in the cardiometabolic space: zodasiran and AROWDimer PA.

We believe there are approximately 750,000 of these patients in the US, and while they often have less day-to-day symptoms than FCS patients, they are clearly at high risk for acute pancreatitis. The one REDEMPLO pricing model has these patients in mind, and the $60,000 annual WAC price is designed to provide real value to patients and healthcare systems in this population.

Speaker #2: 750,000 of these patients in the U.S., and while they often have fewer day-to-day symptoms than FCS patients, they are clearly at high risk for acute pancreatitis.

Speaker #2: Our shafts of three and shafts of four phase three studies are designed to support an SNDA in this ongoing and we are actively serving the FCS population. We will have time to populate, and while those studies help payers properly appreciate Redemplo's value, payers will have time to plan and budget for its possible eventual adoption, pending regulatory review and approval.

Our SHAFTS-3 and SHAFTS-4 phase three studies are designed to support an SNDA in this population, and while those studies are ongoing and we are actively serving the FCS population, we will have time to help payers properly appreciate REDEMPLO's value, and payers will have time to plan and budget for its possible eventual adoption pending regulatory review and approval. Outside REDEMPLO, we have also made good progress with two other pipeline programs in the cardiometabolic space: zodasiran and AROWDimer PA.

Speaker #2: Outside Redemplo, we have also made good programs in the cardiometabolic space. Sodasseran and AeroDimerPA. Let's start with progress with two other pipeline dosed the first subject in the Yosemite phase three clinical trial of Sodasseran, our clinical candidate being developed as a potential treatment for homozygous familial Sodasseran.

Operator: Let's start with Zodasiran. During the recent period, we dosed the first subject in the Yosemite phase three clinical trial of Zodasiran, our clinical candidate being developed as a potential treatment for homozygous familial hypercholesterolemia, or HoFH. HoFH is a rare genetic condition that leads to severely elevated LDL cholesterol and early onset cardiovascular disease. In Yosemite, approximately 60 subjects over the age of 12 will be randomized to receive four doses once every three months of 200mg of Zodasiran or placebo. The primary endpoint is the percent change from baseline to month 12 in fasting LDL-C. The phase two data in this patient population were encouraging, and we hope to have this study fully enrolled in 2026, complete the study in 2027, and, if successful, enable an NDA filing by the end of 2027 and launch in 2028. The next new pipeline program in cardiometabolic is AROWDimer PA.

Let's start with Zodasiran. During the recent period, we dosed the first subject in the Yosemite phase three clinical trial of Zodasiran, our clinical candidate being developed as a potential treatment for homozygous familial hypercholesterolemia, or HoFH. HoFH is a rare genetic condition that leads to severely elevated LDL cholesterol and early onset cardiovascular disease. In Yosemite, approximately 60 subjects over the age of 12 will be randomized to receive four doses once every three months of 200mg of Zodasiran or placebo.

Speaker #2: Condition that leads to severely elevated LDL cholesterol and early onset hypercholesterolemia, or HOFH. Cardiovascular disease in HOFH is a rare genetic condition. Approximately 60 subjects over the age of 12 will be randomized to receive four doses once every three months of 200 milligrams of Sodasseran or placebo.

The primary endpoint is the percent change from baseline to month 12 in fasting LDL-C. The phase two data in this patient population were encouraging, and we hope to have this study fully enrolled in 2026, complete the study in 2027, and, if successful, enable an NDA filing by the end of 2027 and launch in 2028. The next new pipeline program in cardiometabolic is AROWDimer PA.

Speaker #2: is the percent change from baseline to month 12 in fasting LDLC. The phase two data in this patient population were encouraging and we hope to have this study fully enrolled in 2026, complete the study in During the recent period, we The primary endpoint 2027, and a successful enable an NDA filing by the end of 2027 and launch in 2028.

Speaker #2: The next new pipeline program is in cardiometabolic: AeroDimerPA. During the last quarter, we filed a request for regulatory clearance to initiate a Phase 1 and Phase 2 clinical trial of AeroDimerPA.

Operator: In the last quarter, we filed a request for regulatory clearance to initiate a phase one and two clinical trial of AROWDimer PA, being developed as a potential treatment for atherosclerotic cardiovascular disease, or ASCVD, due to mixed hyperlipidemia in which both LDL cholesterol and triglycerides are elevated. This is a very large population without proper treatment options. We believe there are approximately 20 million people in the US with mixed hyperlipidemia. AROWDimer PA is a dual-function RNAi therapeutic designed to silence expression of the PCSK9 and ApoC3 genes in the liver, thus designed to reduce both LDL-C and TGs. This represents an important step forward for the RNAi field, as we believe it is the first clinical candidate to target two genes simultaneously in one molecule, and an important step forward for preventative cardiology, as both LDL and TGs have epidemiologic support as being important drivers of ASCVD risk.

In the last quarter, we filed a request for regulatory clearance to initiate a phase one and two clinical trial of AROWDimer PA, being developed as a potential treatment for atherosclerotic cardiovascular disease, or ASCVD, due to mixed hyperlipidemia in which both LDL cholesterol and triglycerides are elevated. This is a very large population without proper treatment options. We believe there are approximately 20 million people in the US with mixed hyperlipidemia. AROWDimer PA is a dual-function RNAi therapeutic designed to silence expression of the PCSK9 and ApoC3 genes in the liver, thus designed to reduce both LDL-C and TGs.

Speaker #2: Being developed as a potential treatment for atherosclerotic cardiovascular disease (ASCVD) due to mixed hyperlipidemia, in which both LDL cholesterol and triglycerides are elevated.

Speaker #2: This is a very large population without proper treatment options. We believe there are approximately 20 million people in the U.S. with mixed hyperlipidemia. AeroDimerPA is a dual-function RNAi therapeutic designed to silence expression of the PCSK9 liver, thus designed to reduce both LDL-C and TGs.

Speaker #2: and apoC3 genes. Both of these programs fit well strategically with our growing commercial focus on the cardiometabolic space and on the physicians that. Also, during the quarter, we expanded our clinical pipeline in CNS.

Speaker #2: This represents an important step forward for the RNAi field as we believe it is the first clinical candidate one molecule and an important cardiology as both LDL and step forward for preventative TGs have epidemiologic support as being important drivers of ASCVD to target two gene simultaneously in risk.

This represents an important step forward for the RNAi field, as we believe it is the first clinical candidate to target two genes simultaneously in one molecule, and an important step forward for preventative cardiology, as both LDL and TGs have epidemiologic support as being important drivers of ASCVD risk. Both of these programs fit well strategically with our growing commercial focus on the cardiometabolic space, and on the physicians that treat these patients. Also, during the quarter, we expanded our clinical pipeline in CNS.

Operator: Both of these programs fit well strategically with our growing commercial focus on the cardiometabolic space, and on the physicians that treat these patients. Also, during the quarter, we expanded our clinical pipeline in CNS. We filed a CTA to initiate a phase one and two clinical trial of ArrowMAP-T as a potential treatment for tauopathies, including Alzheimer's disease. ArrowMAP-T is Arrowhead's first therapy to utilize a new proprietary delivery system, which in preclinical studies has achieved blood-brain barrier penetration and deep knockdown of target genes across the CNS, including deep brain regions, after subcutaneous injections. Non-clinical evaluations in monkeys with subcutaneous administration of ArrowMAP-T using clinically translatable doses have shown better than 75% knockdown of tissue-level MAP-T mRNA in the CNS. Importantly, monkey tissue-level knockdown has translated into CSF tau protein reductions, with duration of effect supportive of either monthly or quarterly subcutaneous dose regimens.

We filed a CTA to initiate a phase one and two clinical trial of ArrowMAP-T as a potential treatment for tauopathies, including Alzheimer's disease. ArrowMAP-T is Arrowhead's first therapy to utilize a new proprietary delivery system, which in preclinical studies has achieved blood-brain barrier penetration and deep knockdown of target genes across the CNS, including deep brain regions, after subcutaneous injections. Non-clinical evaluations in monkeys with subcutaneous administration of ArrowMAP-T using clinically translatable doses have shown better than 75% knockdown of tissue-level MAP-T mRNA in the CNS.

Speaker #2: We filed a CTA to initiate a Phase 1 and 2 clinical trial of AeroMAP-T as a potential treatment for these patients with calopathies, including Alzheimer's disease.

Speaker #2: AeroMAP-T is Aerohead's first therapy to utilize a new proprietary delivery system which, in preclinical studies, has achieved blood-brain barrier penetration and deep knockdown of target genes across the CNS, including deep brain regions after subcutaneous injections.

Speaker #2: Nonclinical evaluations in monkeys with subcutaneous administration of AeroMAP-T using clinically 75% knockdown of tissue-level MAP-T mRNA in the CNS. Importantly, monkey tissue-level knockdown has translated into CSF, tau protein reductions, with duration of quarterly subcutaneous dose regimens.

Importantly, monkey tissue-level knockdown has translated into CSF tau protein reductions, with duration of effect supportive of either monthly or quarterly subcutaneous dose regimens. This is an exciting program, and we look forward to initiating the study shortly. We also continue to make good progress on our first two obesity programs, ArrowINHBE and ArrowALK7. Together, we have randomized 192 patients, all with a BMI greater than 30. Because we started ArrowINHBE earlier, it is about two quarters further into the phase one study than ArrowALK7.

Speaker #2: This is an exciting program, and we look forward to initiating the study shortly. The effect is supportive of either monthly or... We also continue to make good progress on our first two obesity programs, AeroINHBE and AeroAPP7.

Operator: This is an exciting program, and we look forward to initiating the study shortly. We also continue to make good progress on our first two obesity programs, ArrowINHBE and ArrowALK7. Together, we have randomized 192 patients, all with a BMI greater than 30. Because we started ArrowINHBE earlier, it is about two quarters further into the phase one study than ArrowALK7. Our plan has been to share early data at the end of the year, but due to travel schedules and the holidays, this will push a couple of weeks later into the early part of January. We also expect to have more fulsome data toward the end of the first half of 2026. We also made important progress in this development.

Speaker #2: Together, we have randomized 192 patients, all with a BMI greater than 30. Because we started two quarters further into the Phase 1 study than AeroAPP7.

Our plan has been to share early data at the end of the year, but due to travel schedules and the holidays, this will push a couple of weeks later into the early part of January. We also expect to have more fulsome data toward the end of the first half of 2026. We also made important progress in this development.

Speaker #2: Our plan has been to share early data at the end of the year, but due to travel schedules and the holidays, this will push a couple of weeks later into the early part of January.

Speaker #2: More wholesome data toward the end of the first half of 2026. We also expect to have made important progress in this AeroINHBE earlier; it is about development.

Speaker #2: First, as we announced yesterday, we earned a $200 million milestone payment from Sarepta following a drug safety committee review and subsequent authorization to dose escalate—an achievement of the second pre-specified patient enrollment target for AeroDM1.

Operator: First, as we announced yesterday, we earned a $200 million milestone payment from Sarepta Therapeutics following a Drug Safety Committee review and subsequent authorization to dose escalate and achievement of the second pre-specified patient enrollment target for ARO-DM1. This follows a $100 million milestone earned previously when Arrowhead Pharmaceuticals reached the first of two pre-specified enrollment targets and subsequent authorization to dose escalate in a phase one and two clinical study of ARO-DM1. This partnership continues to be productive, and we look forward to continued progress. In addition to progress on the Sarepta Therapeutics partnership, we announced a new global licensing collaboration agreement with Novartis for ArrowSNCA, Arrowhead Pharmaceuticals' preclinical stage siRNA therapy against alpha-synuclein for the treatment of Parkinson's disease. The collaboration includes a limited number of additional targets outside our pipeline that will utilize Arrowhead Pharmaceuticals' proprietary TRiM platform.

First, as we announced yesterday, we earned a $200 million milestone payment from Sarepta Therapeutics following a Drug Safety Committee review and subsequent authorization to dose escalate and achievement of the second pre-specified patient enrollment target for ARO-DM1. This follows a $100 million milestone earned previously when Arrowhead Pharmaceuticals reached the first of two pre-specified enrollment targets and subsequent authorization to dose escalate in a phase one and two clinical study of ARO-DM1.

Speaker #2: This follows a $100 million milestone earned previously when Aerohead reached the first of two pre-specified enrollment targets and received subsequent authorization to dose escalate in a Phase 1 and 2 clinical study of AeroDM1.

Speaker #2: This partnership continues to be productive, and we look forward to continued progress. In addition to progress on the licensing collaboration agreement with Novartis for AeroSNCA, Arrowhead's preclinical stage Sarepta partnership, we announced a new global siRNA therapy against alpha-synuclein for the treatment of Parkinson's disease.

This partnership continues to be productive, and we look forward to continued progress. In addition to progress on the Sarepta Therapeutics partnership, we announced a new global licensing collaboration agreement with Novartis for ArrowSNCA, Arrowhead Pharmaceuticals' preclinical stage siRNA therapy against alpha-synuclein for the treatment of Parkinson's disease. The collaboration includes a limited number of additional targets outside our pipeline that will utilize Arrowhead Pharmaceuticals' proprietary TRiM platform.

Speaker #2: The collaboration includes a limited number of additional targets outside our pipeline that will utilize Aerohead's proprietary TRIM platform. Aerohead received a $200 million upfront payment from Novartis, and it's also eligible to receive development, regulatory, and sales milestones.

Operator: Arrowhead received a $200 million upfront payment from Novartis and is also eligible to receive development, regulatory, and sales milestone payments of up to $2 billion. Arrowhead is further eligible to receive tiered royalties on commercial sales up to low double digits. As I mentioned before, the recent approval of REDEMPLO is clearly the most important recent development. Arrowhead has been busy across the pipeline and in business development during the recent period. Business development and licensing is critical to our business model, so we are pleased to have these two significant deals closed this year. With that overview, I'd now like to turn the call over to Bruce Given. Bruce. Thanks, Chris. Good afternoon, everyone. I'm happy to give my final update to Arrowhead shareholders at such an important time and with Arrowhead in such a position of strength.

Arrowhead received a $200 million upfront payment from Novartis and is also eligible to receive development, regulatory, and sales milestone payments of up to $2 billion. Arrowhead is further eligible to receive tiered royalties on commercial sales up to low double digits. As I mentioned before, the recent approval of REDEMPLO is clearly the most important recent development. Arrowhead has been busy across the pipeline and in business development during the recent period. Business development and licensing is critical to our business model, so we are pleased to have these two significant deals closed this year.

Speaker #2: Aerohead is further eligible to receive milestone payments of up to $2 million and tiered royalties on commercial sales up to low double digits. As I mentioned before, the recent approval of redempt loads clearly is the most important recent development that Aerohead has been busy with across the pipeline and in business development during the recent period.

Speaker #2: Business development and licensing are critical to our business model, so we are pleased to have these two significant deals close this year. With that overview, I'd now like to turn the call over to Bruce Given.

With that overview, I'd now like to turn the call over to Bruce Given. Bruce.

Speaker #2: Bruce, thanks. Chris, good afternoon, everyone. I'm happy to give my final update to Aerohead shareholders. At such an important time, and with Aerohead in such a position of strength, we have built something truly unique and powerful at Aerohead. With the first FDA approval behind us, it feels like the right time for me to step back into retirement.

Bruce Given: Thanks, Chris. Good afternoon, everyone. I'm happy to give my final update to Arrowhead shareholders at such an important time and with Arrowhead in such a position of strength. We have built something truly unique and powerful at Arrowhead, and with the first FDA approval behind us, it feels like the right time for me to step back into retirement. Let's review some of the key parts of the recent FDA approval that we announced last week. Mostly, I'll discuss the label and information contained in the package insert. REDEMPLO is approved as an adjunct to diet to reduce triglycerides in adults with FCS.

Operator: We have built something truly unique and powerful at Arrowhead, and with the first FDA approval behind us, it feels like the right time for me to step back into retirement. Let's review some of the key parts of the recent FDA approval that we announced last week. Mostly, I'll discuss the label and information contained in the package insert. REDEMPLO is approved as an adjunct to diet to reduce triglycerides in adults with FCS. The recommended dose of REDEMPLO is 25mg, and it can be self-administered at home by subcutaneous injection once every three months. REDEMPLO has no contraindications, warnings, or precautions. The most common adverse reactions include hyperglycemia, headache, nausea, and injection site reactions.

Speaker #2: So, let’s review some of the key parts of the recent FDA approval that we announced last week. Mostly, I’ll discuss the label and information contained in the package insert.

Speaker #2: Redempt load is approved as an adjunct to diet to reduce triglycerides in adults with FCS. The recommended dose of Redempt load is self-administered at home by subcutaneous injection of 25 milligrams once every three months.

The recommended dose of REDEMPLO is 25mg, and it can be self-administered at home by subcutaneous injection once every three months. REDEMPLO has no contraindications, warnings, or precautions. The most common adverse reactions include hyperglycemia, headache, nausea, and injection site reactions. The FDA submission was supported by clinical data from the phase three PALSATE study in patients with both genetic FCS and those with the same clinical manifestations of disease, but without solely a genetic cause, referred to as clinically diagnosed FCS.

Speaker #2: Redempt load has no precautions. The most common contraindications, warnings, and adverse reactions include hyperglycemia, headache, nausea, and injection site reactions. The FDA submission was supported by clinical data from the Phase Three PALISATE study in patients with both genetic FCS and those with the same clinical manifestations of the disease but without solely a genetic cause, referred to as clinically diagnosed FCS.

Operator: The FDA submission was supported by clinical data from the phase three PALSATE study in patients with both genetic FCS and those with the same clinical manifestations of disease, but without solely a genetic cause, referred to as clinically diagnosed FCS. The blinded portion of the trial compared a year of therapy with plozasiran or placebo, dosed every three months, and tested two doses of plozasiran versus placebo. The primary endpoint was change in median triglycerides at month 10. There were also multiplicity-controlled secondary endpoints, all of which were statistically significant, including notably the occurrence of acute pancreatitis, for which the 25 and 50mg doses were combined for comparison to placebo, as called for in the analysis plan. Plozasiran achieved deep and durable reductions in median triglycerides as early as one month when the first measurement was taken.

Speaker #2: The blinded portion of the trial compared a year of therapy with prazosterone or placebo, dosed every three months, and tested two doses of prazosterone versus placebo.

The blinded portion of the trial compared a year of therapy with plozasiran or placebo, dosed every three months, and tested two doses of plozasiran versus placebo. The primary endpoint was change in median triglycerides at month 10. There were also multiplicity-controlled secondary endpoints, all of which were statistically significant, including notably the occurrence of acute pancreatitis, for which the 25 and 50mg doses were combined for comparison to placebo, as called for in the analysis plan. Plozasiran achieved deep and durable reductions in median triglycerides as early as one month when the first measurement was taken.

Speaker #2: The primary endpoint was change in median triglycerides at month 10. There were also multiplicity-controlled secondary endpoints, all of which were statistically significant, including notably the occurrence of acute pancreatitis, for which the 25 mg and 50 mg doses were combined for comparison to placebo, as called for in the analysis plan.

Speaker #2: Prazosterone achieved deep and durable reductions in median triglycerides as early as one month when the first measurement was taken. Overall, these reductions were around 80% from baseline, and reductions were largely maintained, keeping triglyceride levels below the usual guideline-directed threshold of 500 milligrams per deciliter throughout the year of treatment.

Operator: Overall, these reductions were around 80% from baseline, and reductions largely maintained median triglyceride levels below the usual guideline-directed threshold of 500mg/dL throughout the year of treatment. 500mg/dL is the recognized threshold where the risk of pancreatitis increases relative to a normal population. Importantly, patients with genetic FCS versus clinical FCS showed similar reductions from baseline. We see the clinical FCS population as having the same high unmet need as the genetic FCS group, and, as such, we think it is crucial to have shown that both patient populations showed similar large reductions from baseline in triglycerides with REDEMPLO therapy. Plozasiran is also labeled as having reduced the rate of adjudicated pancreatitis events versus placebo, a very welcome finding for FCS patients and their caregivers, and an important validation that reductions in triglycerides can, in fact, lead to reductions in pancreatitis.

Overall, these reductions were around 80% from baseline, and reductions largely maintained median triglyceride levels below the usual guideline-directed threshold of 500mg/dL throughout the year of treatment. 500mg/dL is the recognized threshold where the risk of pancreatitis increases relative to a normal population. Importantly, patients with genetic FCS versus clinical FCS showed similar reductions from baseline. We see the clinical FCS population as having the same high unmet need as the genetic FCS group, and, as such, we think it is crucial to have shown that both patient populations showed similar large reductions from baseline in triglycerides with REDEMPLO therapy.

Speaker #2: 500 milligrams per deciliter is the recognized threshold where the risk of pancreatitis increases relative to a normal population. Importantly, patients with genetic FCS versus clinical FCS showed similar reductions from baseline.

Speaker #2: We see the clinical FCS population as having the same high unmet need as the genetic FCS group. As such, we think it is crucial to have shown that both patient populations showed similar large reductions from baseline in triglycerides with redempt load therapy.

Plozasiran is also labeled as having reduced the rate of adjudicated pancreatitis events versus placebo, a very welcome finding for FCS patients and their caregivers, and an important validation that reductions in triglycerides can, in fact, lead to reductions in pancreatitis.

Speaker #2: Prazosterone is also labeled as having reduced the rate of adjudicated pancreatitis events versus placebo. This is a very welcome finding for FCS patients and their caregivers and an important validation that reductions in triglycerides can, in fact, lead to reductions in pancreatitis.

Speaker #2: Let me a part of Aerohead from the early days of close by saying that it's gratifying to have been our siRNA development and part of the prazosterone program and its inception and again over the last several years.

Operator: Let me close by saying that it's gratifying to have been a part of Arrowhead from the early days of our siRNA developments and part of the plozasiran program at its inception and again over the last several years. More importantly, it's exciting to hear the enthusiasm about this new medicine from patients, caregivers, and physicians. I'd also like to wish all of you an enjoyable Thanksgiving holiday. I'll now turn the call over to Andy Davis. Thank you, Bruce. It's been exactly one week since the commercial launch of REDEMPLO, and the early feedback we've received from healthcare professionals, patient societies, and payers has been very encouraging. We hear lots of enthusiasm about the differentiating attributes of REDEMPLO, which generally fall into five value pillars, some of which the team has touched on briefly already. First, the reduction in triglycerides is both significant and sustained.

Let me close by saying that it's gratifying to have been a part of Arrowhead from the early days of our siRNA developments and part of the plozasiran program at its inception and again over the last several years. More importantly, it's exciting to hear the enthusiasm about this new medicine from patients, caregivers, and physicians. I'd also like to wish all of you an enjoyable Thanksgiving holiday. I'll now turn the call over to Andy Davis.

Speaker #2: And more enthusiasm about this new medicine. Importantly, it's exciting to hear from the patients, caregivers, and physicians. I'd also like to wish all of you an enjoyable Thanksgiving holiday.

Speaker #2: I'll now turn the call over to Andy Davis. Andy, thank you. Bruce, it's been exactly one week since the commercial launch of Redempt Load, and the early feedback we've received from healthcare professionals, patient societies, and payers has been very encouraging.

Andy Davis: Thank you, Bruce. It's been exactly one week since the commercial launch of REDEMPLO, and the early feedback we've received from healthcare professionals, patient societies, and payers has been very encouraging. We hear lots of enthusiasm about the differentiating attributes of REDEMPLO, which generally fall into five value pillars, some of which the team has touched on briefly already. First, the reduction in triglycerides is both significant and sustained.

Speaker #2: We hear lots of enthusiasm about the differentiating attributes of redempt load. What's generally fallen into five value pillars, some of which the team has touched on briefly already.

Speaker #2: First, the reduction in triglycerides is both significant and sustained. In PALISATE, Redempt load reduced triglycerides by an unprecedented 80% from baseline, as early as month one, and maintained this marked reduction with minimal variation throughout the full 12-month treatment period.

Operator: In PALSATE, REDEMPLO reduced triglycerides by an unprecedented -80% from baseline as early as month one and maintained this marked reduction with minimal variation throughout the full 12-month treatment period. This is compared to a -17% reduction in the pooled placebo group. With REDEMPLO, patients now have real hope, many for the first time, of achieving triglyceride levels below guideline-directed risk thresholds associated with acute pancreatitis, such as 500mg per deciliter. In PALSATE, 50% of patients at the 25mg dose achieved TG levels below 500mg per deciliter, with approximately 75% achieving levels below 880mg per deciliter at month 10. Second, the numerical incidence of acute pancreatitis in patients treated with REDEMPLO was lower compared with placebo. As we all know, this is the outcome of most importance for healthcare professionals, patients, and payers. Third, REDEMPLO demonstrated favorable safety and tolerability.

In PALSATE, REDEMPLO reduced triglycerides by an unprecedented -80% from baseline as early as month one and maintained this marked reduction with minimal variation throughout the full 12-month treatment period. This is compared to a -17% reduction in the pooled placebo group. With REDEMPLO, patients now have real hope, many for the first time, of achieving triglyceride levels below guideline-directed risk thresholds associated with acute pancreatitis, such as 500mg per deciliter. In PALSATE, 50% of patients at the 25mg dose achieved TG levels below 500mg per deciliter, with approximately 75% achieving levels below 880mg per deciliter at month 10.

Speaker #2: This compared to a minus 17% reduction in the pool of the placebo group. With redempt load, patients now have real hope—many for the first time—of achieving triglyceride levels below guideline-directed risk thresholds associated with acute pancreatitis, such as 500 milligrams per deciliter.

Speaker #2: In PALISATE, 50% of patients at the 25 milligram dose achieved triglyceride (TG) levels below 500 milligrams per deciliter, with approximately 75% achieving levels below 880 milligrams per deciliter at month 10.

Speaker #2: Second, the numerical incidence of acute pancreatitis in patients treated with Redempt Load was lower compared with placebo. As we all know, this is the outcome of most importance for healthcare professionals, patients, and payers.

Second, the numerical incidence of acute pancreatitis in patients treated with REDEMPLO was lower compared with placebo. As we all know, this is the outcome of most importance for healthcare professionals, patients, and payers. Third, REDEMPLO demonstrated favorable safety and tolerability. Importantly, the US-approved package insert contains no contraindications, no warnings, and no precautions associated with the use of REDEMPLO.

Speaker #2: Third, Redempt Load demonstrated favorable safety and tolerability. Importantly, the U.S.-approved package insert contains no contraindications, no warnings, and no precautions associated with the use of Redempt Load.

Operator: Importantly, the US-approved package insert contains no contraindications, no warnings, and no precautions associated with the use of REDEMPLO. Fourth, REDEMPLO can be self-administered at home with a simple subcutaneous injection once every three months, just four injections per year. Physicians tell us this infrequent dosing schedule is likely to reduce the treatment burden on physicians, patients, and caregivers. Fifth, early feedback on the one REDEMPLO pricing model has been positive. As Chris highlighted, this model creates one consistent price, $60,000 per patient per year, across current and potential future indications, such as severe hypertriglyceridemia. Again, this means that we will not ask different patients to pay different amounts for the same drug based solely on what disease they have. We have been in important discussions with payers, and early signs for market access are encouraging.

Speaker #2: Fourth, redempt load can be self-administered at home with a simple subcutaneous injection once every three months—just four injections per year. Physicians tell us this infrequent dosing schedule is likely to reduce the treatment burden on physicians, patients, and caregivers.

Fourth, REDEMPLO can be self-administered at home with a simple subcutaneous injection once every three months, just four injections per year. Physicians tell us this infrequent dosing schedule is likely to reduce the treatment burden on physicians, patients, and caregivers. Fifth, early feedback on the one REDEMPLO pricing model has been positive. As Chris highlighted, this model creates one consistent price, $60,000 per patient per year, across current and potential future indications, such as severe hypertriglyceridemia. Again, this means that we will not ask different patients to pay different amounts for the same drug based solely on what disease they have.

Speaker #2: And fifth, early feedback on the one redempt load pricing model has been positive. As Chris highlighted, this model creates one consistent price—$60,000 per patient per year—across current and potential future indications, such as severe hypertriglyceridemia.

Speaker #2: Again, this means that we will not ask different patients to pay different amounts for the same drug based solely on what disease they have.

We have been in important discussions with payers, and early signs for market access are encouraging. As a reminder, we believe there are an estimated 6,500 people in the US living with genetic or clinical FCS, and the prescriber base comprises specialist physicians such as lipidologists, endocrinologists, preventive cardiologists, and internal medicine physicians with a focus on lipid disorders. These specialists often operate within multidisciplinary teams that may include gastroenterologists, advanced practice providers, and specialized dieticians.

Speaker #2: We have been in an important discussion with payers, and early signs for market access are encouraging. As a reminder, we believe there are an estimated 6,500 people in the U.S. living with genetic or clinical FCS, and the prescriber base comprises specialist physicians such as lipidologists, endocrinologists, preventive cardiologists, and internal medicine physicians with a focus on lipid disorders.

Operator: As a reminder, we believe there are an estimated 6,500 people in the US living with genetic or clinical FCS, and the prescriber base comprises specialist physicians such as lipidologists, endocrinologists, preventive cardiologists, and internal medicine physicians with a focus on lipid disorders. These specialists often operate within multidisciplinary teams that may include gastroenterologists, advanced practice providers, and specialized dieticians. At launch, we are targeting approximately 5,000 healthcare professionals through personal engagement. Our ReliON REDEMPLO patient support program is operational and designed to make every step of the journey easier. This program is designed to assist patients and physicians with insurance verification, financial assistance options, a first-dose starter kit, and supplemental injection training. We launched just one week ago, but our care coordinators are already actively processing REDEMPLO start forms, conducting patient welcome calls, and engaging payers to obtain approvals.

Speaker #2: These specialists often form teams that may include gastroenterologists, advanced practice providers, and specialized dietitians. At launch, we are targeting approximately 5,000 healthcare professionals through personal engagement.

At launch, we are targeting approximately 5,000 healthcare professionals through personal engagement. Our ReliON REDEMPLO patient support program is operational and designed to make every step of the journey easier. This program is designed to assist patients and physicians with insurance verification, financial assistance options, a first-dose starter kit, and supplemental injection training. We launched just one week ago, but our care coordinators are already actively processing REDEMPLO start forms, conducting patient welcome calls, and engaging payers to obtain approvals.

Speaker #2: And finally, our ReliOn Redempt load patient support program is operational and designed to make every step of the journey easier. This program is designed to assist patients and physicians with insurance verification, financial assistance options, a first dose starter kit, and supplemental injection training.

Speaker #2: We launched just one week ago, but our care coordinators are already actively processing redempt load start forms, conducting patient welcome calls, and engaging payers to obtain approvals.

Speaker #2: And as Chris stated, we're happy to announce that we already have the drug available in-channel ahead of schedule. I will now turn the call over to James Hamilton to discuss the broader R&D portfolio.

Operator: As Chris stated, we're happy to announce that we already have drug available in channel ahead of schedule. I will now turn the call over to James Hamilton to discuss the broader R&D portfolio. Thank you, Andy. I'd like to give a quick review of the status of our late-stage phase three studies and also describe the design of a couple of our early-stage programs. Let's start with the suite of phase three studies of plozasiran designed to potentially support supplemental NDA filing to expand the label beyond genetic and clinical FCS. Shasta 3 and Shasta 4 are phase three studies designed to compare reductions in triglycerides with 25mg plozasiran compared with placebo over 12 months of treatment. Between the two studies, we enrolled approximately 750 patients. In addition, the NEAR3 study enrolled approximately 1,400 patients.

As Chris stated, we're happy to announce that we already have drug available in channel ahead of schedule. I will now turn the call over to James Hamilton to discuss the broader R&D portfolio.

James Hamilton: Thank you, Andy. I'd like to give a quick review of the status of our late-stage phase three studies and also describe the design of a couple of our early-stage programs. Let's start with the suite of phase three studies of plozasiran designed to potentially support supplemental NDA filing to expand the label beyond genetic and clinical FCS. Shasta 3 and Shasta 4 are phase three studies designed to compare reductions in triglycerides with 25mg plozasiran compared with placebo over 12 months of treatment. Between the two studies, we enrolled approximately 750 patients. In addition, the NEAR3 study enrolled approximately 1,400 patients.

Speaker #2: James, thank you. Andy, I'd like to give a quick review of the status of our late-stage Phase 3 studies and also describe the design of a couple of our early-stage programs.

Speaker #2: Let's start with the suite of phase three studies of prazosterone, designed to potentially support supplemental NDA filing to expand the label beyond genetic and clinical FCS.

Speaker #2: Shasta Three and Shasta Four are Phase 3 studies designed to compare reductions in triglycerides with 25 milligrams of prazosterone compared with placebo over 12 months of treatment.

Speaker #2: Between the two studies, we enrolled approximately 750 patients. In addition, the near three studies enrolled approximately 1,400 patients. This study, involving patients with mixed hyperlipidemia, is designed to supplement the safety database when we file the SMBA for prazosterone in severe hypertriglyceridemia.

Operator: This study in patients with mixed hyperlipidemia is designed to supplement the safety database when we file the SMVA for plozasiran in severe hypertriglyceridemia. We are not planning to seek approval in the mixed hyperlipidemia patient population. We completed enrollment in the global SHASTA-3 and SHASTA-4, as well as NEAR3 phase three clinical studies in June 2025. We anticipate completing the primary portions of these studies in mid-2026, with top-line data expected in Q3 2026. If successful, we plan to make submissions before the end of 2026 for regulatory review and potential approval. The SHTG program also features a study named SHASTA-5 to directly assess the ability of plozasiran to reduce the risk of acute pancreatitis as the primary endpoint in SHTG patients at high risk of acute pancreatitis. We are currently enrolling patients in that study.

This study in patients with mixed hyperlipidemia is designed to supplement the safety database when we file the SMVA for plozasiran in severe hypertriglyceridemia. We are not planning to seek approval in the mixed hyperlipidemia patient population. We completed enrollment in the global SHASTA-3 and SHASTA-4, as well as NEAR3 phase three clinical studies in June 2025. We anticipate completing the primary portions of these studies in mid-2026, with top-line data expected in Q3 2026. If successful, we plan to make submissions before the end of 2026 for regulatory review and potential approval.

Speaker #2: We are not planning to seek approval in the mixed hyperlipidemia patient population. We completed enrollment in the global SHASTA-3 and SHASTA-4, as well as NEAR-3 Phase 3 clinical studies, in June of 2025.

Speaker #2: We anticipate completing the primary portions of these studies in mid-2026, with top-line data expected in the third quarter of '26. If successful, we plan to make submissions before the end of 2026 for regulatory review and potential approval.

Speaker #2: The SHTG program also features a study named Shasta Five to directly assess the ability of prazosterone to reduce the risk of acute pancreatitis as the primary endpoint in SHTG patients at high risk of acute pancreatitis.

The SHTG program also features a study named SHASTA-5 to directly assess the ability of plozasiran to reduce the risk of acute pancreatitis as the primary endpoint in SHTG patients at high risk of acute pancreatitis. We are currently enrolling patients in that study. Of note, we will also be assessing pancreatitis risk reductions in Shasta 3 and Shasta 4 as a key secondary endpoint, but Shasta 5 is the first event-driven study to assess acute pancreatitis as the primary endpoint. I would also like to provide an update on our obesity programs, ARO-INHBE and ARO-ALK7.

Speaker #2: We are currently studying. Of note, we will also be enrolling patients in that assessing pancreatitis risk reductions in Shasta III and Shasta IV as a key secondary endpoint, but Shasta V is the first event-driven study to assess acute pancreatitis as the primary endpoint.

Operator: Of note, we will also be assessing pancreatitis risk reductions in Shasta 3 and Shasta 4 as a key secondary endpoint, but Shasta 5 is the first event-driven study to assess acute pancreatitis as the primary endpoint. I would also like to provide an update on our obesity programs, ARO-INHBE and ARO-ALK7. Both of these programs target the known ACTIVIN pathway that is involved in signaling to adipocytes to store fat. ARO-INHBE inhibits one of the ligands in the pathway, and ARO-ALK7 inhibits the receptor on the adipocyte that these ligands bind. Essentially, we are trying to reduce the message sent to store fat and the way the message is received at the adipocytes. ARO-INHBE started enrolling patients in December 2024, and ARO-ALK7 initiated in May 2025.

Speaker #2: I would also like to provide an update on our obesity programs, Arrow Inhibin E and Arrow L7. Both of these programs target the known active-in pathway that is involved in signaling to adipocytes to store fat.

Both of these programs target the known ACTIVIN pathway that is involved in signaling to adipocytes to store fat. ARO-INHBE inhibits one of the ligands in the pathway, and ARO-ALK7 inhibits the receptor on the adipocyte that these ligands bind. Essentially, we are trying to reduce the message sent to store fat and the way the message is received at the adipocytes. ARO-INHBE started enrolling patients in December 2024, and ARO-ALK7 initiated in May 2025.

Speaker #2: Arrow inhibin E inhibits one of the ligands in the pathway, and Arrow L7 inhibits the receptor on the adipocyte that these ligands bind. So, essentially, we are trying to reduce the message sent to store fat and the way the message is received at the adipocyte.

Speaker #2: Arrow Inhibin E started enrolling patients in December 2024, and Arrow L7 initiated in May 2025. Both programs are currently in Phase 1, 2A, first-in-human dose-escalating studies to evaluate safety, tolerability, pharmacokinetics, and pharmacodynamics.

Operator: Both programs are currently in phase I/2a, first-in-human dose-escalating studies to evaluate safety, tolerability, pharmacokinetics, and pharmacodynamics. Both programs include part one designed to assess single and multiple doses as monotherapy, and part two designed to assess multiple doses in combination with tirzepatide. As ARO-INHBE started about two quarters earlier, we have more mature data in that study. The study is nearly fully enrolled, and we are on schedule and currently planning to share initial data from this program around the first week of 2026. This is a rather robust first-in-human study that is collecting multiple measures of drug activity and pathway activity, and we are eager to share initial findings. We were originally planning on sharing the first data around the end of the year, but due to the holidays and travel, the first week of January worked the best for all schedules.

Both programs are currently in phase I/2a, first-in-human dose-escalating studies to evaluate safety, tolerability, pharmacokinetics, and pharmacodynamics. Both programs include part one designed to assess single and multiple doses as monotherapy, and part two designed to assess multiple doses in combination with tirzepatide. As ARO-INHBE started about two quarters earlier, we have more mature data in that study. The study is nearly fully enrolled, and we are on schedule and currently planning to share initial data from this program around the first week of 2026.

Speaker #2: Both programs include Part One, designed to assess single and multiple doses as monotherapy, and Part Two, designed to assess multiple doses in combination with tirzepatide.

Speaker #2: As Arrow's Inhibin E started about two quarters earlier, we have more mature data in that study. The study is nearly fully enrolled, and we are on schedule, currently planning to share initial data from this program around the first week of 2026.

This is a rather robust first-in-human study that is collecting multiple measures of drug activity and pathway activity, and we are eager to share initial findings. We were originally planning on sharing the first data around the end of the year, but due to the holidays and travel, the first week of January worked the best for all schedules.

Speaker #2: This is a rather robust first-in-man study that is collecting multiple measures of drug activity and pathway activity, and we are eager to share initial findings.

Speaker #2: We were originally planning on sharing the first data around the end of the year, but due to the holidays and travel, the first week of January worked best for all schedules.

Speaker #2: For Arrow L7, we intend to provide a brief snapshot of early safety and target engagement results from that study. Both targets have strong genetic validation, and both programs have yielded promising results in preclinical studies.

Operator: For ARO-ALK7, we intend to provide a brief snapshot of early safety and target engagement results from that study. Both targets have strong genetic validation, and both programs have yielded promising results in preclinical studies, so it will be interesting to see similarities and differences in patient response in the clinical trials. I will now turn the call over to Dan Apel. Thank you, James, and good afternoon, everyone. I'll provide a brief outline of our financial results. As we reported today, our net loss for fiscal year 2025 was $2 million for a loss of $0.01 per share based on 133.8 million fully diluted weighted average shares outstanding. This near break-even result compares with a net loss of approximately $599 million for a loss of $5 per share based on 119.8 million fully diluted weighted average shares outstanding in fiscal year 2024.

For ARO-ALK7, we intend to provide a brief snapshot of early safety and target engagement results from that study. Both targets have strong genetic validation, and both programs have yielded promising results in preclinical studies, so it will be interesting to see similarities and differences in patient response in the clinical trials. I will now turn the call over to Dan Apel.

Speaker #2: So, it will be in-patient response in the clinical trials. It will be interesting to see similarities and differences. I will now turn the call over to Dana Pell.

Speaker #2: Thank you, James. And good afternoon, everyone. I'll provide a brief outline of our financial results. As we reported today, our net loss for fiscal year 2025 was $2 million.

Dan Apel: Thank you, James, and good afternoon, everyone. I'll provide a brief outline of our financial results. As we reported today, our net loss for fiscal year 2025 was $2 million for a loss of $0.01 per share based on 133.8 million fully diluted weighted average shares outstanding. This near break-even result compares with a net loss of approximately $599 million for a loss of $5 per share based on 119.8 million fully diluted weighted average shares outstanding in fiscal year 2024.

Speaker #2: Our loss of one cent per 133.8 million fully diluted shares compares to a net loss of approximately $599 million for a loss of $5 per share based on 119.8 million fully diluted weighted average shares outstanding in fiscal year 2024. This near break-even result is based on diluted weighted average shares outstanding.

Speaker #2: Revenue for fiscal year 2025 totaled $829 million and was driven entirely by our licensed and collaboration agreements with Sarepta, Sanofi, and GSK. Of the $829 million, roughly $697 million pertained to the Sarepta arrangement.

Operator: Revenue for fiscal year 2025 totaled $829 million and was driven entirely by our license and collaboration agreements with Sarepta Therapeutics, Sanofi, and GSK. Of the $829 million, roughly $697 million pertained to the Sarepta Therapeutics arrangement. Of that $697 million, $587 million relates to the ongoing recognition of initial Sarepta Therapeutics consideration, $94 million relates to the achievement of the first DM1 milestone, and $16 million relates to the reimbursement of incurred collaboration program costs. Additionally, the license to Sanofi for Greater China rights to plozasiran contributed $130 million to our fiscal 2025 revenue. Lastly, to round things out, we recorded $2.6 million earlier in the year related to a milestone payment under the GSK HBV agreement. Turning to expenses, total operating expenses for fiscal year 2025 were approximately $731 million compared to $605 million for fiscal 2024, an increase of $126 million.

Revenue for fiscal year 2025 totaled $829 million and was driven entirely by our license and collaboration agreements with Sarepta Therapeutics, Sanofi, and GSK. Of the $829 million, roughly $697 million pertained to the Sarepta Therapeutics arrangement. Of that $697 million, $587 million relates to the ongoing recognition of initial Sarepta Therapeutics consideration, $94 million relates to the achievement of the first DM1 milestone, and $16 million relates to the reimbursement of incurred collaboration program costs. Additionally, the license to Sanofi for Greater China rights to plozasiran contributed $130 million to our fiscal 2025 revenue.

Speaker #2: Of that $697 million, $587 million relates to the ongoing recognition of initial Sarepta consideration, $94 million relates to the achievement of the first DM1 milestone, and $16 million relates to the reimbursement of incurred collaboration program costs.

Speaker #2: Additionally, the license to Sanofi for Greater China rights to prazosterone contributed $130 million to our fiscal 2025 revenue. Lastly, to round things out, we recorded $2.6 million earlier in the year related to a milestone payment under the GSK HBV agreement.

Lastly, to round things out, we recorded $2.6 million earlier in the year related to a milestone payment under the GSK HBV agreement. Turning to expenses, total operating expenses for fiscal year 2025 were approximately $731 million compared to $605 million for fiscal 2024, an increase of $126 million. The year-over-year increase was driven by $101 million of higher R&D expenses and $25 million of higher SG&A costs, both of which I will explain in brief. The key drivers of research and development spend included costs to run our clinical trials, our clinical manufacturing costs, as well as expenses related to active programs in the preclinical stage.

Speaker #2: Turning to expenses, total operating expenses for fiscal year 2025 were approximately $731 million, compared to $605 million for fiscal 2024. This represents an increase of $126 million.

Speaker #2: The year-over-year increase was driven by $101 million in higher R&D expenses and $25 million in higher SG&A costs, both of which I will explain in brief.

Operator: The year-over-year increase was driven by $101 million of higher R&D expenses and $25 million of higher SG&A costs, both of which I will explain in brief. The key drivers of research and development spend included costs to run our clinical trials, our clinical manufacturing costs, as well as expenses related to active programs in the preclinical stage. 2025 R&D costs were heavily impacted by our phase three clinical trials for plozasiran and SHTG. It's worth noting that in fiscal year 2025, nearly two-thirds of our clinical trial spend can be attributed to the late-stage development of plozasiran and SHTG. As we have mentioned, the SHTG registration studies are now fully enrolled, and we expect data to read out next year. Accordingly, the majority of remaining phase three registration clinical trial costs are expected to occur over the next 12 months.

Speaker #2: The key drivers of research and development spend included costs to run our clinical trials and our clinical manufacturing.

Speaker #1: 2025 , R&D costs were heavily a impacted by three clinical trials for possessing and it's worth noting that in fiscal year nearly 2025 , two thirds of our clinical trial spent can be attributed to the late stage development of an in .

2025 R&D costs were heavily impacted by our phase three clinical trials for plozasiran and SHTG. It's worth noting that in fiscal year 2025, nearly two-thirds of our clinical trial spend can be attributed to the late-stage development of plozasiran and SHTG. As we have mentioned, the SHTG registration studies are now fully enrolled, and we expect data to read out next year. Accordingly, the majority of remaining phase three registration clinical trial costs are expected to occur over the next 12 months.

Speaker #1: As we have mentioned, the Hhg are now in registration after fully enrolling the studies, and we expect to read out the next data next year.

Speaker #1: Accordingly , the majority of remaining phase three registration of clinical trial costs are expected to occur over the next 12 months . Our costs increased 25 million year over by year , driven primarily by our preparations for the commercialization of dental .

Operator: Our SG&A costs increased by $25 million year-over-year, driven primarily by our preparations for the commercialization of REDEMPLO. All of us here at Arrowhead Pharmaceuticals are enormously proud of the capabilities we have built to commercialize REDEMPLO, not only in our commercial functions, but also across regulatory, supply chain, order-to-cash, and indeed across all of our enabling support functions. Turning now to cash flow, net cash provided by operating activities during fiscal year 2025 was $180 million. Paired with net cash used in operating activities of $463 million in the prior year, for a net positive change year-over-year of $643 million. This increase in cash from operating activities is driven by cash received from licensing and collaboration agreements, partially offset by the aforementioned increase in R&D and SG&A costs.

Our SG&A costs increased by $25 million year-over-year, driven primarily by our preparations for the commercialization of REDEMPLO. All of us here at Arrowhead Pharmaceuticals are enormously proud of the capabilities we have built to commercialize REDEMPLO, not only in our commercial functions, but also across regulatory, supply chain, order-to-cash, and indeed across all of our enabling support functions. Turning now to cash flow, net cash provided by operating activities during fiscal year 2025 was $180 million. Paired with net cash used in operating activities of $463 million in the prior year, for a net positive change year-over-year of $643 million.

Speaker #1: All of us here at Arrowhead are proud of the enormously capable functions we have built to commercialize, not only in our commercial functions, but also across regulatory and supply chain.

Speaker #1: Order to cash and indeed across all of our of our enabling support . Turning now to cash flow . Net provided functions by operating activities during cash fiscal year 2025 was compared with net 180 million , used in cash activities of 463 million in the prior year , with a net positive change year over year of $643 million .

Speaker #1: This increase in cash from operating activities is driven by cash licensing received from collaboration agreements, partially offset by the aforementioned increase in R&D and costs.

This increase in cash from operating activities is driven by cash received from licensing and collaboration agreements, partially offset by the aforementioned increase in R&D and SG&A costs. Turning to the balance sheet, our cash and investments, including available for sale securities, totaled $919 million as of 30 September 2025, compared to $681 million as of 30 September 2024. The increase in our cash and investments was primarily related to our licensing and collaboration agreements with Sarepta Therapeutics, Sanofi, and GSK, partly offset by our ongoing cash burn.

Speaker #1: balance sheet , our cash and investments , available for including securities , totaled sale 919 million as of 2025 , September 30th , compared to 681 million as of September 30th , 2020 .

Operator: Turning to the balance sheet, our cash and investments, including available for sale securities, totaled $919 million as of 30 September 2025, compared to $681 million as of 30 September 2024. The increase in our cash and investments was primarily related to our licensing and collaboration agreements with Sarepta Therapeutics, Sanofi, and GSK, partly offset by our ongoing cash burn. Our common shares outstanding as of the end of the quarter were 135.7 million, down 2.4 million from the prior quarter, due mainly to the repurchase of shares from Sarepta Therapeutics. I'll use this opportunity to reiterate two developments that are subsequent to the fiscal year and leading up to today, which were financially meaningful for Arrowhead Pharmaceuticals and our balance sheet. Firstly, as Chris mentioned earlier on the call, we announced a licensing and collaboration agreement with Novartis for ArrowSNCA.

Speaker #1: For the increase in our cash and investments was primarily related licensing and collaboration to our with Sarepta , Sanofi , and GSK . Partly offset by our ongoing burn cash .

Speaker #1: A common shares as of the end of the outstanding quarter were 135.7 million , down 2.4 million from the prior quarter , due mainly to the repurchase of from Sarepta shares .

Our common shares outstanding as of the end of the quarter were 135.7 million, down 2.4 million from the prior quarter, due mainly to the repurchase of shares from Sarepta Therapeutics. I'll use this opportunity to reiterate two developments that are subsequent to the fiscal year and leading up to today, which were financially meaningful for Arrowhead Pharmaceuticals and our balance sheet. Firstly, as Chris mentioned earlier on the call, we announced a licensing and collaboration agreement with Novartis for ArrowSNCA. Arrowhead's preclinical stage siRNA program targeting alpha-synuclein for the treatment of synucleinopathies such as Parkinson's disease.

Speaker #1: I'll use this opportunity to reiterate two developments that are subsequent to the fiscal year and leading up to today, which were financially meaningful for Arrowhead and our balance sheet.

Speaker #1: Firstly , as mentioned Chris earlier on the call , announced a we licensing and collaboration agreement with Novartis for arrow Snca arrow heads preclinical stage program targeting siRNA alpha synuclein for the treatment of Synucleinopathies such as Parkinson's disease .

Operator: Arrowhead's preclinical stage siRNA program targeting alpha-synuclein for the treatment of synucleinopathies such as Parkinson's disease. Novartis will also be eligible to select a limited number of additional collaboration targets outside of Arrowhead's current pipeline to be developed using our proprietary TRIM platform. The closing occurred last month, and we have already received $200 million in the bank as an upfront payment. As a reminder, we are also eligible to receive up to $2 billion in future milestone payments from Novartis, as well as royalties on commercial sales. Secondly, just yesterday, we announced we earned our second development milestone under the Sarepta collaboration agreement for ARO-DM1. As Chris mentioned, this triggers a $200 million obligation from Sarepta that will be recorded in the first quarter of fiscal 2026, and we expect to receive the cash in January of 2026.

Speaker #1: Novartis will also be eligible to select a limited number of additional collaboration targets outside of Arrowhead's current pipeline to be developed using our proprietary trim platform.

Novartis will also be eligible to select a limited number of additional collaboration targets outside of Arrowhead's current pipeline to be developed using our proprietary TRIM platform. The closing occurred last month, and we have already received $200 million in the bank as an upfront payment. As a reminder, we are also eligible to receive up to $2 billion in future milestone payments from Novartis, as well as royalties on commercial sales. Secondly, just yesterday, we announced we earned our second development milestone under the Sarepta collaboration agreement for ARO-DM1.

Speaker #1: The closing occurred month , and we last have already received 200 million in the bank as an upfront payment . As a reminder , we are also eligible to up to receive 2 billion in future milestone payments from well as royalties on Novartis , as commercial sales .

Speaker #1: Secondly , just yesterday we announced we earned our second development milestone under the Sarepta collaboration agreement for one , as Chris mentioned , this triggers a $200 million obligation from Sarepta that will be in the recorded quarter of first 2026 .

As Chris mentioned, this triggers a $200 million obligation from Sarepta that will be recorded in the first quarter of fiscal 2026, and we expect to receive the cash in January of 2026. This is, of course, additional to the $100 million earned for the first DM1 milestone in fiscal Q4 2025. Finally, we are not providing detailed financial guidance at this time for the coming fiscal year. Beyond reiterating that, while we view the launch of REDEMPLO as a truly transformational event for the company, we do not anticipate that the commercial sales of REDEMPLO will have a substantial impact on our financial statements in fiscal year 2026.

Speaker #1: And we expect fiscal to cash receive the in January . Of 2026 . This is , of course , additional to the 100 million earned for the first Dm1 milestone in fiscal quarter four , 2025 .

Operator: This is, of course, additional to the $100 million earned for the first DM1 milestone in fiscal Q4 2025. Finally, we are not providing detailed financial guidance at this time for the coming fiscal year. Beyond reiterating that, while we view the launch of REDEMPLO as a truly transformational event for the company, we do not anticipate that the commercial sales of REDEMPLO will have a substantial impact on our financial statements in fiscal year 2026. We also believe our cash runway, even in the absence of any further capital from new deals or other sources, and all the while funding a broad, ambitious set of commercial and clinical programs, to be sufficient to extend into fiscal year 2028. With that, I will now turn the call back to Chris. Thanks, Dan. Arrowhead Pharmaceuticals has been working to bring important new medicines to patients in need for over 15 years.

Speaker #1: Finally, we are not providing detailed financial guidance at this time for the coming fiscal year, reiterating that we view the launch of Beyond Adempas as a truly transformational event for the company. However, we do not anticipate that the commercial sales will have a substantial impact on our financial statements in fiscal year 2026.

Speaker #1: We also believe our runway cash, even in the absence of any further capital from new deals or sources and all the other funding, while a broad, ambitious set of commercial and clinical programs, will be sufficient to extend into fiscal year 2028.

We also believe our cash runway, even in the absence of any further capital from new deals or other sources, and all the while funding a broad, ambitious set of commercial and clinical programs, to be sufficient to extend into fiscal year 2028. With that, I will now turn the call back to Chris.

Speaker #1: With that, I will now turn the call back to Chris.

Speaker #2: Dan Thanks , . Arrowhead has been working to bring medicines important new patients in need to over 15 years . As Bruce mentioned , it's very gratifying to approved by see FDA and the the overwhelmingly encouraging feedback we received FCS from the community it is just .

Chris Anzalone: Thanks, Dan. Arrowhead Pharmaceuticals has been working to bring important new medicines to patients in need for over 15 years. As Bruce mentioned, it's very gratifying to see REDEMPLO approved by the FDA and the overwhelmingly encouraging feedback we've received from the FCS community. REDEMPLO is just one part of a large pipeline that we've created to help potentially millions of patients in a diverse set of disease areas. We've spent years building the TRIM platform to enable us to bring RNAi where it is needed. We are now able to address seven different cell types and have current clinical programs in five of these.

Operator: As Bruce mentioned, it's very gratifying to see REDEMPLO approved by the FDA and the overwhelmingly encouraging feedback we've received from the FCS community. REDEMPLO is just one part of a large pipeline that we've created to help potentially millions of patients in a diverse set of disease areas. We've spent years building the TRIM platform to enable us to bring RNAi where it is needed. We are now able to address seven different cell types and have current clinical programs in five of these. Further, we will meet our 20 in 25 goal, whereby we will have 20 individual drug candidates in clinical trials by the end of this year. Our partnering has been helpful but judicious, with approximately half of our clinical pipeline wholly owned and half partnered.

Speaker #2: one part of a large pipeline that we've help potentially millions But created to of patients in a diverse set of disease areas . We've spent years building the trend platform to enable us to bring RNAi where it is needed .

Speaker #2: We are now able to address seven different types and have cell clinical current programs these in five of . Further , we will meet our 20 and 25 goal whereby we will have 20 individual drug candidates clinical in trials by the end of this year Our partnering has .

Further, we will meet our 20 in 25 goal, whereby we will have 20 individual drug candidates in clinical trials by the end of this year. Our partnering has been helpful but judicious, with approximately half of our clinical pipeline wholly owned and half partnered. We have late-stage studies ongoing, again, both independently and with partners, that may potentially lead to multiple new commercial launches over the next few years. In addition, we have a strong financial position that enables us to properly invest in our growth today and in the future.

Speaker #2: been helpful with with judicious half of our approximately clinical wholly pipeline , owned and half partnered . We have late stage studies ongoing again , both independently and with potentially lead to multiple new that may commercial launches over the next few years .

Operator: We have late-stage studies ongoing, again, both independently and with partners, that may potentially lead to multiple new commercial launches over the next few years. In addition, we have a strong financial position that enables us to properly invest in our growth today and in the future. We believe we now have everything we need to be in the next class of large, and ultimately profitable, biotech companies. Thank you for joining us today. I would now like to open the call to your questions. Operator? Thank you. To ask a question, please press star 11 on your telephone and wait for your name to be announced. To withdraw your question, please press star 11 again. We ask that you please limit yourself to one question. One moment, please. Our first question comes from the line of Luca Issi with RBC Capital Markets. Well, great.

Speaker #2: In we have a strong position that financial enables us addition , properly to invest in our growth today and in the future . We believe we have everything we need to be now in the next class of large and ultimately biotech companies .

Speaker #2: In we have a strong position that financial enables us addition , properly to invest in our growth today and in the future . We believe we have everything we need to be now in the next class of large and ultimately biotech companies profitable Thank you for joining today , and I like to us would now open the call to your questions .

We believe we now have everything we need to be in the next class of large, and ultimately profitable, biotech companies. Thank you for joining us today. I would now like to open the call to your questions. Operator?

Speaker #2: Operator .

Speaker #3: Thank you . To ask a question , please press star one one on your telephone and wait for your name to be announced .

Operator: Thank you. To ask a question, please press star 11 on your telephone and wait for your name to be announced. To withdraw your question, please press star 11 again. We ask that you please limit yourself to one question. One moment, please. Our first question comes from the line of Luca Issi with RBC Capital Markets. Well, great.

Speaker #3: To withdraw your question , please press one star one again . we ask that you And please limit yourself to one question . One moment please .

Speaker #3: first question comes Our line of Luca from the with RBC Capital ESI Markets

Speaker #4: Oh Thanks so

Speaker #4: much for taking my question , great . congrats on your retirement . I should All the say so . next . chapter . maybe if I can And then stick with you just maybe talk about what's the plan to show a benefit in terms of acute pancreatitis for aspirin ?

Operator: Thanks so much for taking my question. Bruce, congrats on your re-retirement, I should say. All the best in your next chapter. Maybe if I can stick with you, can you just maybe talk about what's the plan to show benefit in terms of acute pancreatitis for plozasiran? Are you confident shots at three and four in Q3 2026 can actually hit on acute pancreatitis, or is the base case scenario that those two trials are maybe underpowered to show benefit, and you actually need shots at five to actually hit on acute pancreatitis given that obviously that population is enriched for history of acute pancreatitis? The only reason why I'm asking is it looks like you doubled the size of the n, I should say, in the shots at five trial, according to clinical.gov, as of Monday last week.

Luca Issi: Thanks so much for taking my question. Bruce, congrats on your re-retirement, I should say. All the best in your next chapter. Maybe if I can stick with you, can you just maybe talk about what's the plan to show benefit in terms of acute pancreatitis for plozasiran? Are you confident shots at three and four in Q3 2026 can actually hit on acute pancreatitis, or is the base case scenario that those two trials are maybe underpowered to show benefit, and you actually need shots at five to actually hit on acute pancreatitis given that obviously that population is enriched for history of acute pancreatitis?

Speaker #4: Are you confident that three and four in hit the Q3 2026 can actually acute pancreatitis ? Or is the base case scenario those two or maybe underpowered to show a benefit and you actually need Shasta five to actually hit on acute given population is enriched for acute history of reason why pancreatitis .

Speaker #4: Looks like the only thing you like doubled is the N. I should say in the Shasta Phase 5 trial, according to ClinicalTrials.gov.

The only reason why I'm asking is it looks like you doubled the size of the n, I should say, in the shots at five trial, according to clinical.gov, as of Monday last week. Again, any call there is much appreciated. Thanks so much.

Speaker #4: Of week . So again , Monday last any color there much appreciated . Thanks so much .

Speaker #4: Of the week. So again, Monday last, any color there much appreciated. Thanks so much.

Speaker #1: And Sure . thank you for your your kind regards . Shasta three and four were powered on the of basis triglyceride reduction , which is primary endpoint .

Operator: Again, any call there is much appreciated. Thanks so much. Well, sure, Luca. Thank you for your kind regards. Shots at three and four were powered on the basis of triglyceride reduction, which is the primary endpoint. We did not specifically power shots at three and four for pancreatitis. However, it was on our mind, and as was also done in the core studies, there is the intent and by design the capability to pool both shots at three and four for evaluating versus placebo on reduction of pancreatitis. Of course, we only have one dose of plozasiran instead of two different doses like we had, for instance, in the phase two program.

Bruce Given: Well, sure, Luca. Thank you for your kind regards. Shots at three and four were powered on the basis of triglyceride reduction, which is the primary endpoint. We did not specifically power shots at three and four for pancreatitis. However, it was on our mind, and as was also done in the core studies, there is the intent and by design the capability to pool both shots at three and four for evaluating versus placebo on reduction of pancreatitis. Of course, we only have one dose of plozasiran instead of two different doses like we had, for instance, in the phase two program.

Speaker #1: So we the did not power Shasta three and four for . pancreatitis specifically However , it was on our mind and and as as was also done in the core studies , you know , there .

Speaker #1: The intent is by design, and the capability to pool Shasta, both three and evaluating versus, you know, placebo on the reduction of pancreatitis.

Speaker #1: And of course , we only have one dose of two doses , instead of two different doses like we had , for instance , in the phase two program .

Speaker #1: So , you know , there's there's I would say reasonably good power for , for seeing a difference in acute pancreatitis . But we're dependent on it not because we've designed a chassis five specifically to obviously be able to have a primary endpoint of acute pancreatitis .

Operator: There's, I would say, reasonably good power for seeing a difference in acute pancreatitis, but we're not dependent on it because we've designed SHASTA-5 specifically to obviously be able to have a primary endpoint of acute pancreatitis. We did change the design a bit in SHASTA-5 recently to make it a more generalizable population in patients with persistent chylomicronemia and a history of pancreatitis. The original design was a much more enriched population, but it would have actually been less representative than the newly designed trial. It's not so much a matter that we've increased power so much as we broadened the patient population to be more inclusive of the high-risk population in SHTG. We certainly oftentimes refer to it as a belt and suspenders approach.

There's, I would say, reasonably good power for seeing a difference in acute pancreatitis, but we're not dependent on it because we've designed SHASTA-5 specifically to obviously be able to have a primary endpoint of acute pancreatitis. We did change the design a bit in SHASTA-5 recently to make it a more generalizable population in patients with persistent chylomicronemia and a history of pancreatitis. The original design was a much more enriched population, but it would have actually been less representative than the newly designed trial.

Speaker #1: We change the did design a bit in Shasta five recently to make it a more generalizable in in population patients with with persistent chylomicronemia history of and a pancreatitis .

Speaker #1: The original design a much more enriched was population , but it would have actually been less representative than the newly designed trial . So it's not so much a we've matter that increased power so much as we broadened the power , the patient population to to inclusive of the high risk population in Htg .

It's not so much a matter that we've increased power so much as we broadened the patient population to be more inclusive of the high-risk population in SHTG. We certainly oftentimes refer to it as a belt and suspenders approach. There's obviously a decent chance that we will show statistical significance in the shots at three and four programs, but we're not entirely dependent on that because of shots at five, which is a study of the first of its kind specifically designed to demonstrate a benefit versus placebo in acute pancreatitis.

Speaker #1: So we certainly we oftentimes refer to it as a belts and suspenders approach . You know , there's , you know , obviously a decent chance that we will show statistical significance in the Shasta three and four programs .

Operator: There's obviously a decent chance that we will show statistical significance in the shots at three and four programs, but we're not entirely dependent on that because of shots at five, which is a study of the first of its kind specifically designed to demonstrate a benefit versus placebo in acute pancreatitis. Got it. Thanks so much. Congrats again. Thank you. One moment, please. Our next question comes from the line of Prakhar Agrawal with Cantor Fitzgerald. Hi. Thank you for taking my questions, and congrats on the quarter as well as the updates throughout the quarter. Maybe on the obesity side, I had a couple of questions.

Speaker #1: But we're not entirely dependent on that because of Shasta five , which is a study . The first of its kind , specifically designed to to demonstrate a benefit versus placebo in acute pancreatitis .

Speaker #4: Got it. Thanks so much. Congrats again.

Speaker #3: you . Thank One moment please . Our comes from the line next of question Prakhar Agrawal with Cantor Fitzgerald .

Luca Issi: Got it. Thanks so much. Congrats again.

Operator: Thank you. One moment, please. Our next question comes from the line of Prakhar Agrawal with Cantor Fitzgerald.

Speaker #5: Hi . taking my Thank you for questions and congrats on the quarter as well as the updates throughout the quarter obesity side . .

Prakhar Agrawal: Hi. Thank you for taking my questions, and congrats on the quarter as well as the updates throughout the quarter. Maybe on the obesity side, I had a couple of questions. On NMNE for the update early next year, if you can just provide more details on how much data will be disclosed, especially on the MAT side, and how much follow-up will you have on NMNE for both monotherapy and combo cohorts? Also, the same question on ARC7, what cohorts will be disclosed, and will there be any weight loss data at all from ARC7 early in the year? Thank you so much.

Speaker #5: I had a couple of questions . So on Inhibin E for the update early next year , if just you can provide more details on how much data will Maybe on the be disclosed , especially on the matte side , and how much follow up on have for both will you monotherapy and combo cohorts , and also the same question on Alk7 .

Operator: On NMNE for the update early next year, if you can just provide more details on how much data will be disclosed, especially on the MAT side, and how much follow-up will you have on NMNE for both monotherapy and combo cohorts? Also, the same question on ARC7, what cohorts will be disclosed, and will there be any weight loss data at all from ARC7 early in the year? Thank you so much. Yeah, sure. Prakhar, this is James. I can cover that. NMNE is a little bit ahead, as Chris mentioned, probably by a couple of quarters. The study is nearly fully enrolled. We have a good amount of data in both the SAD and MAD healthy volunteer or obese healthy volunteer cohorts. We'll have biomarker data, MRI data, as well as safety in those cohorts.

Speaker #5: What cohorts will be disclosed and will there be any weight loss data at all from Alk7 early in the Thank you so year ?

Speaker #5: much .

Speaker #1: sure . Yeah , This is James . I can cover that . So for Inhibin is a little bit ahead . As Chris mentioned , probably by a couple of So the quarters . nearly fully study is enrolled .

James Hamilton: Yeah, sure. Prakhar, this is James. I can cover that. NMNE is a little bit ahead, as Chris mentioned, probably by a couple of quarters. The study is nearly fully enrolled. We have a good amount of data in both the SAD and MAD healthy volunteer or obese healthy volunteer cohorts. We'll have biomarker data, MRI data, as well as safety in those cohorts.

Speaker #1: have a good We amount of data . in both the Sad . mad healthy

Speaker #2: Volunteer or volunteer cohorts .

Speaker #2: obese healthy

Speaker #1: We'll have a biomarker.

Speaker #2: Data , MRI .

Speaker #1: Data, as well as safety.

Speaker #2: In those cohorts. And then.

Speaker #1: combo The cohorts are almost .

Speaker #2: Fully enrolled . I think waiting . we're

Speaker #1: On a few more patients .

Operator: The combo cohorts are almost fully enrolled. I think we're waiting on a few more diabetic patients to enroll the highest dose combo cohorts, and that should have probably not through end of study, but ample post-dose follow-up in both the diabetic and the non-diabetic cohorts from NMNE. ARC7 will be a little bit more limited, focused mostly on monotherapy safety and knockdown data, knockdown of the target for that study. Yeah. Keep in mind here that we want to present data that are interpretable, and we're not going to have all cohorts. We're not going to have all patient data in all cohorts, even if they're fully enrolled. We don't get data in real time necessarily. You'll have probably two bites of this apple, maybe three bites, but certainly two bites of the apple.

Speaker #1: diabetic

The combo cohorts are almost fully enrolled. I think we're waiting on a few more diabetic patients to enroll the highest dose combo cohorts, and that should have probably not through end of study, but ample post-dose follow-up in both the diabetic and the non-diabetic cohorts from NMNE. ARC7 will be a little bit more limited, focused mostly on monotherapy safety and knockdown data, knockdown of the target for that study.

Speaker #2: enroll . . Combo

Speaker #1: highest . The dose .

Speaker #1: Cohorts that, and should have.

Speaker #2: not .

Speaker #2: not . Probably of

Speaker #1: study .

Speaker #2: But ample

Speaker #1: Up Through end .

Speaker #2: In both the diabetic and non-diabetic cohorts from Inhibin, and then Alk7 will be a little bit more limited. Focused mostly on safety and monotherapy.

Speaker #2: data . of Knockdown the for that target study . And keep in mind here that that we want to present data that that are interpretable and and we're not going to have all We're not going to have all cohorts .

Chris Anzalone: Yeah. Keep in mind here that we want to present data that are interpretable, and we're not going to have all cohorts. We're not going to have all patient data in all cohorts, even if they're fully enrolled. We don't get data in real time necessarily. You'll have probably two bites of this apple, maybe three bites, but certainly two bites of the apple. Our goal here in this first slug of data is to give you an idea about how these are going, and then the fuller story should come out once we have the more fulsome data set later in 2026.

Speaker #2: patients , all patient data in cohorts , even they're if fully all enrolled . We don't get we don't in real get time necessarily .

Speaker #2: And data so and you'll have probably two bites of the Apple , maybe three But but certainly two bites of the apple . You know , our goal bites .

Speaker #2: here in this first leg of data is to is to give you an idea about how these are going then and And then the fuller the fuller story should come out .

Operator: Our goal here in this first slug of data is to give you an idea about how these are going, and then the fuller story should come out once we have the more fulsome data set later in 2026. Got it. Thank you so much. You're welcome. Thank you. Our next question comes from the line of Maury Raycroft with Jefferies. Hi. Thanks for taking my question, and congrats on the progress, and best wishes, Bruce, in retirement. I was going to ask a follow-up to Luca's question earlier. We're expecting to see the patient baseline profile for your SHTG pivotals next week. What are your estimates on AP events accrual based on your patient's baseline characteristics, and also your change in plans to broaden the AP adjudication criteria?

Speaker #2: Once we fulfill the more in later in Q4.

Speaker #5: Got much it. Thank you so.

Speaker #1: welcome You're .

Speaker #3: Thank you. Our next question comes from the line of Maury Raycroft with Jefferies.

Prakhar Agrawal: Got it. Thank you so much.

Chris Anzalone: You're welcome.

Operator: Thank you. Our next question comes from the line of Maury Raycroft with Jefferies.

Speaker #6: Hi. Thanks for taking my question, and congrats on the best progress and wishes, Bruce, on your retirement. I was going to ask a follow-up to Luca's question earlier.

Maury Raycroft: Hi. Thanks for taking my question, and congrats on the progress, and best wishes, Bruce, in retirement. I was going to ask a follow-up to Luca's question earlier. We're expecting to see the patient baseline profile for your SHTG pivotals next week. What are your estimates on AP events accrual based on your patient's baseline characteristics, and also your change in plans to broaden the AP adjudication criteria?

Speaker #6: We're expecting to see the patient for your baseline QTc pivotal next week. What are your estimates on AP events accrual based on the patient's baseline characteristics and also your change in broadening plans to the AP adjudication criteria?

Speaker #1: You know , Maury , I think it's a little bit hard to answer the question . Just because have we adapted our now protocols to to go ahead and adopt the the modified Atlanta , since criteria those have been accepted by both FDA and EMA .

Operator: Maury, I think it's a little bit hard to answer the question just because we have adapted our protocols now to go ahead and adopt the modified Atlanta criteria, since those have been accepted by both FDA, EMA, and here in the US, at least, payers. This is really going to be our first experience with using that particular scale, which makes it a little hard to estimate exactly how many events we will have. It's hard to say. What you will see next week is you will see the percentage of patients that had a history of pancreatitis that were enrolled in the study. Based on that, I think you'll see that there's a good chance that we'll have the necessary number of events.

Bruce Given: Maury, I think it's a little bit hard to answer the question just because we have adapted our protocols now to go ahead and adopt the modified Atlanta criteria, since those have been accepted by both FDA, EMA, and here in the US, at least, payers. This is really going to be our first experience with using that particular scale, which makes it a little hard to estimate exactly how many events we will have. It's hard to say. What you will see next week is you will see the percentage of patients that had a history of pancreatitis that were enrolled in the study.

Speaker #1: Here in the U.S., at payers at least, this is really going to be our first experience with using that particular scale, which makes it a little too hard to estimate exactly how many events we will have.

Speaker #1: So it's hard to say what what you will see week is next you will see the of percentage patients that had a history of pancreatitis that were enrolled in the and based on that , you know that I think you'll that there's a good chance that we'll see have , you the know , number of necessary events .

Based on that, I think you'll see that there's a good chance that we'll have the necessary number of events. I'm a little bit uncomfortable trying to give any real predictions when we're using a scale that we haven't used before.

Speaker #1: But I'm a little bit uncomfortable trying to give any real predictions using a scale that we haven't used before.

Operator: I'm a little bit uncomfortable trying to give any real predictions when we're using a scale that we haven't used before. Understood. That's helpful. Thanks for taking my question. Thanks, Maury. Thank you. Our next question comes from the line of Jason Gerberry with Bank of America. Hi. This is Gina Ahn for Jason. Congrats on all the progress this quarter, and thank you so much for taking our question. Just a couple from us. I guess first on your ARO-MAP-T program, can you maybe just discuss which aspects of the drug is maybe differentiated from J&J's recently failed anti-tau antibody and what kind of still gives you the confidence in the target after the failure?

Speaker #6: Understood . taking my question That's helpful . .

Maury Raycroft: Understood. That's helpful. Thanks for taking my question.

Speaker #2: Thanks, Lauren. Thanks for.

Speaker #3: Thank you. Our next question comes from the line of Jason with Bank of America.

Bruce Given: Thanks, Maury.

Operator: Thank you. Our next question comes from the line of Jason Gerberry with Bank of America.

Speaker #7: Hi . This is Gina on for Jason . Congrats on all the progress this And thank you so much quarter . taking for our questions .

[Analyst] (Bank of America): Hi. This is Gina Ahn for Jason. Congrats on all the progress this quarter, and thank you so much for taking our question. Just a couple from us. I guess first on your ARO-MAP-T program, can you maybe just discuss which aspects of the drug is maybe differentiated from J&J's recently failed anti-tau antibody and what kind of still gives you the confidence in the target after the failure?

Speaker #7: Just a couple from I guess . us , First on your aero mapped program , just can you maybe discuss which aspects of the is maybe drug differentiated from recently failed anti-tau antibody and what kind of still gives you the confidence target in the failure ?

Speaker #7: And then kind of just based on your current cash position and the progress that you've made on partner these mile partnership milestone do you have any any triggers , updates on your visibility on a launching Is that more tied to kind of the seeing how FCS and study ?

Operator: Just kind of based on your current cash position and the progress that you've made on these partnership milestone triggers, do you have any maybe updates on your visibility on launching a CBOT study? Is that more tied to kind of seeing how the FCS and potential SHTG launches are progressing? Can you just remind us any potential milestone triggers from the Sarepta programs that you're expecting in 2026? Thank you so much. All right. I count three questions. Gene, do you want to take the first one? Sure. Yeah, I'll take the first one on the MAPT program. The J&J antibody, the monoclonal as well as other monoclonals, are IV-administrated monoclonal antibodies. Probably a small fraction of those molecules cross the blood-brain barrier.

Just kind of based on your current cash position and the progress that you've made on these partnership milestone triggers, do you have any maybe updates on your visibility on launching a CBOT study? Is that more tied to kind of seeing how the FCS and potential SHTG launches are progressing? Can you just remind us any potential milestone triggers from the Sarepta programs that you're expecting in 2026? Thank you so much.

Speaker #7: Progressing? Launches are just... And can you remind us of any triggers or milestones from the programs that you're expecting in 2026? Thank you so much.

Speaker #2: All right. I count three questions. I'll take.

Speaker #1: Sure. Yeah, I'll take.

Speaker #1: the first one on . the the the first one . .

Chris Anzalone: All right. I count three questions. Gene, do you want to take the first one?

Speaker #1: So Program . the JNJ .

Speaker #2: The antibody, monoclonal as well as other monoclonals, are.

James Hamilton: Sure. Yeah, I'll take the first one on the MAPT program. The J&J antibody, the monoclonal as well as other monoclonals, are IV-administrated monoclonal antibodies. Probably a small fraction of those molecules cross the blood-brain barrier. They're primarily focused on binding to extracellular tau, so tau that's been released from damaged cells or has been secreted and that can propagate and bind to tau that's outside of the cell. Our approach is very different. We use a targeting ligand to facilitate delivery of the siRNA across the blood-brain barrier into the neuron and silence the expression of tau.

Speaker #1: IV Administrated

Speaker #1: .

Speaker #2: Monoclonal antibodies, probably a.

Speaker #1: Small

Speaker #2: Of .

Speaker #1: Those fractions. Those molecules cross the.

Speaker #2: Blood barrier . brain And then are primarily . focused on binding to .

Speaker #1: Tau. Extracellular So tau.

Speaker #2: That's been released from damaged.

Operator: They're primarily focused on binding to extracellular tau, so tau that's been released from damaged cells or has been secreted and that can propagate and bind to tau that's outside of the cell. Our approach is very different. We use a targeting ligand to facilitate delivery of the siRNA across the blood-brain barrier into the neuron and silence the expression of tau. We're sort of turning off the faucet for all of the expression and preventing the neurofibrillary tangles to form in the first place. We should get, over time, be able to reduce the level of intracellular tau and extracellular tau, whereas the monoclonal antibodies are really just able to get the extracellular tau. That's the key differentiator. On the other two questions, I'll answer the last one first, the SREP milestone.

Speaker #1: Cells .

Speaker #2: Or has .

Speaker #1: Been secreted .

Speaker #2: And that can propagate and bind to tau. That's outside of the.

Speaker #1: Cell. Our approach is.

Speaker #2: Very different .

Speaker #1: We use a targeting ligand to facilitate the delivery of the across blood.

Speaker #2: Brain barrier . into the

Speaker #2: silence .

Speaker #1: The expression of tau, we're sort of turning off the faucet all of for. So, the expression, preventing.

Speaker #2: The neurofibrillary tangles form in the.

We're sort of turning off the faucet for all of the expression and preventing the neurofibrillary tangles to form in the first place. We should get, over time, be able to reduce the level of intracellular tau and extracellular tau, whereas the monoclonal antibodies are really just able to get the extracellular tau. That's the key differentiator.

Speaker #1: First place . So we should . get that .

Speaker #2: Time, be able to reduce the overall level of.

Speaker #2: intracellular . Whereas the Tau . monoclonal antibodies are really just able to get the .

Speaker #1: Tau .

Speaker #2: And extracellular .

Speaker #1: That's the extracellular tau. So, key differentiator.

Speaker #2: And on the

Speaker #2: other two questions I'll answer the last . one . First , the strategy milestone . So we are eligible to the receive first of $550 million annuities in February .

Chris Anzalone: On the other two questions, I'll answer the last one first, the SREP milestone. We are eligible to receive the first of five $50 million annuities in February. We expect that over the next several months. That's correct. February, right?

Operator: We are eligible to receive the first of five $50 million annuities in February. We expect that over the next several months. That's correct. February, right? Yes. Correct. On the visibility on the CBOT, as you know, that CBOT is for the dimer. That's a big opportunity for us. We are moving as quickly as we can to that CBOT. We'll have a good idea, I think, this summer if we have a drug. We'll know PCSK9 knockdown, we'll know APOC3 knockdown, we'll know LDL decreases, we'll know triglyceride decreases. Given what those data look like, I think, again, as early as this summer, we'll know if we have something that really could be an important treatment for these mixed hyperlipidemia patients.

Speaker #2: So we expect that over the months . That's correct . February . next several Yes Right . . On the visibility on the on the on the cvot .

Speaker #2: So , so that that Cvot , as you know , is is for the dimer . That's a big for us . And opportunity so we are moving as we quickly as can to that We'll have a good idea .

Dan Apel: Yes. Correct.

Chris Anzalone: On the visibility on the CBOT, as you know, that CBOT is for the dimer. That's a big opportunity for us. We are moving as quickly as we can to that CBOT. We'll have a good idea, I think, this summer if we have a drug. We'll know PCSK9 knockdown, we'll know APOC3 knockdown, we'll know LDL decreases, we'll know triglyceride decreases. Given what those data look like, I think, again, as early as this summer, we'll know if we have something that really could be an important treatment for these mixed hyperlipidemia patients.

Speaker #2: I slot . summer if think this we have a drug you know , we'll we'll know Pcsk9 knockdown , we'll know Apoc3 we'll know knockdown , LDL know decreases , we'll triglyceride decreases .

Speaker #2: And so given given what those data look like , I think again , as early as this summer , I think we'll we have something that really could , know if could , could be an important treatment for these hyperlipidemia mixed patients .

Speaker #2: Should that be successful , should that look good We are ? not waiting on anything to to to start those studies other than finishing this phase two are our plan is to be able to roll one , directly into pivotal studies after these phase one two studies again should they should they all go there's well and nothing you know , there's nothing gaining there other than the data than looking good .

Operator: Should that be successful, should that look good, we are not waiting on anything to start those studies other than finishing this phase one, two. Our plan is to be able to roll directly into pivotal studies after these phase one, two studies. Again, should they all go well, and there's nothing gaining there other than the data looking good. We also are hoping to have parallel pivotal studies, one that will be a CBOT, and one that will be looking at simply lowering LDL over the course of the year. As you know, that has been an approval endpoint in the past for PCSK9 inhibitors. We think that could be a good way to get to market very quickly and, frankly, help us to pay for the CBOT. That's our plan now.

Should that be successful, should that look good, we are not waiting on anything to start those studies other than finishing this phase one, two. Our plan is to be able to roll directly into pivotal studies after these phase one, two studies. Again, should they all go well, and there's nothing gaining there other than the data looking good. We also are hoping to have parallel pivotal studies, one that will be a CBOT, and one that will be looking at simply lowering LDL over the course of the year. As you know, that has been an approval endpoint in the past for PCSK9 inhibitors. We think that could be a good way to get to market very quickly and, frankly, help us to pay for the CBOT.

Speaker #2: We also are hoping to have parallel pivotal studies , one that will be a lot . And will that then one that looking at at simply lowering LDL over the course of the year .

Speaker #2: As you know , that an approval endpoint has been in the past for for Pcsk9 inhibitors . And we think that could be a good way to get market very quickly .

Speaker #2: And frankly , help us to pay for the cvot that's . So our plan now . We'll have a better idea much about about how quickly we can move summertime in the once we start to see those data , we're looking forward to seeing those data .

That's our plan now. We'll have a much better idea about how quickly we can move in the summertime once we start to see those data. We're really looking forward to seeing those data.

Operator: We'll have a much better idea about how quickly we can move in the summertime once we start to see those data. We're really looking forward to seeing those data. Thank you. You're welcome. Thank you. Our next question comes from the line of Edward Tenthoff with Piper Sandler. Great. Thank you very much. Bruce, wishing you all the best. James, wishing you all the best. It really is a super exciting time for the company. I wanted to get a sense just with respect to upcoming data readouts next year, specifically asking, do you think you'll have your first look from the AROWDimer PA next year? What other data sets beyond the obesity data in the first half should we be thinking about? Thanks, Dan. We have a bunch of, I think, potentially very interesting data readouts throughout 2026.

Speaker #7: Thank you .

Speaker #2: You're welcome .

[Analyst] (Bank of America): Thank you.

Speaker #3: Thank you. Our next question comes from the line of Edward Tenthoff with Piper Sandler.

Chris Anzalone: You're welcome.

Operator: Thank you. Our next question comes from the line of Edward Tenthoff with Piper Sandler.

Speaker #1: Great .

Speaker #8: you very Thank much . And , Bruce , wishing you all the best and James , wishing you all the best of luck .

Edward Tenthoff: Great. Thank you very much. Bruce, wishing you all the best. James, wishing you all the best. It really is a super exciting time for the company. I wanted to get a sense just with respect to upcoming data readouts next year, specifically asking, do you think you'll have your first look from the AROWDimer PA next year? What other data sets beyond the obesity data in the first half should we be thinking about?

Speaker #8: It really is a super time for the exciting company . I wanted to get a sense just with respect to upcoming data readouts next year , specifically think asking , do you you'll have your first look from the aero dimer PA next year what other data ?

Speaker #8: Beyond sets obesity data in the And first half? Be thinking should we about?

Speaker #2: Thanks . We have we have a bunch of , I think potentially very data interesting readouts throughout 2026 . As mentioned you , obesity will be the will be the first , you know , as I mentioned , we should have two bites of that apple or thereabouts .

Chris Anzalone: Thanks, Dan. We have a bunch of, I think, potentially very interesting data readouts throughout 2026. As you mentioned, obesity will be the first. As I mentioned, we should have two bites of that apple or thereabouts. We'll have our first early data set in the very first part of January. Then as the data mature in both those programs, say, towards the end of the second quarter, something around then, we'll have a much larger data set. We think those are important. In the summertime, we expect to have dimer data. We think those are extraordinarily important.

Operator: As you mentioned, obesity will be the first. As I mentioned, we should have two bites of that apple or thereabouts. We'll have our first early data set in the very first part of January. Then as the data mature in both those programs, say, towards the end of the second quarter, something around then, we'll have a much larger data set. We think those are important. In the summertime, we expect to have dimer data. We think those are extraordinarily important. The idea that we might have a drug candidate that can simultaneously lower LDL and triglycerides to treat the 20 million or so people in the United States with mixed hyperlipidemia is a very exciting opportunity. Again, I think we'll know if we have something that could really fit there in the summertime.

Speaker #2: And we'll have our first early data set , you know , in the , in the very first part of . And then January as , as the in both data mature those programs stay towards , you know , the , the , the end of the second quarter , around then we'll have a much larger data We think those are set .

Speaker #2: in the important summertime , we expect to have dimer . Those are data within extraordinarily important . You know , the idea that we have might have a drug that can candidate simultaneously lower LDL and triglycerides to treat the 20 million or so people in the United States with mixed is a hyperlipidemia very exciting opportunity .

The idea that we might have a drug candidate that can simultaneously lower LDL and triglycerides to treat the 20 million or so people in the United States with mixed hyperlipidemia is a very exciting opportunity. Again, I think we'll know if we have something that could really fit there in the summertime. Also, in the summertime, I think we'll have our first bit of ARO-MAP-T data. We'll be looking for tau levels in the CSF. That also would be extraordinarily exciting. We could be at once sitting on one of the most exciting potential Alzheimer's drugs in the clinic.

Speaker #2: think we'll again , we'll I if know we have something that could really fit there in the summertime . Also , in the summertime , I think we'll have our first bid of of aero data , and we'll looking be for , for tau the in CSF levels .

Operator: Also, in the summertime, I think we'll have our first bit of ARO-MAP-T data. We'll be looking for tau levels in the CSF. That also would be extraordinarily exciting. We could be at once sitting on one of the most exciting potential Alzheimer's drugs in the clinic. Hopefully, we'll be de-risking the entire blood-brain barrier platform that can enable us to treat a variety of CNS diseases. That is an important readout. Of course, also in the third quarter or so, we expect to have the readout for SHASTA III and IV that are designed to enable our SNDA by the end of the year. At the end of the year, we expect to file our SNDA. Look, there will be other things happening during the year, but those, to me, feel like the primary ones.

Speaker #2: That also would be extraordinarily exciting . We can be at one sitting on one of the most exciting potential Alzheimer's drug drugs in the clinic .

Speaker #2: And hopefully will be de-risking the blood entire brain barrier platform that that can enable us to treat a variety of of of CNS diseases .

Hopefully, we'll be de-risking the entire blood-brain barrier platform that can enable us to treat a variety of CNS diseases. That is an important readout. Of course, also in the third quarter or so, we expect to have the readout for SHASTA III and IV that are designed to enable our SNDA by the end of the year. At the end of the year, we expect to file our SNDA. Look, there will be other things happening during the year, but those, to me, feel like the primary ones. Of course, we'll be in the market. We'll be in the market, and we'll be really looking forward to seeing how the adoption curve that we're down below is going to have.

Speaker #2: And so that's an important readout . Of course , also in the in the third quarter or so , we expect to have the readout for Shasta three and four .

Speaker #2: You know , that are designed to enable the NDA by the end of the year . And at the end then , of course , we expect to have of the expect to file our snda .

Speaker #2: So , look , there will other other be things happening during the year . But but those to me feel like like the primary ones .

Speaker #2: And of course we'll be in the market , will be in the market and , and you know , we'll be really looking forward to seeing seeing how seeing the adoption curve that we're have going to .

Operator: Of course, we'll be in the market. We'll be in the market, and we'll be really looking forward to seeing how the adoption curve that we're down below is going to have. Great. Any update on AROWRAGE just to be comprehensive? Thank you. Yeah. Thank you. Yes. As you know, Ted, the data so far for AROWRAGE have been enticing. We've seen that we can knock down RAGE deeply, both looking at circulating biomarkers as well as valve. That's super interesting. Where we've struggled is looking for biomarkers to show potential clinical benefit. Rather than running directly into a large asthma or COPD phase two, we were hoping to have a baby step to see some evidence of that. We have started a challenge study.

Speaker #8: Great . Any update on range ? Aero Just to be Thank you comprehensive . .

Edward Tenthoff: Great. Any update on AROWRAGE just to be comprehensive? Thank you.

Speaker #2: Thank you . Yes . Yeah . So so as you know , Ted , the data so far for aero range have been enticing .

Chris Anzalone: Yeah. Thank you. Yes. As you know, Ted, the data so far for AROWRAGE have been enticing. We've seen that we can knock down RAGE deeply, both looking at circulating biomarkers as well as valve. That's super interesting. Where we've struggled is looking for biomarkers to show potential clinical benefit. Rather than running directly into a large asthma or COPD phase two, we were hoping to have a baby step to see some evidence of that. We have started a challenge study.

Speaker #2: You know , we've seen that we can knock down rage deeply . Both looking at at circulating biomarkers as well as Bal . That's super interesting .

Speaker #2: Where we've struggled is , is looking for biomarkers to show potential clinical benefit . And so rather than running directly into a large asthma or COPD phase two , we are hoping to have a baby step to to see some evidence of of that .

Speaker #2: And so we have started challenge a study . I don't expect to have data In 26 , maybe . at the very end of 26 , but we've just started And that .

Operator: I don't expect to have data in 2026, maybe at the very end of 2026, but we've just started that. My hope is that that will show us that knocking down RAGE is an important thing. Look, it's been an undruggable target for some time, and now we can drug it. Now let's see what that does for us. I think at the end of that, we can then ask ourselves, do we want to build out a pulmonary franchise, or do we want to partner that? I think a positive challenge study readout would allow us to partner that under attractive terms. Great. Well, guys, congrats on all the great progress. I'm really excited to see the REDEMPLO launch. It's a great drug. Thank you, Ted. Thank you. Our next question comes from the line of Mani Foroohar with Leerink Partners. Yes.

I don't expect to have data in 2026, maybe at the very end of 2026, but we've just started that. My hope is that that will show us that knocking down RAGE is an important thing. Look, it's been an undruggable target for some time, and now we can drug it. Now let's see what that does for us. I think at the end of that, we can then ask ourselves, do we want to build out a pulmonary franchise, or do we want to partner that? I think a positive challenge study readout would allow us to partner that under attractive terms. Great. Well, guys, congrats on all the great progress. I'm really excited to see the REDEMPLO launch. It's a great drug. Thank you, Ted.

Speaker #2: so my hope is that that will that is that will show that , that , us that knocking down rage is an important thing .

Speaker #2: Look , it's been an undruggable target for some And , time . and now we can drug it . And so now let's let's see what let's that does for us .

Speaker #2: I think at the end of that, we can then ask: do we want to build out our own pulmonary franchise, or do we want to partner that?

Speaker #2: And I know, a positive think, you challenge study readout would allow us to partner that in attractive, attractive terms.

Speaker #8: Well , Great . guys , congrats on the all great progress and excited to see the really great launch . It's a drug .

Speaker #2: Thank you Ted .

Speaker #3: Thank you. Our next question comes from the line of Manny Foroohar at Partners with Leerink.

Operator: Thank you. Our next question comes from the line of Mani Foroohar with Leerink Partners. Yes.

Speaker #9: guys . Thanks for taking the Hey question . Congrats on the progress on the first product launch , and wishes also to Bruce best on his the Re retirement .

Operator: Thanks again for the question. Congrats on the progress and the first product launch. Best wishes also to Bruce on his re-retirement. Though something tells me you're going to pop up again soon. I don't think you're done with us. Apropos of the question, I want to follow up on the broader pipeline I know Ted touched on, new AROWRAGE study, etc. How do we think about AROWDimer application in terms of pursuing CBOTs and the right target for that technology? Where are the right places for you to put that to work now that you've got sort of a very different place in terms of your balance sheet? Actually, Bruce, do you want to take where that fits? Yeah, I'm happy to take that. Obviously, we're excited about plozasiran and APOC3 inhibition generally for patients with severe hypertriglyceridemia.

Mani Foroohar: Thanks again for the question. Congrats on the progress and the first product launch. Best wishes also to Bruce on his re-retirement. Though something tells me you're going to pop up again soon. I don't think you're done with us. Apropos of the question, I want to follow up on the broader pipeline I know Ted touched on, new AROWRAGE study, etc. How do we think about AROWDimer application in terms of pursuing CBOTs and the right target for that technology? Where are the right places for you to put that to work now that you've got sort of a very different place in terms of your balance sheet?

Speaker #9: So something tells me you're going to pop up again soon . I don't think you're done with us . Apropos of the question , I .

Speaker #9: I would like to follow up on some of the broader pipeline. Ted touched on the air raid study, etc. How do we think about aero dimer applications in terms of pursuing CVOTs in the right target for that or for that technology?

Speaker #9: And where are the right places for you to put work now that you've got sort of a very different place in terms of your balance sheet?

Speaker #2: Bruce, why take where that can fit?

Speaker #1: happy to I'm take that . Yeah , You know , obviously we're excited about the and Apoc3 inhibition generally for patients with severe hypertriglyceridemia .

Chris Anzalone: Actually, Bruce, do you want to take where that fits?

Bruce Given: Yeah, I'm happy to take that. Obviously, we're excited about plozasiran and APOC3 inhibition generally for patients with severe hypertriglyceridemia. That's been essentially very, very poorly treated populations for a long time. LDL, the LDL side of the equation, on the other hand, has been really a different story. Other than HoFH, there's a pretty good number of tools in the tool chest for dealing with LDL. The patients on that LDL side of the equation, especially patients with heterozygous familial hypercholesterolemia, which is a pretty good-sized population, for instance.

Speaker #1: That's been essentially very , an poorly treated population . For a long time . You know , LDL the , you LDL side of the equation on the other hand , has been a really a different story .

Operator: That's been essentially very, very poorly treated populations for a long time. LDL, the LDL side of the equation, on the other hand, has been really a different story. Other than HoFH, there's a pretty good number of tools in the tool chest for dealing with LDL. The patients on that LDL side of the equation, especially patients with heterozygous familial hypercholesterolemia, which is a pretty good-sized population, for instance. The 20-some million patients in the US alone that have mixed hyperlipidemia has been an interesting population. We could address the LDL part. We've done really a terrible job historically of being able to address the triglyceride piece of that. The post-hoc analyses that have been done of CVOTs have shown that for the same LDL reduction, you can really rank order the risk that patients have by how high their triglycerides are.

Speaker #1: And other than Hofh , there's there's a pretty good number of tools in the chest for dealing with LDL . You know , the patients that , that on LDL side of the especially patients with equation , heterozygous , you familial hypercholesterolemia , which is size pretty good population , for instance .

Speaker #1: But , you know , the 20 some million patients in the US alone that have mixed hyperlipidemia has been an interesting population . You know , we could we could address the LDL part .

The 20-some million patients in the US alone that have mixed hyperlipidemia has been an interesting population. We could address the LDL part. We've done really a terrible job historically of being able to address the triglyceride piece of that. The post-hoc analyses that have been done of CVOTs have shown that for the same LDL reduction, you can really rank order the risk that patients have by how high their triglycerides are. Of course, the Mendelian randomization data has also said that triglycerides are an independent predictor of events and mortality in that mixed hyperlipidemia population.

Speaker #1: We've done a really terrible a job of historically , being able to address the triglyceride piece that . And , you know , and the the post hoc analyses that have been done of Cvots have shown that for the same LDL reduction , you can really rank order the that patients have risk by how high their triglycerides are .

Speaker #1: And of course , the Mendelian randomization data has also said that triglycerides are independent predictor of of events and mortality , in that that mixed hyperlipidemia population and it's huge .

Operator: Of course, the Mendelian randomization data has also said that triglycerides are an independent predictor of events and mortality in that mixed hyperlipidemia population. It's huge. It's a very big population. There's never really been a very good way of addressing both sides of the problem in mixed hyperlipidemia, both the LDL and the triglycerides. Here we're talking about a drug that could potentially do it with a single, say, quarterly injection, get both their LDL and their triglycerides, probably on top of a statin. I think you're going to always have a statin there if the patients can tolerate it. You could have a daily statin and a quarterly dimer injection and potentially treat that 20 million patients to low-risk levels of LDL and triglycerides.

Speaker #1: It's a very big population . So , you know , there's never really been a very good way of addressing , both sides of the problem .

It's huge. It's a very big population. There's never really been a very good way of addressing both sides of the problem in mixed hyperlipidemia, both the LDL and the triglycerides. Here we're talking about a drug that could potentially do it with a single, say, quarterly injection, get both their LDL and their triglycerides, probably on top of a statin. I think you're going to always have a statin there if the patients can tolerate it. You could have a daily statin and a quarterly dimer injection and potentially treat that 20 million patients to low-risk levels of LDL and triglycerides.

Speaker #1: In mixed hyperlipidemia , both the LDL and the triglycerides . And here we're talking about a drug that could potentially do it with a single , you know , say quarterly .

Speaker #1: injection You know , get , you know , both their LDL and their triglycerides , probably on top of a statin . I think you're going to always have a statin there .

Speaker #1: If the patients can tolerate But you could have it . daily stat and a quarterly dimer injection . And and you potentially , treat you know , that that 20 million patients , you know to to low risk levels of LDL and triglycerides .

Speaker #1: That would be quite an amazing opportunity , I think from a marketing perspective , compared to what you can do today , which is you can probably get the LDL taken care of today , but you probably can't at worthwhile in the all triglycerides .

Operator: That would be quite an amazing opportunity, I think, from a marketing perspective compared to what you can do today, which is you can probably get the LDL taken care of today, but you probably can't do much at all worthwhile in the triglycerides. This is what makes this, to us, such an interesting proposition. Yeah. As you know, Manny, what we used to, our former strategy was to make plozasiran, now REDEMPLO, a three-step drug. Step one is FCS. Step two is SHTG. Step three, after a CVOT, would be to be part of a treatment in mixed hyperlipidemia. Once we were able to perfect, at least in animals, the dimer platform, it didn't make any sense any longer. We liked the idea of keeping REDEMPLO as a pure-play pancreatitis drug. Full stop.

That would be quite an amazing opportunity, I think, from a marketing perspective compared to what you can do today, which is you can probably get the LDL taken care of today, but you probably can't do much at all worthwhile in the triglycerides. This is what makes this, to us, such an interesting proposition.

Speaker #1: So this is what makes this to us such an interesting proposition.

Speaker #2: you Manny , And as know , what we used to our former strategy was to was to make aldosterone . Now a three step drug .

Chris Anzalone: Yeah. As you know, Manny, what we used to, our former strategy was to make plozasiran, now REDEMPLO, a three-step drug. Step one is FCS. Step two is SHTG. Step three, after a CVOT, would be to be part of a treatment in mixed hyperlipidemia. Once we were able to perfect, at least in animals, the dimer platform, it didn't make any sense any longer. We liked the idea of keeping REDEMPLO as a pure-play pancreatitis drug. Full stop. I think we'll have a tool to more completely treat that mixed hyperlipidemia population should this dimer translate well from animals to humans.

Speaker #2: FCS step . Step two is Step one is step three . After a Cvot would be this , you know , would be to to be part of a in treatment mixed hyperlipidemia .

Speaker #2: Once we were able to perfect at least in animals , the dimer platform , make it didn't any didn't make any sense any longer .

Speaker #2: We like the idea of keeping her as a pure play pancreatitis drug, full stop. And now I think we'll have a tool to more completely treat mixed hyperlipidemia in this population, should this dimer translate well from animals to humans.

Operator: I think we'll have a tool to more completely treat that mixed hyperlipidemia population should this dimer translate well from animals to humans. That's helpful. As a follow-up, when you think about potential dimer applications, etc., how are you thinking about the data next year from Horizon and potentially applications of combining what hopefully will be a validated APOA target with other approaches to their risk-elevating elements of the lipid profile? Yeah, sure. Of course, our siRNA is targeting APOA, is partnered with Amgen. We would have to work with them on any kind of dimer applications. There are other applications beyond, of course, the PCSK9, APOC3. I mean, we're looking at other dimers in the CV space, both targeting hepatocytes and extrahepatic cell types. This is probably not the only dimer that you'll see out of Arrowhead. All right. Thanks, guys.

Speaker #9: helpful . up ? That's think about potential dimer applications , etc. , how are you thinking about the data from next year horizon and how and potential applications of combining what hopefully will be a validated lp-pla target with other with other approaches to risk elevating elements of lipid profile .

Speaker #9: And as a

Mani Foroohar: That's helpful. As a follow-up, when you think about potential dimer applications, etc., how are you thinking about the data next year from Horizon and potentially applications of combining what hopefully will be a validated APOA target with other approaches to their risk-elevating elements of the lipid profile?

Speaker #1: Yeah, sure. So, of course.

Speaker #2: Our .

Speaker #1: siRNA targeting our LP. Little is partnering.

Speaker #2: With Amgen .

Speaker #1: So we would have to work with.

James Hamilton: Yeah, sure. Of course, our siRNA is targeting APOA, is partnered with Amgen. We would have to work with them on any kind of dimer applications. There are other applications beyond, of course, the PCSK9, APOC3. I mean, we're looking at other dimers in the CV space, both targeting hepatocytes and extrahepatic cell types. This is probably not the only dimer that you'll see out of Arrowhead.

Speaker #2: Them on . any kind of dimer .

Speaker #1: Applications. But there are other applications.

Speaker #2: . Beyond

Speaker #1: course that . Of Pcsk9

Speaker #1: apoc3 .

Speaker #2: We're looking at other, I mean, dimers in the CV space, both targeting sites and ...

Speaker #1: Extrahepatic cell types .

Speaker #2: . So

Speaker #1: This is probably .

Speaker #2: Not the only dimer that you'll see out of Arrowhead.

Speaker #9: Thanks, guys. That's really helpful. Congrats to all right again.

Speaker #2: Thank you .

Speaker #3: Thank you. Our next question comes from the line of Patrick Trujillo with H.C. Wainwright.

Mani Foroohar: All right. Thanks, guys. That's really helpful. Congrats again.

Operator: That's really helpful. Congrats again. Thank you. Thank you. Our next question comes from the line of Patrick Trucchio with H.C. Wainwright. Thanks. Congrats on all the progress. I have a few follow-up questions. The first is regarding REDEMPLO. I'm wondering if the FDA has provided clarity on what level of pancreatitis evidence would be required for a future pancreatitis risk reduction claim, particularly in the high-risk FCS patient population. Separately, I'm wondering if there's been discussions around a potential pediatric pathway, given that FCS presents in childhood. Then, a follow-up on the MAPT program. I'm wondering what level of CSF tau knockdown or biomarker response you would consider clear clinical proof of concept in humans, given I think you have greater than 75% knockdown in the NHP data. Bruce, why don't you take the first, and then I'll take the MAPT.

Chris Anzalone: Thank you.

Operator: Thank you. Our next question comes from the line of Patrick Trucchio with H.C. Wainwright.

Speaker #1: Thanks, congratulations on all the.

Speaker #8: Progress . I have a few follow up questions . Just the first is just regarding redemption . I'm wondering if the FDA has provided on what clarity level of pancreatitis evidence would be required for a future pancreatitis risk reduction claim in particularly in the high risk patient population and separately , if there's I'm wondering been discussions around potential pediatric pathway just given it .

Patrick Trucchio: Thanks. Congrats on all the progress. I have a few follow-up questions. The first is regarding REDEMPLO. I'm wondering if the FDA has provided clarity on what level of pancreatitis evidence would be required for a future pancreatitis risk reduction claim, particularly in the high-risk FCS patient population. Separately, I'm wondering if there's been discussions around a potential pediatric pathway, given that FCS presents in childhood. Then, a follow-up on the MAPT program.

Speaker #8: FCS , you know , presents in childhood and then just a follow on up the on the map program . I'm wondering what level of CSF tau knockdown or biomarker response would you consider clear clinical proof of concept in humans ?

I'm wondering what level of CSF tau knockdown or biomarker response you would consider clear clinical proof of concept in humans, given I think you have greater than 75% knockdown in the NHP data.

Speaker #8: Just given? I think you had greater than 75% knockdown in the NHP data.

Speaker #2: You take the Bruce, will first and then take that to.

Speaker #1: So the first was level of AP that we think the FDA is . required it on to have label . Yeah . You know , we have not discussed with the FDA what it would specifically take to get a claim per se .

Chris Anzalone: Bruce, why don't you take the first, and then I'll take the MAPT. The first was level of AP that we think the FDA is required to have it on the label.

Operator: The first was level of AP that we think the FDA is required to have it on the label. Yeah. We have not discussed with the FDA specifically what it would take to get a claim per se. I'm not sure we've really felt that was necessary. I mean, I think physicians have no real question about the relationship of triglycerides to pancreatitis risk, especially now that it's been proven. Payers haven't seemed to be concerned about that either, at least in the US. I'm not sure what the value of a claim would be. Of course, at this point, it's untested whether the agency would consider providing that claim. I don't know that we've really thought of it as being necessary, Patrick, to be clear. In FCS. Patrick, is your question on FHCG or FCS? Actually, the high-risk FHCG patient population. Yeah.

Bruce Given: Yeah. We have not discussed with the FDA specifically what it would take to get a claim per se. I'm not sure we've really felt that was necessary. I mean, I think physicians have no real question about the relationship of triglycerides to pancreatitis risk, especially now that it's been proven. Payers haven't seemed to be concerned about that either, at least in the US. I'm not sure what the value of a claim would be. Of course, at this point, it's untested whether the agency would consider providing that claim. I don't know that we've really thought of it as being necessary, Patrick, to be clear. In FCS. Patrick, is your question on FHCG or FCS?

Speaker #1: not sure I'm felt that was we've really necessary . I mean , I think physicians , you know , have no real question about the relationship of triglycerides to pancreatitis risk , especially now that it's been it's been proven and payers haven't seemed to be concerned that either .

Speaker #1: not sure I'm felt that was we've really necessary . I mean , I think physicians , you know , have no real question about the relationship of triglycerides to pancreatitis risk , especially now that it's been it's been proven and payers haven't seemed to be concerned that about At least in the US .

Speaker #1: So not sure I'm what the of a of a value claim would be . It's and of course , at this point it's untested whether .

Speaker #1: Whether the agency would consider providing that, you know, that claim. I don't know that we've really thought of it as being necessary.

Speaker #1: Patrick , to be .

Speaker #2: In Patrick ,

Speaker #2: Question on: Is your clear FDG or FCS?

Speaker #8: It was around, actually the high-risk StG patient population.

Speaker #1: Yeah , but the answer , is the same . I think we at least have not them asking them , know , would they you give a claim what it would take to get that claim ?

Patrick Trucchio: Actually, the high-risk FHCG patient population.

Bruce Given: Yeah. The answer is the same, I think. We at least have not approached them asking them, would they give a claim, what it would take to get that claim. It's very possible that what they would require is something like SHASTA V. The SHASTA V was really designed primarily on the possibility that the payers in countries outside the US might require an actual dedicated outcome study. It was more payer-focused than it was regulatory-focused. We really were not committed one way or the other about whether it'd be submitted to regulators asking for a label change.

Operator: The answer is the same, I think. We at least have not approached them asking them, would they give a claim, what it would take to get that claim. It's very possible that what they would require is something like SHASTA V. The SHASTA V was really designed primarily on the possibility that the payers in countries outside the US might require an actual dedicated outcome study. It was more payer-focused than it was regulatory-focused. We really were not committed one way or the other about whether it'd be submitted to regulators asking for a label change. We were more interested really in protecting the possibility that there would be payers outside of the US that would require a specific proof of concept in a dedicated study. We really haven't raised this with regulators anywhere on a global basis at this point.

Speaker #1: It's very possible that what they would require is like five , Shasta but , you know , Shasta the five was really designed primarily , you know , on the the possibility that that the payers in countries US outside the might require actual an outcome dedicated .

Speaker #1: study it was So more payer focused than it was regulatory focused you know , we . And , you know , we really were committed not one way or the other about whether it be submitted to regulators asking for a label We change .

Speaker #1: were more really interested in protecting the there would possibility that be payers outside of the US . It would require , you know , a specific proof of proof of concept in dedicated a study we really haven't raised this .

Speaker #1: were more really interested in protecting the there would possibility that be payers outside of the US . It would require , you know , a specific proof of proof of concept in dedicated a study we really haven't raised this . with with regulators , you know , anywhere in a basis So global at this .

We were more interested really in protecting the possibility that there would be payers outside of the US that would require a specific proof of concept in a dedicated study. We really haven't raised this with regulators anywhere on a global basis at this point.

Speaker #1: point

Speaker #2: undress You the question .

Speaker #1: The pedes question , we absolutely plan to do pediatric work in FCS . We we we have those plans in We place . have a pediatric plan Europe in , you know , and and in the US , the only thing holding us back right now is just that we have to have a formulation that we can that we can use for weight based dosing .

Operator: Do you want to address the peds question? The peds question. We absolutely plan to do pediatric work in FCS. We have those plans in place. We have a pediatric plan in Europe and in the US. The only thing holding us back right now is just that we have to have a formulation that we can use for weight-based dosing. That's just we're in the process of getting that formulation put together so that we can go ahead and do those studies. We're absolutely planning on doing that. James, do you want to talk about MAPT knockdown? Yeah, sure. In terms of what we're looking for, based on the SINO data, as you mentioned, at the tissue level, we were seeing 75%+ reductions, and similar reductions in the CSF in monkeys. I mean, we typically translate well from SINOs into the clinic, into humans.

Chris Anzalone: Do you want to address the peds question?

Bruce Given: The peds question. We absolutely plan to do pediatric work in FCS. We have those plans in place. We have a pediatric plan in Europe and in the US. The only thing holding us back right now is just that we have to have a formulation that we can use for weight-based dosing. That's just we're in the process of getting that formulation put together so that we can go ahead and do those studies. We're absolutely planning on doing that.

Speaker #1: And that's just, you know, we're in the process of getting that formulation put together so that we can go do those studies.

Speaker #1: But we're absolutely doing that.

Speaker #2: You

Speaker #2: About that, I want to talk. Planning on...

Speaker #1: sure . knockdown . In terms of what what we're looking for . on the . Based

Chris Anzalone: James, do you want to talk about MAPT knockdown?

James Hamilton: Yeah, sure. In terms of what we're looking for, based on the SINO data, as you mentioned, at the tissue level, we were seeing 75%+ reductions, and similar reductions in the CSF in monkeys. I mean, we typically translate well from SINOs into the clinic, into humans.

Speaker #2: Data , as you mentioned , at .

Speaker #1: The .

Speaker #2: At this level, we were seeing 75% plus and similar reductions in the tissue.

Speaker #2: In CSF, monkeys. I mean.

Speaker #1: We typically .

Speaker #2: Translate well from Cynos into the clinic, into humans. And I think.

Speaker #1: Based on .

Speaker #2: Some of the .

Speaker #1: Other data .

Speaker #2: Out there with .

Speaker #1: The Intrathecally administered Aso .

Speaker #2: They were .

Operator: I think based on some of the other data out there with the intrathecally administered ASO, they were able to achieve CSF reductions of about 50% to 60%. Those CSF reductions corresponded to improvements in tau PET, improved tau PET signals. I think that's probably where we're aiming for in our clinical study, at least 50% to 60% reduction in the CSF. That's what others have shown, and that seems to have translated into a meaningful tau PET signal. Great. Thanks so much. You're welcome. Thank you. Our next question comes from the line of Andrea Newkirk with Goldman Sachs. Good afternoon. Thanks for taking the question. Maybe one more on the REDEMPLO launch. Recognize it's only been about a week since the approval.

Speaker #1: Able to achieve CSF .

I think based on some of the other data out there with the intrathecally administered ASO, they were able to achieve CSF reductions of about 50% to 60%. Those CSF reductions corresponded to improvements in tau PET, improved tau PET signals. I think that's probably where we're aiming for in our clinical study, at least 50% to 60% reduction in the CSF. That's what others have shown, and that seems to have translated into a meaningful tau PET signal.

Speaker #2: Reductions of .

Speaker #1: About 50 to 60% .

Speaker #2: And those .

Speaker #1: CSF reductions corresponded to improvements in tau PET and PET signals. So,

Speaker #1: CSF reductions . corresponded to improvements in tau Pet . and Pet signals . So , tau You

Speaker #1: I know that.

Speaker #2: Probably where we're aiming for in our clinical study is at least a 50% to 60% reduction in.

Speaker #1: CSF. That's in the others.

Speaker #2: Have shown. And that.

Speaker #1: Seems to .

Speaker #2: Have translated into a meaningful tau PET signal.

Speaker #8: Thanks so much. Great.

Speaker #2: You're welcome .

Speaker #3: Thank you. Our next question comes from the line of Andrea Newkirk with Goldman Sachs.

Patrick Trucchio: Great. Thanks so much. You're welcome.

Operator: Thank you. Our next question comes from the line of Andrea Newkirk with Goldman Sachs.

Speaker #10: Good afternoon. Thank you for taking my question. I have one more regarding the launch. I recognize it's only been about a week since launch approval, but now that you have launched, I’m just curious if you’d be willing to comment on your expectations for the cadence of the initial launch.

Andrea Newkirk: Good afternoon. Thanks for taking the question. Maybe one more on the REDEMPLO launch. Recognize it's only been about a week since the approval. Now that you have launched, just curious if you'd be willing to comment on your expectations for the cadence of the initial launch here in FCS and how you think it may be similar or different from that of the Tringolza launch, particularly in the context of the significant pricing differential that you have. Thank you so much.

Operator: Now that you have launched, just curious if you'd be willing to comment on your expectations for the cadence of the initial launch here in FCS and how you think it may be similar or different from that of the Tringolza launch, particularly in the context of the significant pricing differential that you have. Thank you so much. Yeah. Happy to take that, Andrea. This is Andy. We do have very high ambitions for the REDEMPLO launch. Expect it to be best in class. As you know, there are a number of reasons why we believe that to be the case, largely around the attributes of REDEMPLO that we do believe make it a special molecule in this category. We talked about, obviously, the significant and sustained TG reduction. We've talked about the reduced incidence of acute pancreatitis.

Speaker #10: Urine FCS and how you think it may be similar or different from that of the launch, particularly in the context of the significant pricing differential that you have.

Speaker #10: Thank you so much .

Speaker #2: Yeah , happy to take that . Andrea . This is Andy . So we do have very high ambitions for the launch . Expect it to be be best in class .

Andy Davis: Yeah. Happy to take that, Andrea. This is Andy. We do have very high ambitions for the REDEMPLO launch. Expect it to be best in class. As you know, there are a number of reasons why we believe that to be the case, largely around the attributes of REDEMPLO that we do believe make it a special molecule in this category. We talked about, obviously, the significant and sustained TG reduction. We've talked about the reduced incidence of acute pancreatitis.

Speaker #2: as you know there are a And number of reasons why we to be the believe that case largely around the attributes of redemption that we do believe make it special molecule in this we talked category , about , obviously , the significant sustained TG and reduction we've talked about the incidence of acute reduced pancreatitis , but even more importantly , we hear a lot of positive feedback around the safety and tolerability no profile .

Speaker #2: So, contraindications, no warnings, and no precautions. We do have a lot of physicians and patients who are very enthusiastic about the once every three-month dosing regimen.

Operator: Even more importantly, we hear a lot of positive feedback around the safety and tolerability profile. No contraindications, no warnings, and no precautions. We do have a lot of physicians and patients who are enthusiastic about the once-every-three-month dosing regimen. With those product attributes, we have very high ambitions for the launch of REDEMPLO in FCS specifically. Thank you. Our next question comes from the line of Mike Ulse with Morgan Stanley. Good afternoon. Thanks for taking the question, and congratulations on all the progress as well. Maybe just to follow up on the SHASTA III and IV studies, you mentioned adopting the modified Atlanta criteria. Just curious, now that you've seen some more detail around the core studies, are you considering any sort of adjustments or fine-tuning to your studies going forward? Thanks.

Even more importantly, we hear a lot of positive feedback around the safety and tolerability profile. No contraindications, no warnings, and no precautions. We do have a lot of physicians and patients who are enthusiastic about the once-every-three-month dosing regimen. With those product attributes, we have very high ambitions for the launch of REDEMPLO in FCS specifically.

Speaker #2: So with those product attributes , we have very high for the launch ambitions of of in FCS , specifically .

Speaker #3: Thank you. And our next question comes from the line of Mike Oats with Morgan Stanley.

Operator: Thank you. Our next question comes from the line of Mike Ulse with Morgan Stanley.

Speaker #11: Good afternoon . taking the Thanks for question . And congratulations on all the progress as well . Maybe just to follow up on the Shasta three and four studies , you mentioned adopting the modified Atlanta criteria , but just curious , now that you've seen some more detail around the core studies , are you considering any sort of , you know , adjustments or fine to your tuning studies going forward ?

Mike Ulz: Good afternoon. Thanks for taking the question, and congratulations on all the progress as well. Maybe just to follow up on the SHASTA III and IV studies, you mentioned adopting the modified Atlanta criteria. Just curious, now that you've seen some more detail around the core studies, are you considering any sort of adjustments or fine-tuning to your studies going forward? Thanks.

Speaker #11: Thanks .

Speaker #1: Other than than other adopting the Atlanta criteria , I think we're feeling pretty good about the design and , you know , it was negotiated with the FDA .

Operator: Other than adopting the Atlanta criteria, I think we're feeling pretty good about the design. It was negotiated with the FDA. I don't think we saw anything in core that would cause us to see a need to change anything else. Nothing that comes to mind. James, would you see it any differently? You've looked closely at this too. Yeah. I agree. It didn't inspire any changes in the protocol, so. Yeah. Great. Thank you. Thank you. Our next question comes from the line of Madison Elzotti with B. Riley. Good afternoon. Thanks for taking our question. I wanted to ask about your neuromuscular franchise. Just given your integrin targeted delivery mechanism, which one could assume may be safer and perhaps more targeted than a TFR-mediated approach, should we expect DMPK knockdown and splice correction data comparable to kind of the pure benchmark levels?

Chris Anzalone: Other than adopting the Atlanta criteria, I think we're feeling pretty good about the design. It was negotiated with the FDA. I don't think we saw anything in core that would cause us to see a need to change anything else. Nothing that comes to mind. James, would you see it any differently? You've looked closely at this too.

Speaker #1: I don't think we saw anything in core that, you know, would cause us to see a need to change anything else.

Speaker #1: know , You nothing that comes to mind . James , would you see it any differently ? You looked closely at this , too .

Speaker #1: Yeah, I agree it didn't inspire.

Speaker #2: Changes in any of the protocols.

Speaker #1: So yeah .

James Hamilton: Yeah. I agree. It didn't inspire any changes in the protocol, so.

Speaker #11: Great . Thank you .

Chris Anzalone: Yeah.

Speaker #3: Thank you. Our next question comes from the line of Madison El-Sayed with B. Riley.

Mike Ulz: Great. Thank you.

Operator: Thank you. Our next question comes from the line of Madison Elzotti with B. Riley.

Speaker #4: Good afternoon . Thanks for taking our question . I wanted to ask about your neuromuscular franchise just your given . integrin targeted delivery mechanism , which , you know , one could assume maybe safer and perhaps more targeted than a TFR mediated approach .

Madison El-Saadi: Good afternoon. Thanks for taking our question. I wanted to ask about your neuromuscular franchise. Just given your integrin targeted delivery mechanism, which one could assume may be safer and perhaps more targeted than a TFR-mediated approach, should we expect DMPK knockdown and splice correction data comparable to kind of the pure benchmark levels? Relatedly, wondering which dose do you anticipate observing really optimal biomarker activity? I believe previously you said that even a low dose may be active. Thanks.

Speaker #4: We should expect DMPK knockdown and splice correction data comparable to the kind of peer benchmark levels. Relatedly, I am wondering at which dose we anticipate observing optimal biomarker activity?

Operator: Relatedly, wondering which dose do you anticipate observing really optimal biomarker activity? I believe previously you said that even a low dose may be active. Thanks. Sure. I think most of that will defer to Sarepta. Probably can't comment on the dose where we'd expect to see maximal knockdown. We don't know that yet, so I wouldn't want to venture a guess there yet. In terms of the knockdown, I mean, I think that is probably a goal, to have something that looks at least similar to or equivalent to what others have shown for DMPK knockdown and splice correction with this platform. Got it. If I may, are there any milestones associated with hitting a certain threshold, or are the milestones largely related to regulatory progression? Yeah. Basically, on regulatory and commercial, there are no sort of activity-based or PD-based milestones. Got it.

Speaker #4: I believe previously you said that even the low dose may be active. Thanks.

Speaker #1: Sure. I think most of that will defer to Sarepta. I probably can't comment on the dose at where we'd expect to.

James Hamilton: Sure. I think most of that will defer to Sarepta. Probably can't comment on the dose where we'd expect to see maximal knockdown. We don't know that yet, so I wouldn't want to venture a guess there yet. In terms of the knockdown, I mean, I think that is probably a goal, to have something that looks at least similar to or equivalent to what others have shown for DMPK knockdown and splice correction with this platform.

Speaker #2: Maximal knockdown. We yet don't know that. And so.

Speaker #1: I wouldn't want to.

Speaker #2: Venture guess .

Speaker #1: There yet in terms .

Speaker #2: Of the knockdown .

Speaker #1: think I that is .

Speaker #2: Probably .

Speaker #1: A .

Speaker #2: Goal .

Speaker #1: have is to something that looks similar to or equivalent to what others have.

Speaker #2: Shown at DMPK for knockdown.

Speaker #1: And splice correction .

Speaker #2: With this platform .

Speaker #4: Got it. And then, if I may, are there any milestones associated with hitting a certain threshold or other milestones largely related to regulatory progression?

Madison El-Saadi: Got it. If I may, are there any milestones associated with hitting a certain threshold, or are the milestones largely related to regulatory progression?

Speaker #2: Yeah , based solely on regulatory and commercial . There are there are no sort of activity based or PD based milestones .

James Hamilton: Yeah. Basically, on regulatory and commercial, there are no sort of activity-based or PD-based milestones.

Speaker #4: Got it. Got it. Thanks.

Speaker #2: You're welcome .

Speaker #3: Thank you. Our last question comes from the line of Joseph, Tom with TD Cowen.

Madison El-Saadi: Got it. Got it. Thanks.

Operator: Got it. Thanks. You're welcome. Thank you. Our last question comes from the line of Joseph Tone with TD Cowen. Hi there. Good afternoon. Thank you for taking my question. Just another quick one on the dimer. Just curious, based on your work in FHCG, what proportion of patients are already on an anti-PCSK9 treatment? Is this an under-treated population on both sides? Can you give us an indication in terms of the triglyceride and LDL cutoffs that you're looking at in patients enrolled into the early dimer study? Thank you. Sure. Yeah. I think based on the work that we've done, I mean, a lot of those patients may be on a statin, probably less so on FIB rates, and very few of them on PCSK9 inhibitors. It's actually not that commonly used in that population.

James Hamilton: You're welcome.

Operator: Thank you. Our last question comes from the line of Joseph Tone with TD Cowen.

Speaker #12: Hi . There . Good afternoon . Thank you for taking my question . Just another quick one on the the dimer . Just curious based on your work in StG , what proportion of patients are already on an Anti-pcsk9 treatment ?

Joseph Thome: Hi there. Good afternoon. Thank you for taking my question. Just another quick one on the dimer. Just curious, based on your work in FHCG, what proportion of patients are already on an anti-PCSK9 treatment? Is this an under-treated population on both sides? Can you give us an indication in terms of the triglyceride and LDL cutoffs that you're looking at in patients enrolled into the early dimer study? Thank you.

Speaker #12: Is this an undertreated population on both sides? And then can you give us an indication in terms of the triglyceride and LDL cutoffs that you're looking at in patients enrolled in the early dimer study?

Speaker #12: Thank you .

Speaker #1: Sure. Yeah, I think based on the work that we've done...

Speaker #2: Done , Lot of those

Speaker #2: I mean , a .

Speaker #1: Patients may be on a statin, probably.

James Hamilton: Sure. Yeah. I think based on the work that we've done, I mean, a lot of those patients may be on a statin, probably less so on FIB rates, and very few of them on PCSK9 inhibitors. It's actually not that commonly used in that population. In terms of the cutoffs and the inclusion criteria, we allow patients in that study with mixed hyperlipidemia with triglycerides up to 880. This is a pretty high threshold. They have to have either non-HDL of 100 or an LDL greater than 70 to get into the study. They have to have true mixed hyperlipidemia, both high triglycerides and high non-HDL or LDL cholesterol.

Speaker #2: so Less on .

Speaker #1: Fibrates .

Speaker #2: And very few of them on PCSK9 inhibitors.

Speaker #1: It's actually not .

Speaker #2: That

Speaker #2: commonly .

Speaker #1: population in terms of the cutoffs and the inclusion criteria.

Speaker #2: .

Speaker #1: We had patients in that study with mixed hyperlipidemia, with triglycerides up to 880. So, this is a pretty high threshold. And they have to either.

Operator: In terms of the cutoffs and the inclusion criteria, we allow patients in that study with mixed hyperlipidemia with triglycerides up to 880. This is a pretty high threshold. They have to have either non-HDL of 100 or an LDL greater than 70 to get into the study. They have to have true mixed hyperlipidemia, both high triglycerides and high non-HDL or LDL cholesterol. Thank you. I'll now hand the call back over to President and CEO Chris Anzalone for any closing remarks. Thanks very much for joining us today. Again, thank you to Bruce for all he has brought to the company. He is re-retiring. He is not going to be gone, however. I do trust that he will still be around and helping us out going forward. Again, thanks to Bruce, and thanks to James for continued and ongoing leadership.

Speaker #1: have

Speaker #2: A

Speaker #2: .

Speaker #1: of .

Speaker #2: 100 or an LDL greater than 70 to get into.

Speaker #1: The study. So, they have to have a true.

Speaker #2: Mixed

Speaker #1: high

Speaker #2: And non-HDL or LDL triglycerides and cholesterol.

Speaker #3: Thank you. I'll now hand the call back over to President and CEO Christopher Anzalone for any closing remarks.

Operator: Thank you. I'll now hand the call back over to President and CEO Chris Anzalone for any closing remarks.

Speaker #2: Thanks very much for joining us today. Again, thank you. Thank you to Bruce for all he has brought to the company.

Chris Anzalone: Thanks very much for joining us today. Again, thank you to Bruce for all he has brought to the company. He is re-retiring. He is not going to be gone, however. I do trust that he will still be around and helping us out going forward. Again, thanks to Bruce, and thanks to James for continued and ongoing leadership.Thank you all for joining us today. I hope you have a pleasant Thanksgiving holiday.

Speaker #2: He is he is retiring . He is not going to be gone . However , and I do trust that he will still be around helping us out going and forward .

Speaker #2: So again , thanks to thanks to Bruce and thanks to James for , for for continued and ongoing leadership . Again , thank you all for joining us today , and I hope you have a pleasant Thanksgiving holiday .

Operator: Thank you all for joining us today. I hope you have a pleasant Thanksgiving holiday. Ladies and gentlemen, thank you for participating. This does conclude today's program, and you may now disconnect.

Operator: Ladies and gentlemen, thank you for participating. This does conclude today's program, and you may now disconnect.