Arrowhead Pharma achieves major milestone with Redempolo FDA approval, targeting significant market impact amid robust pipeline and strategic partnerships.

Ladies and gentlemen, welcome to the Arrowhead Pharmaceuticals Conference call. Throughout today's recorded presentation, all participants will be in a listen-only mode. After the presentation, there will be an opportunity to ask questions. I will now hand the conference call over to Vince Anzalone, Vice President of Investor Relations for Arrowhead. Please go ahead, Vince.

Thank you.

Andrew.

Good afternoon and thank you for joining us today to discuss Arrowhead's results for its 2025 fiscal year ended September 30, 2025. With us today from management are President and CEO Dr. Chris Anzalone, who will provide an overview. Bruce Given, outgoing Chief Medical Scientist, who will discuss our R&D activities. Will provide an overview of the Rademflo. 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 RMD, who will discuss our development programs and Dan Appel, 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 to 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 10K and our quarterly reports on Form 10Q. 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 Gibbons final earnings call. He's been a valuable member of the Arrowhead team for almost 15 years. He will continue to help arrowed as a trusted advisor. But now that Redemflo 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. Later in the call you will hear from Bruce who will discuss the Redempilo FDA approval which he came back to Arrowhead 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 performance prior responsibilities as Chief Medical Officer and Head of R and D. So 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 Redempo on November 18, we announced that the FDA approved Redemflo, 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's first FDA approved medicine, marking a major milestone for the company as it transitions into commercial stage. Rudempolo 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. Prademplo 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 sds. After many months of preparation, our commercial team was able to hit the ground running and and I'm happy to report that we have drug in channel a mere week after approval. We also launched rely on Redemflo, a patient support program providing support services and resources for patients at each stage of the treatment journey with Regemflo, including financial assistance options for eligible patients. In addition, we also announced the one Redemflo 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 of a medicine. According to a value? 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. Redemflo 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 fds. 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 fds. The broader patient population with substantially increased risk of acute pancreatitis are those with persistent coliculidemia, meaning fasting triglycerides greater than 880 milligrams per deciliter. We believe there are approximately 750,000 of these patients in the US and while they often have less day to day symptoms than FDS patients, they are clearly at high risk for acute pancreatitis. The one red envelope pricing model has these patients in mind. The $60,000 annual WAC price is designed to provide real value to patients and and healthcare systems in this population. Our Shasta 3 and Shasta 4 Phase 3 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 redemflo's value and payers will have time to plan and budget for its possible eventual adoption pending regulatory Review and approval. OutsiderDemflo we have also made good progress with two other pipeline programs in the cardiometabolic space, Zodaceran and Aerodimer pa. Let's start with Zodaceran. During the recent period we dosed the first subject in the Yosemite Phase 3 clinical trial of Zodaceran. Our clinical candidates 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. Yosemite Approximately 60 subjects over the age of 12 will be randomized to receive four doses once every three months of 200 milligrams of Dastaran 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 is in cardiometabolic is Aerodimer PA during The last quarter we filed a request for regulatory clearance to initiate a Phase 12 clinical trial of Arodimer PA being developed as 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. Erydimer PA is a dual function RNAi therapeutic designed to silence expression of the PCSK9 and Apoc3 genes in the liver that's 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. 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 the CTA to initiate a Phase 12 clinical trial of Aromapt as potential treatments for tauopathies, including Alzheimer's disease. Aromapt 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 Aromapt 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 effects 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, ARO-IONHPE and ARO-ALP7. Together we have randomized 192 patients all with a BMI greater than 30. Because we started ARO-INHBE earlier, it is about 2/4 further into the phase 1 study in ARO-AL7. 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 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 business development. 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 and achievement of the second pre specified patient enrollment target for Arrow DM1. This follows a $100 million milestone earned previously when Arrowhead reached the first of two pre specified enrollment targets and subsequent authorization to dose escalate in a Phase 1. 2 clinical study of Arrow DM1. This partnership continues to be productive and we look forward to continued progress. In addition to progress on the Strepta Partnership, we announced a new global licensing collaboration agreement with Novartis for Arrow snca, Arrowhead's 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's proprietary TRIM platform. 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 Redempolo is clearly the most important recent development, but 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 Gibbon.

Bruce thanks, Chris. Good afternoon everyone. I'm happy to give my final update to erhud 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. 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. Redempolo is approved as an adjunct to diet to reduce triglycerides in adults with FCS. The recommended dose of Redemflo is 25mg and it can be self administered at home by subcutaneous injection once every three months. Redemflo has no contraindications, warnings or precautions. The most common adverse reactions include hyperglycemia, headache, nausea and injection site reactions. The FDA's submission was supported by clinical data from the Phase 3 PALISADE 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 plazaceran or placebo dosed every three months and tested two doses of place versus placebo. The primary endpoint was change in BDN 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 50 milligram doses were combined for comparison to placebo as called for in the analysis plan. Plazaceran achieved deep and durable reductions of 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 medium triglyceride levels below the usual guideline directed threshold of 500 mg per deciliter throughout the year of treatment. 500 mg per deciliter is the recognized threshold where the risk of pancreatitis increases relative to a normal population. Importantly, patients with genetic STs versus clinical STs showed similar reductions from baseline. We see the clinical FCS population as having the same high unmet need as the genetic SCS group, and as such we think it is crucial to have shown that both patient populations showed similar large reductions from baseline triglycerides with regempylotherapy. Redemflo 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. 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 Plesaziram program at its inception and again over the last several years. And more importantly, it's exciting to hear the enthusiasm about this new medicine from patients and 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. Andy thank you, Bruce.

It's been exactly one week since the commercial launch of Redempolo, 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 Redempo, 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. In Palisade, Redempla 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 compared to a minus 17% reduction in the pooled placebo group with rudempolo. 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. In Palisade, 50% of patients at the 25 milligram dose achieve Tg levels below 500 milligrams per decoliter, with approximately 75% achieving levels below 880 milligrams per deciliter at month 10. Second, the numerical incidence of acute pancreatitis in patients treated with rudemplo was lower compared with placebo. As we all know, this is the outcome of most importance for healthcare professionals, patients and payers. Third, Redemflo demonstrated favorable safety and tolerability. Importantly, the US approved package insert contains no contraindications, no warnings and no precautions associated with the use of radempolo. Fourth, Redemflo 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. And fifth, early feedback on the one Redempo 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. 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 dietitians. At launch we are targeting approximately 5,000 healthcare professionals through personal engagement and finally, our rely on redemflo 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 Redemflo start forms, conducting patient welcome calls and engaging payers to obtain approvals. And 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 and D portfolio. James 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 plazaceran 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 25 mg plazacciran compared with placebo over 12 months of treatment. Between the two studies, we enrolled approximately 750 patients. In addition, the miR3 study enrolled approximately 1400 patients. This study in patients with mixed hyperlipidemia is designed to supplement the SAFETY database when when we filed the SMDA for plazaceran and 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 miR3 phase 3 clinical studies in June of 2025. We anticipate completing the primary portions of these studies in mid-2026 with top line data expected in 3Q26. 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 plazacerin 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 arrow inhib. And E and AROALC 7. Both of these programs target the known activin pathway that is involved in signaling to adipocytes to store fat. Aro inhibin E inhibits one of the ligands in the pathway and aroalk 7 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. Arrow and Hibbene started enrolling patients in December 2024 and Arrow Elk 7 initiated in May of 2025. Both programs are currently in Phase 1 2, a 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 Erwin Hibony 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 and man 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 for ARO-ALC7. 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 clinical trials. I will now turn the call over to Dan Appel.

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. Revenue for fiscal year 2025 totaled $829 million and was driven entirely by our license and collaboration agreements with Sarepta, Sanofi and GSK. Of the 829 million, roughly $697 million pertain to the Sarepta arrangement of that 697 million, 587 million relates to the ongoing recognition of initial Serepta consideration, 94 million relates to the achievement of the first DiEM1 milestone and 16 million relates to the reimbursement of incurred collaboration program costs. Additionally, the license to Sanofi for Greater China rights to Plazaswin contributed 130 million to our fiscal 2025 revenue. And 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 SGA 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 2025RD costs were heavily impacted by our phase 3 clinical trials. For Pizazerine and SHTG. It's worth noting that in fiscal year 2025, nearly 2/3 of our clinical trial spend can be attributed to the late stage development of Clodasserin and shtg. As we have mentioned, the SHTG registration of studies are now fully enrolled and we expect data to read out next year. Accordingly, the majority of remaining phase 3 registration of clinical trial costs are expected to occur over the next 12 months. Our SGA costs increased by 25 million year over year, driven primarily by our preparations for the commercialization of radempo. All of us here at Arrowhead are enormously proud of the capabilities we have built to commercialize rudempo 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 and D and SVA costs. Turning to the balance sheet, our cash and investments, including available for sale securities, totaled 919 million as of September 30, 2025 compared to 681 million as of September 30, 2024. The increase in our cash and investments was primarily related to our licensing and collaboration agreements with Sarepta, Sanofi and gsk, partly offset by our ongoing cash burn. Our common shares outstanding as of the end of the quarter were 1:35.7 million, down 2.4 million from the prior quarter, due mainly to the repurchase of shares from Sarepta. 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. Firstly, as Chris mentioned earlier on the call, we announced a licensing and collaboration agreement with Novartis for Arrow snca, Arrowhead's preclinical stage SIRNA program targeting Alpha Synucline 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 Aerodm1. 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 quarter four, 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 Redempo as a truly transformational event for the company, we do not anticipate that the commercial sales Redempo 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. Airad 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 Redemflo approved by the FDA and the overwhelmingly encouraging feedback we received from the FCS community. But Redemflo 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 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 and 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. 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 and 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. And we ask that you please limit yourself to one question. One moment please. Our first question comes from the line of Luca Essi with RBC Capital Markets.

Oh great. Thanks so much for taking the question. And Bruce, congrats on your re retirement. I should say so all the best. In your next chapter. And then 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 plazaceran? Are you confident Shasta 3 and Q4. In Q3 2026 can actually hit acute pancreatitis? Or is the base case scenario those two trials are maybe underpowered to show benefit and you actually need Shasta 5 to actually hit 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 Shasta 5 trial according to clinicaltrials.gov. As of Monday last week. So again, any call there. Much appreciated. Thanks so much.

Sure Luke, thank you for Your kind regards. Shasta 3 and 4 were powered on the basis of triglyceride reduction, which is the primary endpoint. So we did not specifically power Shasta 3 and 4 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 Shasta 3 and 4 for evaluating versus placebo on reduction of pancreatitis. And of course, we only have one dose of Plazaceran instead of two doses. You know, two different doses like we. Had, for instance, in the Phase two program. So, you know, there's, I would say, reasonably good power for, you know, 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 much more enriched population, but it would have actually been less representative than the newly designed trial. So 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. So we certainly we oftentimes refer to as a belts and suspenders approach. You know, there's obviously a decent chance that we will show statistical significance in the Shasta 3 and 4 programs, but we're not entirely dependent on that because of Shasta 5, which is a study, 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 Prakar 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. So on ARO-IONHPE for the update early next year, if you can just provide more details on how much data will be disclosed, especially on the MADs side. And how much follow up will you have on NME for both monotherapy and combo cohorts? And also the Same question on Mark 7, what cohorts will be disclosed? And will there be any weight loss. Data at all from alk7 early in the year? Thank you so much.

Yeah, sure. Ricardo, this is James. I can cover that for inhibin is a little bit ahead, as Chris mentioned, probably by a couple quarters. So the study is nearly fully enrolled. We have a good amount of data in both the single ascending dose and multiple ascending dose healthy volunteer or obese healthy volunteer cohorts so we'll have biomarker data, MRI data, as well as safety in those cohorts. And then 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 inhibone. And then Elk 7 will be a little bit more limited, focused mostly on monotherapy safety and knockdown data, knockdown of the target for that study. And 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 bytes, but certainly two bytes of the apple. Our goal here in this first flag 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 complete data set later in 26. Got it.

Thank you so much. You're welcome.

Thank you. Our next question comes from the line of Maury Raycroft with Jeffries.

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.

You know, 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 the Modified Atlanta Criteria since those have been accepted by both FDA and EMA and here in the US at least payers. And 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. So 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. And based on that, I think you'll see that there's a good chance that we'll have the necessary number of events. But 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, Maureen.

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

Hi, this is Gina on for Jason. Congrats on all the progress this quarter and thank you so much for taking part question. Just a couple from us, I guess. First on your Aromap-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 and then just kind of based on your current cash position and the progress that you've made on these partner milestones, partnership milestone triggers, do you have any maybe updates on your visibility on launching a CVOT study? Is that more tied to kind of seeing how the FCS and potential SHTG launches are progressing? And then can you just remind us like 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, want to take the first one?

Sure. Yeah, I'll take the first one on the Aromap-T program. So the J&J antibody, the monoclonal as well as other monoclonals are IV administrated monoclonal antibodies, probably a small fraction of those molecules across the blood brain barrier and then are 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 towel that's outside 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. So we're sort of turning off the faucet for all of the expression at preventing the neurofibrillary tangles to form in the first place. So 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.

So that's the key differentiator. And on other questions, I'll answer the last one first, the Sarepta milestone. So we are eligible to receive the first of five $50 million annuities in February. So we expect that over the next several months. That's correct. February, right, Dan? Yes, correct on the visibility on the cvot. So that cvot, as you know, is for the dimer That's a big opportunity for us. And so we are moving as quickly as we can to that C bot. We'll have a good idea. I think this summer, if we have a drug, we'll know PCSK9 knockdown, we'll know APO C3 knockdown, we'll know LDL decreases, we'll know triglyceride decreases. And so given what those data look like, I think again, as early as the summer, I think we'll know if we have something that really could be an important treatment for these mixed hyperlipidemia patients. Should that be successful? Should that look good? We are not waiting on anything to start those studies other than finishing this phase 1 2. Our plan is to be able to roll directly into pivotal studies after these phase 12 studies. Again, should they all go well and there's nothing, there's nothing gaining there other than the data looking good. We also are hoping to have parallel pivotal studies. You know, one that will be a CVOT and then 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 PTSK9 inhibitors. And we think that could be a good way to get to market very quickly and frankly help us to pay for the C bot. So 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.

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. And Bruce, wishing you all the best. And James, wishing you all the best of luck. 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 aerodimer PA next year? And what other data sets beyond the obesity data in the first half should we be thinking about?

Thanks, Ted.

We have, we have a bunch of, I think, potentially very interesting data readouts throughout 2026. As you mentioned, obesity will be the first. You know, as I mentioned, we should have two bites at Apple or thereabouts, and we'll have our first early data set, you know, in the very first part of January. And then as the data mature in both those programs stay towards, you know, 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. You know, 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. And 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 aromap 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 and hopefully will be de risking the entire blood brain barrier platform that can enable us to treat a variety of CNS diseases. And so that's an important readout. Of course, also in the third quarter. Or so, we expect to have the. Readout for Shasta 3 and 4 that are designed to enable the RSMDA by the end of the year. And, and then of course, at the end of the year we expect to have file our snda. So look, there will be other things happening during the year, but those to me feel like the primary ones. And of course, we'll be in the. Market. And we will be really looking forward to seeing how, seeing the adoption curve that Redempolo is going to have.

Great. Any update on Arrow Rage just to be comprehensive? Thank you. Yeah, thank you. Yes.

So, as you know, Ted, the data so far for arrowage have been enticing. You know, 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. And so 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. And so we have started a challenge study. I don't expect to have data in 26, maybe at the very end of. 26, but we've just started that. And so my hope is that 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. And so 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? And I think you know, a positive challenge study readout would allow us to partner that in attractive under attractive terms.

Great. Well, guys, congrats on all the great progress. I'm really excited to see the redempo launch. It's a great job.

Thank you, Jay.

Thank you. And our next question comes from the line of Manny Faroohar with leering partners.

Thanks for getting the question. Congrats on the progress in the first product launch. And 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 question. I want to follow up on the broader pipeline. I know Ted touched on new air. Raid study, et cetera. How do we think about arrow dimer applications in terms of pursuing CVOT and. The right target for that technology? And 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? Bruce, you want to take where that can fit? Yeah, I'm happy to take that. Obviously, we're excited about and APOC 3 inhibition generally for patients with severe hyperdriglyceridemia that's been essentially very, very poorly treated population for a long time. Ldl, the LDL side of the equation, on the other hand, has been really a different story. And other than hofh, there's a pretty good number of tools in the tool chest for dealing with ldl. You know, the patients on that LDL side of the equation, especially patients with. Heterozygous, you know, familial hypercholesterolemia, which is. A pretty good sized population, for instance. But, you know, the 20 million patients in the US alone that have mixed hyperlipidemia has been an interesting population. You know, we could address the LDL part. We've done really a terrible job historically of being able to address the triglyceride piece of that. And, you know, the post hoc analyses that have been done of C bots have shown that, you know, for the same LDL reduction, you can really rank order the risk that patients have by how high their triglycerides are. And of course, the Mendelian randomization data has also said that triglycerides are an independent predictor of events and mortality in that mixed hyperlipidemia population. And it's huge. It's a very big population. So 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. And 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 gonna always have a statin there if the patients can tolerate it. But you could have a daily statin and a quarterly dimer injection and potentially treat, you know, that 20 million patients, you know, to low risk levels of LDL and triglycerides. 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, you know. Worthwhile in the triglycerides. So this is what makes this, you know, to us, such an interesting proposition.

Yeah, as you know, Manny, what we, what we used to, our former strategy was to, was to make Lozacerab, nowrodempolo, you know, a three step drug. Step one is fcs. Step step two is fhcg. Step three after a CBOT would be this, you know, would be to be part of a treatment to, in mips, hyperlipidemia. Once we were able to perfect, at least in animals, the Aro Dimer PA platform, it didn't make any sense any longer. We like the idea of keeping Redemflo as a pure play pancreatitis drug, full stop. And now I think we'll have a tool to more completely treat that mixed hyperlipidemia population should this Aro Dimer PA translate well from animals to humans.

That's helpful. And as a follow up, when you. Think about potential dimer applications, et cetera. How are you thinking about the data next year from Horizon and potentially applications. Of combining what hopefully will be a. Validated LP target with other approaches to. Their risk, elevating elements of the lipid profile.

Yeah, sure.

So of course our SIRNA targeting LP is partnered with Amgen, so we would have to work with them on any kind of dimer applications. But there are other applications beyond, of course, the PCSK9APOC3. I mean, we're looking at other dimers in the CB space, both targeting hepatocytes and extra hepatic cell types. So this is probably not the only dimer that you'll see out of Arrow.

All right, thanks guys, that's really helpful and congrats again. Thank you.

Thank you. Our next question comes from the line of Patrick Truccio with H.C. wainwright.

Thanks. Congrats on all the progress. I have a few follow up questions. Just the first is just regarding Redemflo. 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 SHTG patient population. And separately, I'm wondering if there's been discussions around potential pediatric pathway. Just given FCS presents in childhood and then just a follow up on the MAP T program, I'm wondering what level of CSF tau knockdown or biomarker response would you consider clear clinical proof of concept in humans? Just given I think you have greater than 75% knockdown in the NHP data. Bruce, why don't you take the first. And then take that too?

So the first was level of AP. That we think the FDA is required. To have it on label. Yeah. You know, 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, you know, have no real question about the relationship of triglycerides to pancreatitis risk, especially now that it's been proven. And payers haven't seemed to be concerned about that either, at least in the US So I'm not sure, you know, what the value of a claim would be. And 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 SHTG or fcs? It was around actually the high risk SHTG patient population. Yeah, but the answer is the same. I think, you know, we at least have not approached asking them, you know, you know, 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 5. But the Shasta 5 was really designed primarily, you know, on the possibility that the payers in countries outside the US might require an actual dedicated outcome study. So it was more payer focused than. It was regulatory focused.

And we really were not committed one way or the other about whether it would 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. So we really haven't raised this with regulators. Anywhere on a global basis at this point. You want to address the peds question? The peds question. We absolutely plan to do pediatric work at 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, a formulation that we can, you know, that we can use for weight based dosing. And that's just, you know, we're in the process of getting that formulation put. Together so that we can go ahead and do those studies. But we're absolutely planning on doing that.

James, you want to talk about maps you knock down?

Yeah, sure. In terms of what we're looking for, based on the cynomolgus monkey data, as you mentioned, at the tissue level, we were seeing 75% plus reductions and similar reductions in the CSF in monkeys. I mean, we typically translate well from sinos into the clinic into humans. And 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%. And those CSF reductions corresponded to improvements in tau PET, improved tau PET signals. So, you know, I think that's probably where we're aiming for in our clinical study is at least 50 to 60% reduction in the CSF. That's what others have shown and that. Seems to have translated into a meaningful taupet 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 Radempo launch. Recognize it's only been about a week since the approval, but 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 Trengola 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. So we do have very high ambitions for the RADIMFLO launch. Expect it to be best in class. And as you know, there are a number of reasons why we believe that to be the case, largely around the attributes of Redemflo that we do believe make it a special molecule in this category. We talked about, obviously, the significant and sustained triglyceride reduction. We've talked about the reduced incidence of acute pancreatitis. But even more importantly, we hear a lot of positive feedback around the safety and tolerability profile. So no contraindications, no warnings and no precautions. And we do have a lot of physicians and patients who are enthusiastic about the once every three month dosing regimen. So with those product attributes, we have very high ambitions for the launch of Redemflo in SCS specifically.

Thank you. Our next question comes from the line of Mike Ultz with Morgan Stanley.

Good afternoon. Thanks for taking the question and congratulations. On all the progress as well. Maybe just a follow up on the. Shasta 3 and 4 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.

Other than, other than adapting the Atlantic criteria, I think we're feeling pretty good about the design and 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? 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 Elsadi 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 peer benchmark levels? And relatedly wondering at 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 maximum knockdown. We don't know that yet, so I wouldn't want to venture a guess there yet. In terms of the knockdown, I think that is probably a goal is 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. And then if I may, are there any milestones associated with hitting a certain. Threshold or are the milestones largely related to regulatory progression? Yeah, based only on regulatory and commercial. There are no sort of activity based or PD based milestones. Got it, Got it. Thanks. You're welcome.

Thank you. Our last question comes from the line of Joseph Tome with TD Cowan.

Hi there. Good afternoon. Thank you for taking my question. Just another quick one on the dimer. Just curious based on your work in SHTG what proportion of patients are already on an anti PCSK9TR treatment? 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 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 fibrates, and very few of them on PCSK9 inhibitors. It's actually not that commonly used in that population in terms of the cutoffs. In the inclusion criteria. So we allow patients in that study with mixed hyperlipidemia with triglycerides up to 880. So this pretty high threshold. And they have to have either a non HDL of 100 or an LDL greater than 70 to get into the study. So they have to have, through 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. Thank you to Bruce for all he has brought to the company. He is re retiring. He is not going to be gone, however, and I do trust that he will still be around and helping us out going forward. So again, thanks to Bruce and thanks to James for continued and ongoing leadership. Again, thank you all for joining us today, and 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.