Arrowhead Pharmaceuticals, Inc. (ARWR) Earnings Call Transcript & Summary

Good morning, everyone, and welcome to the Arrowhead Pharmaceuticals investor webcast. [Operator Instructions] As a reminder, this call is being recorded, and a replay will be made available on the Arrowhead website following the conclusion of the event. I'd now like to turn the call over to Vince Anzalone, Senior Vice President of Finance and Investor Relations at Arrowhead Pharmaceuticals. Please go ahead, Vince.

Thank you, Tara, and thanks, everybody, for joining us today. We're excited to present the data that we presented yesterday at the European Society of Cardiology in Munich for what we think is groundbreaking data from the SHASTA-3 and 4 studies of plozasirian. So before we start, I just want to make sure everybody knows that we will be making forward-looking statements today, so I refer to our SEC filings for risk factors. I also want to remind people that the SHTG indication has not been viewed or approved by any regulatory authorities around the world, so it should be considered investigational. And the results here are preliminary. So they should not be used with -- for HCPs or patients or in product promotion in any way. This is an investor-focused communication today. So we're very fortunate today to have 2 external speakers who are leaders in the field. Dr. Gerald Watts from the University of Western Australia in Perth who gave our hotline late-breaker presentation yesterday. And also, Dr. Norge -- Dr. Borge Nordestgaard, sorry, from Copenhagen University Hospital, who was the discussant for our presentation yesterday. And here's the flow. So today, I'll give a short introduction and a review of our -- of Arrowhead generally in the cardiometabolic pipeline. Dr. Jennifer Hellawell, who is Head of Clinical Development at Arrowhead, will talk about severe hypertriglyceridemia, or SHTG. Again, Dr. Watts will do an encore presentation of the SHASTA-3 and 4 full results. Dr. Nordestgaard will talk -- will give a discussion on the results and the clinical implications. Andy Davis, our Head of Cardiometabolic commercial will talk about our current -- the current status of our commercialization efforts in SHTG. And then I'll give some key takeaways. And then we'll have a little bit of time at the end for you to ask questions to the panel. It will be a limited amount of time, so we should be able to take maybe 5 or 6 questions. So I'd ask that you all limit your questions to one. If you have a follow-up, please go back in the queue. So Arrowhead, this is a very brief introduction of Arrowhead as a company. As most of you probably know, we're an RNAi therapeutics platform company. with a broad pipeline of both wholly owned and partnered candidates. And importantly, in 2025, we launched our first commercial product in REDEMPLO, which is the trade name for plozasiran. It's currently approved to reduce triglycerides in patients with FCS in the U.S., in the EU, Canada, Australia, and China. We think this is a potential multibillion-dollar opportunity across different future occasions. And importantly, we see the potential for multiple independent and partnered launches of other products outside of REDEMPLO over the coming years. Our pipeline is very broad, and we'll go over a quick overview of what it looks like in a moment. But importantly, we have a good mix of early, mid, late stage and now commercial stage assets, also targeting the most ultra-rare disease all the way up to the highest prevalence cardiovascular indications and that pipeline has tended to grow by 2 to 3 new clinical programs per year. So we're very productive. All of this is built on a proprietary technology platform that we call TRiM or targeted RNAi molecules. It's optimized for deep and durable gene silencing using the RNAi pathway and we think that Arrowhead is the clear leader in fulfilling the promise of RNAi therapeutics because we are now capable of bringing RNAi to where our disease lives, not just inside the liver. And I'll show you a slide of the different tissue types we can get to. But we do believe that Arrowhead has best-in-class with liver-expressed genes as well as outside the liver. And then lastly, and this is important for any development stage biotech company. We have a strong balance sheet and the financial resources to get to multiple important commercial launches as well as clinical milestones. And that -- those financial resources are complemented and supplemented by additional nondilutive capital that we expect from existing partnerships with leading pharmaceutical companies. So this is a schematic of the 7 different cell types that we are working to get the TRiM platform too, liver, lung, skeletal muscle, CNS adipose tissue, ocular and cardiomyocytes. And again, we think Arrowhead is the clear leader in fulfilling the long-term promise of RNAi by bringing it to tissues where disease starts. And here's a very long pipeline. But again, the takeaway is we have a broad pipeline and lots of opportunities for growth. So before I turn it over to Dr. Watts, I just want to give a very brief summary of what we think are the important points of the data that were presented yesterday. So in the SHASTA-3 and 4 studies, we achieved triglyceride reductions of about 80% from baseline across the SHTG spectrum. And importantly, more than 90% of the patients on that study got TG levels below 500 mg per deciliter, which is a key risk threshold for acute pancreatitis. We -- in the studies, we reduced the cumulative AP events, again, across the population by 78% with a really impressive 100% reduction in the patients at highest risk. And those are patients where their TGs are above 880 mg per deciliter and have a prior documented history of acute pancreatitis. Again, that 100% risk reduction was extremely impressive in what we think is paradigm shifting for the treatment of SHTG. Next, we have a consistent and favorable safety and tolerability profile. And frankly, if you look at our [indiscernible], which Gerald will talk about shortly, the -- everything from prior studies in different patient populations has held and the safety and tolerability profile continues to look either equivalent to what we've seen previously or even better. It's very safe and well tolerated, which is an important point here. And then lastly, we -- these data have also been accepted for publication in a major medical journal with more details to follow shortly. So now I will turn it over to Jennifer Hellawell, who'll talk about the disease of SHTG.

Thanks, Vince. Good morning, everyone. Today, I'd like to take a step back and provide an overview of severe hypertriglyceridemia, a vastly misunderstood condition that affects almost 1 in 100 patients worldwide. Hypertriglyceridemia actually represents a spectrum of disease with severe clinical manifestations and considerable unmet need across the spectrum. At one end of the spectrum are patients with moderate hypertriglyceridemia, usually defined as triglycerides in the range of 150 to 500 milligrams per deciliter, and this is a condition that affects upwards of 10 million people in the U.S. with substantial ASCVD burden and overlap with other cardiometabolic risk factors. At the other end of the spectrum are patients with familial chylomicronemia syndrome or FCS, a rare condition characterized by persistent chylomicronemia or triglycerides greater than 880 milligrams per deciliter, and an extremely high risk of acute pancreatitis. This condition, of course, can be genetically or clinically diagnosed. However, in the middle of the distribution is severe hypertriglyceridemia. This is generally defined as serum triglyceride levels of greater than 500 milligrams per deciliter. And this is a condition that affects approximately 1 in 100 persons or greater than 3 million people in the United States alone. Severe hypertriglyceridemia can have similarly dire clinical consequences, including an increased risk of life-threatening acute pancreatitis. Much like atherosclerosis risk in these patients is driven primarily by both higher levels of the causal lipoprotein in this case, triglycerides and history of prior clinical events. In this case, acute pancreatitis episodes. For this reason, patients with the highest triglycerides and prior AP events are often referred to as high-risk severe hypertriglyceridemia. And this subset is thought to represent about 1 million people in the United States. These patients have an extremely high risk of acute pancreatitis as well with many patients suffering multiple recurrent attacks and a variety of related severe clinical sequela throughout their lifetimes. Unfortunately, conventional triglyceride-lowering therapies such as fibrates and omega-3 fatty acids rely primarily on functional lipoprotein lipase, or LPL pathways, which are often dysfunctional in these patients, thereby leading to very modest effects on triglyceride levels. Importantly, until recently, none have been shown to reduce the risk of acute pancreatitis. Apolipoprotein C3 or APOC3 is a key lipoprotein involved in triglyceride hydrolysis and clearance through both LPL-dependent and independent pathways and has recently emerged as a therapeutic target across the spectrum of hypertriglyceridemic disorders. While severe hypertriglyceridemia can sometimes be diagnosed as an incidental finding on routine lipid channels, the patient journey with severe hypertriglyceridemia is typically characterized by an evolution from a hidden, more asymptomatic phase to acute medical emergencies of debilitating abdominal pain, prompting emergency room visits, hospitalizations and even stays in intensive care units. This period of acute stabilization is then followed typically by discharge to complex, sometimes confusing long-term outpatient management. The cornerstone of management historically involves extreme dietary restrictions, limiting total fat intake to just 10% to 15% of daily calories or under 20 to 30 grams daily, alongside the complete elimination of alcohol and added sugars. Patients must also aggressively manage secondary risk factors like uncontrolled type 2 diabetes and obesity to improve overall insulin sensitivity. Patients silently struggle with considerable impacts to quality of life as they grapple with fatigue, low energy and chronic anxiety about the [indiscernible] pancreatitis, while managing a challenging and limiting lifestyle and medical regimen. With this shared understanding of the dire unmet need and the therapeutic potential of targeting APOC3 with Arrowhead's proprietary TRiM siRNA technology, we undertook our Phase III SHASTA program of plozasiran in adults with severe hypertriglyceridemia. Now it is my pleasure to turn it over to Dr. Gerald Watts to share the results from those studies.

Thank you very much. I'm most grateful to be here. Mr. Chairman, ladies and gentlemen, potential investors. Jennifer has set a marvelous precedent here for the need for new therapy in this patient group. So this is what -- this is the title of of the work that was presented there with a string of coauthors entitled plozasiran for severe hypertriglyceridemia on the bases of what Jennifer has said already and risk of pancreatitis probably its most severe sequela. The SHASTA-3 and the SHASTA-4 pivotal trials, 12 months results, I should -- I'd like to mention things that are important to SHASTA are too lovely -- lookout mountains in Northern California. And this may well be representative of the potential of this trial to be a landmark trial as those mountains are. So the background again to reiterate what Jennifer said that severe hypertriglyceridemia defined above the cutoff points shown up there, 5.6 and 500 milligrams per deciliter, about 1% of the population translating probably to 5 million to 10 million people worldwide, increases the risk of acute pancreatitis. These cardiac microparticles and triglyceride particles lodging the pancreas and set off an inflammatory event. It's a heterogeneous disorders driven by multiple factors, genetic factors and secondary causes over nutrition obesity in type 2 diabetes. The next one is an important point, really, that despite best standard of care, many patients don't achieve those treatment goals of less than 5.6%. And so that the risk of end organ damage, in particular in the pancreas, acute pancreatitis persists. The opportunities that have arisen is knowledge about APOC3 as a key regulator of the metabolism of triglycerides and this has now become a validated therapeutic target, with our head leading the way with its trend pathway. Plozasiran is, in fact, first in class hepatocyte targeted at sRNA that reduces the hepatic synthesis of APOC3 and was evaluated in adults with severe hypertriglyceridemia, in these 2 SHASTA-3 and 4 studies. So 2 trials were undertaking. But we have background. Apologies for those who are aware of this. This is a summary of what APOC3 does that damages triglyceride metabolism. On the left-hand side, APOC3 inhibits the breakdown of triglycerides via taking 2 hits at the lipoprotein lipase dependent and lipoprotein lipase independent pathway in the liver. So it follows that if you can remove APOC3 out of the system as you can, through one injection of plozasiran as shown in the middle of the figure. And on the right-hand side, you remove this unwanted inhibitor and that depresses the activity of lipoprotein lipase and the activity of receptors that clear triglycerides. So that's the science behind it. So that's one opportunity that one had to address the balance to redress the balance and the gap treatment. And the other opportunity is the randomized controlled clinical trial. So this was the design that was employed. 2 trials were undertaken on the basis of advice from the regulators in the U.S., SHASTA-3 and SHASTA-4. Patients -- adult patients with hypertriglyceridemia -- severe hypertriglyceridemia were randomized to 25 milligrams of plozasiran or placebo. [indiscernible] the same design with 4 injections subcutaneous injections of plozasiran over 12 months, ending with an open-label extension study prerequisite as a bridge to potential new therapies in those -- for those who it's indicated. So that was a study design, 2 trials, quite a challenge running 2 trials but they were done. And the results will be presented initially individually for those trials. And then as a pooled analysis for the acute pancreatitis endpoint as a pooled inherits for safety end points. So who were the individuals that were studied. It's a busy slide and apologies. I will just let you know who they were on mass. The summary is that were mainly middle-aged people. were overweight, male, white history of cardiovascular disease in approximately 1/3 diabetes in approximately just over half key pancreatic is present in 1 in 5 individuals. It was already a proportion of them had acute pancreatitis, and this was a very important group as we shall see. The average triglycerides, the mean value was 9 millimoles to 10 millimoles per liter, appears half the population in the kind of micronemic range in the other half, up from 100 -- sorry, from 10 millimoles per liter down to 5. HbA1c, which is a measure of glycemic control is good and important to note that lipid lowering therapy, which is the best standard of care for this condition at present, namely fibrates, omega-3 fatty acids, statins, ezetimibe and combination therapy was taken by the majority of patients as clinically indicated. So that was a group of male -- predominantly male adult patients. This was the primary endpoint. So the primary endpoint was the triglyceride level, the percentage triglyceride level at 12 months. And you can see here up here of the placebo groups of the 2 SHASTA trials and at the bottom of [indiscernible] you can see as we could evaluate a rapid reduction in triglycerides by 3 months, that was sustained and here we are. It was within group change of about 80%, that remains statistically significant after adjusting for the fall in placebo. I mean, this was a -- we've seen this before in FCS and other trials that once these patients with hypertriglyceridemia joint trial, actually, they seem to do quite well. And it's consistent and reflects the recommendation that best standard of care is important and, in fact, demonstrates that plozasiran actually adds to really super best standard of care. So that's important. So from the primary endpoint, there's a select cocktail here, secondary endpoints, triglyceride reduction at 10 months, interesting secondary end point, 80% reduction. Remnant cholesterol at 12 months, about 70% reduction, about 50% of the adjusted for the falling drug in remnants in placebo, non-HDL-cholesterol about 26%, 20% reduction and adjusting to the fall in placebo, APOC3 and triglycerides at 12 months in a very high-risk grip with baseline level. So more than 20 and more than 10 millimoles per liter. So all these changes were statistically significant rotate placebo implying that all these secondary endpoints of the trial were met. Now this is an important slide. These are the proportion of people in the 2 trials, SHASTA-3 and SHASTA-4 attained these goals that Jennifer and Vince revert to. I mean, doctors think in terms of proportionate people getting to goals, easier to think about because that's what you communicate to patients. So here, you can see 90% in the 2 trials, 90% achieved triglyceride goals of less than 5.6 millimoles per liter. With the placebo actually showing a 50% -- 50% of those actually fell below those goals, as you would anticipate from the previous presentations. Now turning here on the right to a goal of less than 1.7 millimoles per liter, which is entirely normal and in the fasting state. You see here that plozasiran in both trials as shown here, half, 50% of the population over 50% achieved a normal complete normalization of fasting triglycerides. And this is where very clearly outdid the effect of super best standard of care. So that was a good take-home message that you can really move the distribution from severe to moderate majority and 50% of the entire population down to a normal triglyceride level explaining why it worked out to be superior to super their standard of care. So turning now to the pool data. We have to join the both studies to look at looking at acute pancreatitis to maintain statistical power, a good opportunity. And this, again, was approved by the regulators. On the left-hand side, you see total events, the total burden of acute pancreatitis. So there may have been some patients who contributed to events. This is a Kaplan-Meier curve, which is an outcome of interest, the total burden of acute pancreatitis in the placebo group and in the intervention group and clear evidence that there is an 80% relative risk reduction 41% absolute risk reduction translating into 24 people with the characteristics of this trial that you needed to treat with plozasiran to prevent 1 acute pancreatitis event or concussion events in 1 year. On the right-hand side is the time to first event and there was a pronation of an average of about months. And again, this was statistically significant. 82% the hazard ratio of approximately and that was to be significant. The other analysis takes it a little bit further, and it's an exploratory but highly important analysis looking at the highest risk groups. In other words, those who at baseline had fasting triglycerides more than 500 milligrams per deciliter and a history of acute pancreatitis, really quite a marked reduction in the relative risk reduction, well over 90% highly significant 34% absolute risk reduction because clearly, this group as were at a higher absolute risk and then translated into a maximum of 3 people that needed to be treated by event. And a further analysis in 1 looked at those with triglycerides greater than 10-millimeter million and a history of go pancreatitis. There was reduction in the incidence of acute pancreatitis event. Now these are small numbers. and they were exploratory, but it gives you a feel for what the great potential is of this intervention in people with the characteristics that make them at highest risk of acute pancreatitis. Few time to absorb that because this is a key data. So moving on again analysis, both the SHASTA-3 and 4 come into adverse convince. It's a busy table, the standard outcomes ranging from all treatment-related adverse events to the most common ones, injection site sensitivity, platelet count liver enzymes. And down here is a substudy of approximately 36 patients randomized to placebo, 2:1 manner and 23 to plozasiran. So I'll just take you through this very briefly that I'd first say that the retention rate of patients in the trial was very high, over 90% and compliance with the 4 injections, almost 100% with no injection site reactions, which is absolutely extraordinary actually much more than what we see with other sRNAs in our clinical practice. It might be related to the way the TRiM platform is designed. So treatment of emergent amples events, leading discontinued emission rates were low 1.2%, similar between the groups. There was no anaphylaxis or systemic hypersensitivity. There was worsening of glycemia using a variety of nonspecific endpoints that appear to be slightly higher with intervention compared with placebo. No clinically meaningful changes in plate accounts. In fact, no changes at all in the playbook count of note, which is a program with the earlier interventions that were not galNac-conjugated no significant elations in ALT or AST and none that met this sort of metric law called his law sounds as a law actually of the land in the cowboy movie comes up, it's never a positive actually. And again, important relating to this group down here, no statistically significant increases in treatment increase in hepatic fat fraction when you look at it with magnetic resonance imaging. So very, very reassuring. Just to give a little bit more context concerning glycemic control, the only hard endpoint that could have been defined, but I have to say that this was not a prespecified endpoint was [indiscernible] hemoglobin, which is a measure of long-term blundsugar control used to monitor people with diabetes. And this refers to the absolute values and the relative changes over time, a smidgen of an increase in HbA1c that is exceptionally small and less than 0.25 to their absolute scale with the periods of no significant difference at the end of the intervention, and that's the percentage change, slightly high, but no apparent change from this visual inspection at the end of intent. So quite reassuring and certainly better than all previous studies with or and better really than that seen with a competitor agent. So we've reached at Barcode of all these movements of this presentation. I just reemphasize what the conclusions were casasiran administered every 3 months, reduced triglycerides and acute pancreatitis or bench in patients with severe hypertriglyceridemia and receiving conventional background therapy and diet. Let me go a bit further actually because it was in the trial, the background treatment was actually excellent, super excellent. Drugs reduction of 80%, but were evident at 3 months and sustained over 12 months with an associated reduction of acute pancreatitis of 80% or 1% relationship. Over 90% of patients treated with plozasiran dropped me triglycerides below the level that's being used to demonstrate high risk of acute pancreatitis 5.6 mills per liter of 500 milligrams per deciliter down half of them normalized the level of triglyceride. This is really impressive. This normalization and sustained in the 12 months was probably the basis for the reduction in net conclusion related to the high-risk groups just to drive it home that those in the high-risk group appear to get the greatest benefit but there was benefit across all the spectrum that trying to strive from 500 and about 90% of patients with a history of acute pancreatitis, and 100% reduction in the -- sorry, I'll say that again. There was a 90 -- over 90% reduction in the relative risk of -- in all patients with the history of acute pancreatitis and 100% of the highest risk group. Safety was reaffirmed and the fundings support the value of APOC3 targeted therapy for plozasiran for preventing acute pancreatitis in severe hypertriglyceridemia with significant implications for changing clinical practice once this is approved, or the label by the regulators, once this gets into clinical guidelines and a great potential to actually shift a practice in a manner consistent with a model of care that has been missing for many years for this high-risk group of patients, something that we need to develop as we move along. So thank you for your attention and congratulations to Arrowhead for funding this study and all the patients who contributed to these difficult studies, actually, 2 studies. It's really quite abrasive. So I think -- and now I'll hand over to my friend and colleague and those are my disclosures notice through the Chair, of course.

Thank you so much, Gerald. And thanks for the invitation to be here as was already said, I was also invited to give the oral comment yesterday at the Congress and Munich European Society of Cardiology. That's what I showed yesterday and I started with this slide to try to show where is the problem. So the graph is really showing the distribution of triglyceride shown on the x-axis in a typical general population study, 64% has what has been referred to here as normal levels less than 150-milligram get 1.7 million per liter. And then there's 34% that has mild to moderate hypertriglyceridemia up to 500-milligram petite. And here, after that level, that's what is referred to as severe hypertriglyceridemia found in typically 1 in 100 in world populations. What you also can see on this slide is that with the red arrow way out to the right, there's this genetic condition familial chylomicronemia syndrome. We often refer to roughly one in a million has this perhaps a little bit more common. They can adverse high-teens. We now have 5 different drugs that has tried to reduce triglycerides in these situations. But first, we had 3 different types of drug blend asset that had a problem with lowering of platelets, and it was approved in Europe only, but never in the U.S. and then olezarsen from the same company and now processor. So all these 3 have been shown. What we're moving to now is this much more common condition in severe hypertriglyceridemia, 1 in 100. We already heard from Jennifer Hellawell, some numbers for the United States and the world also how common is -- and olezarsen has already showed results for that roughly about a year ago. And now we have this very, very important study with plozasiran in this quite common condition. And what I show here is now that all these 5 drugs have now shown to reduce acute pancreatitis. And the rough number for all 5 studies is 80% reduction. So it is extremely consistent. Either you have the very severe genetic condition familiar symptom or you have the broader conditions severe hypertriglyceridemia, roughly an 80% reduction by using these type of drugs that are all able C3 inhibitors. And we already heard about how the mechanism is. So side effects I have what Gerald Watts showed us. The only thing that really was something endeavors worsening of glycemic control, 14% in the active dog versus 9% in the placebo but this is a class effect. This is also set for the other drugs. There's no mystery about plozasiran in general. And personally, compared to how a bad situation in this Page 9, this is really nothing. And many of them already so they will be looked after for the glycemic control anyway. What I really tried to highlight in re there was very low drug discontinuation. And for me, when I see a study like that, that tells me there's very, very few side effects that the patient notice. And of course, -- when you have new works like that, we need a lot more follow-up. We need to do a long term sub in the U.S.A. and EMA in Europe, they were asked for more security. But for now, it looks really, really promising. On top, the SHASTA-3 and has the 4 baseline the 757 with hypertriglyceridemia, meaning levels above 5.7 millimoles to 500-milligram per day later. In these studies, there were 32% that had ASCVD based on 59% diabetes and 21% acute pancreatitis. So there's 1 point that I'd like to mention for you. So even at the best line with EC, there actually was more for square harvest disease, meaning [indiscernible] than acute pancreatitis. So down below, I put some of my own personal data I have access to all data that lived in Denmark for the last many years. And here, I showed the 1 from 2008 to 21, 3.4 million people with an triglyceride measurements and all these we looked at here, they had no ASCVD, myocardial infarction store or acute pancreatitis at baseline. There was 29,000 severe hypertriglyceridemia at the same level as before. And the point I would like to show to you here is that when we look at this group in Denmark, and I'm sure it will be the same in any other country in the world. Then the incidence of a parotitis was 2, and there was 400 cases until we could find in all of Denmark. Denmark is a special country, we have 100% follow-up. Everybody is captured in the registries. So [indiscernible] heart-attack stroke, there was 2,000 cases and the incident was 18. So it's actually in this group of patent a completely primary prevention, there was 5x as much as phoscrotic cardiovascular disease as acute pancreatitis. And on an incident basis 9x more. Why do I say that? I think because of the way the patients were recruited, it was acute pancreatitis that we could see an effect on it. But long term, for this patient group, there's a big need for further investment, trying to actually go for both diseases, both reduce acute pancreatitis and long-term also first codices disease. So here's my clinical implication. In blue, I show this is a huge unmedical need. -- and I actually worked to be with wart and he knows very well severe hypertriglyceridemia causing acute pancreatitis and also ACD. These patients in the past really never had much we could offer them, and particularly the ones with the very high level is very difficult. In green I show fantastic news now. We now have efficient therapies. These APOC3 inhibitors where plozasiran is one of the 2 that are development right now to lower tiglycides and acute pancreatitis. And for me, I think I would love to see more studies that actually focus on not only preventing a good baguettes, but also long-term autocratic cardiovascular disease. So with that, I'd like to hand over to Andy from Arrowhead.

Thank you, Dr. Nordestgaard, and good afternoon, everyone. I'd like to walk through with the SHASTA-3 and SHASTA-4 data meeting for our commercial opportunity in severe hypertriglyceridemia, building on the clinical results just reviewed. Let's start by level setting on the potential market opportunity for plozasiran. As Jennifer and Dr. Nordestgaard previously set up severe hypertriglyceridemia isn't a single population. It's really a spectrum. At the broadest level, SHTG is defined as triglycerides at or above 500 milligrams per deciliter and affects more than 3 million people in the U.S. Within that, we define a high-risk SHTG segment, triglycerides at or above 880 milligrams per deciliter or above 500 milligrams per deciliter with the prior history of acute pancreatitis, affecting approximately 1 million people who carry meaningfully higher AP risks. And at the far end of that spectrum, of course, sits clinical and genetic FCS where triglycerides are persistently elevated above 880 milligrams per deciliter and prior AP history is prevalent, a population of more than 6,500 people in our estimation at extremely high AP risk. The SHASTA-3 and SHASTA-4 we reviewed today, together with the FCS data from PALISADE behind REDEMPLO's FCS approval now give us clinical evidence across the entire spectrum. What's notable is that plozasiran's value proposition doesn't change as you move across that spectrum, it holds. Across these patient groups, we see deep and sustained TG reduction on the order of approximately 80% from baseline maintained throughout the treatment period. Over 90% of plozasiran treated patients in the Shasta program reached triglyceride levels below 500 milligrams per deciliter, an important risk threshold at month 12. Importantly, we saw a statistically significant reduction in AP risk that is pluzasterin reduced cumulative AP events by nearly 80% versus placebo. And the safety profile also remains favorable. Notably, we saw no hypersensitivity, no meaningful change in platelets, no clinically meaningful change in liver enzymes and importantly, no liver fat elevation relative to placebo. Also, the expected physiological change in HbA1c is consistent with the APOC3 inhibitor class. And lastly, dosing remains simple, a convenient 25-milligram dose every 3 months, just 4 injections per year and no titration requiring. This consistency across the SHTG spectrum matters commercially. Physicians treating the broader SHTG population won't need to relearn this medicine, the profile they already trust in FCS carries forward. Given that consistency, our initial commercial focus for the SHTG opportunity will be deliberate and focused. We're prioritizing the high-risk SHTG segment, shaded here, patients with triglycerides at or above 880 milligrams per liter and those with triglycerides between 880 milligrams per deciliter, who also carry a prior history of acute pancreatitis. These are the patients with the greatest clinical urgency. Importantly, we're not starting from 0 here. A subset of this high-risk segment, as shown here in the small blue boxes, already meets the clinical criteria for FCS and redemplo is reaching these patients today, recurrent hospitalization for unexplained abdominal pain, a family history of HTG induced pancreatitis, or a history of pancreatitis are all criteria that support a clinical FCS diagnosis. And patients presenting this way are being identified and treated under our current label. To summarize, this is not a strategy of chasing the full addressable SHTG population on day 1. It's a strategy of going first where clinical need, payer willingness to pay and the evidence supporting REDEMPLO, our greatest. To put a number on that clinical urgency in the high-risk segment, defined as TG is at or above 80 or above 500 milligrams per deciliter with a prior history of acute pancreatitis, seen here in the green outline. The number needed to treat with plozastrin to prevent 1 acute pancreatitis event is 9 patients over 1 year. And for those patients with a prior history of AP, irrespective of TG cutpoint shown here in the blue rectangle, the number needed to treat is a remarkable 3 over 1 year. NNT reflects how many patients need to be treated to prevent 1 event. The lower the number, the greater the impact per patient treated, and NNT in the single digits, like we see here, represents a landmark result and demonstrates compelling value to payers when assessing cost benefit. Also, it's a number we believe will strongly resonate with physicians who treat this population. Turning now to our go-to-market approach. We've identified over 20,000 health care professionals across largely 4 specialties, lipidologists, endocrinologists, preventive cardiologists and internal medicine and primary care, who treat the roughly 1 million high-risk SHTG patients in the U.S. today. This is a targeted call plan, these 4 specialties concentrate the patients we're prioritizing and it allows us to direct our commercial resources efficiently as we prepare for a potential SHTG launch. Finally, our commercialization efforts are already well advanced. Our medical education and communication strategy is developed, and our medical science liaisons are in the field conducting scientific exchange. Our marketing and market access strategy is developed, and we're executing compliantly against key go-to-market activities. The expansion and optimization of distribution channels and patient services are well underway. Regulatory interactions are planned in the near term, and we're building toward day 1 readiness across patients, providers and payers. In short, much of the planning and infrastructure required to support a potential SHTG launch, is or in motion will have any regulatory decision. With that, I'll turn the call back to Vince.

Thanks, Andy, and thanks to all the speakers today. This is a really great set of presentations. I appreciate it. So takeaways. So what's important? And I think it goes without saying that Arrowhead is thrilled with these data. This is going to sound like [indiscernible], but this is really the slam dunk or the home run or the grand slam or whatever sports analogy you want to use for what we had hoped for with these data. It's really phenomenal. Plozasiran continues to demonstrate an attractive profile and importantly, a consistent and favorable safety and tolerability profile. Second, as Andy just mentioned, it's an extraordinarily compelling value proposition across the board for physicians, for patients, and for payers. And Andy highlighted this, but I want to highlight it again, an NNT of 24 over a year for the overall study population in SHTG is already impressive and potentially paradigm shifting for the treatment. And then when you go to the high-risk patients, the 1 who've had a prior history of AP NNT of 3, and just to put some perspective on that, this is oversimplified, but essentially, it means all you have to do in that population is treated in patients to prevent 1 event of acute pancreatitis. And as a review, acute pancreatitis is a very severe and chronic and recurrent frankly, very costly thing for the health care systems to treat. So again, this is a really compelling value proposition across the board. Next, we are still on schedule to file our sNDA to request approval for the SHTG population before the end of this year. And just a reminder that we did recently purchased the priority review voucher which potentially accelerates our path to launching in this large population in the U.S. And then, again, as Andy just mentioned, our launch readiness efforts are well underway. And over the long term, we see this opportunity in SHTG just in the U.S., potentially being a $3 billion to $4 billion a year opportunity. And we're really just getting started with lipid disorders. This is -- there's a lot of information in this slide. I'm not going to cover all of it, but just to orient yourself on the left side, is elevated LDL and the diseases that, that leads to. On the far end of the spectrum, the most severely elevated LDL is or homozygous familiar hypercholesterolemia for that part of the population, we have an investigational product called Zodasiran, which we also presented some data from a small sub-study in China today at the Congress. And those data look really promising. And we hope that plozasiran becomes an important medicine for that part of the population. As you go to the far right, that's -- these are diseases characterized by elevated TGs. And again, the most severe is FCS, both clinically and genetically diagnosed and then the SHTG population, which we talked about today, and then in the middle of this, in the intersection of elevated TGs and elevated LDL as population called mixed hyperlipidemia, and that's a patient population with persistently elevated LDL persistently elevated TGs and a high risk of CBD. And we have a new dual functional sRNA product called ARO dimer PA that's investigational. It's in a Phase I/II study right now directly in mixed hyperlipidemia patients. It's a drug that targets both the PCSK9 gene and the APOC3 gene simultaneously in 1 drug. It's a really phenomenal technology that we're extraordinarily excited about that we'll have our first readout for the first-in-man study. next month in September. And again, more to come on that shortly. But the takeaway here is that Arrowhead is already active across the spectrum of lipid disorders and that's only growing. We foresee in the future additional products in the cardiometabolic space, and we're building our commercial infrastructure to support potentially multiple products. So what does that look like in the short term? Over the coming years, even with just the programs that we've disclosed that we've talked about, we do see the possibility for multiple independent launches. As I mentioned, we launched REDEMPLO and FCS in 2025. We hope to file our sNDA for plozasiran for SHTG before the end of this year and provided we received a positive review and approval. Our hope is that we launched that in 2027. Following that, the HoFH study of zodaserant should read out around the middle of next year, which would set us up nicely for the next commercial launch for Arrowhead in 2028. And then beyond that, we have the dimer program I mentioned for ASCVD and then additional programs for obesity and mash and then others that are undisclosed at this point. So this is just the start for our commercial franchise. So thank you, everybody. We appreciate the time today, and we have about 10 minutes to open up the call to questions. So Terry, do you want to compile the question list, please.

[Operator Instructions] So our first question comes from Brian Cheng at JPMorgan.

Congrats on the data presentation yesterday, and thanks for taking our questions this morning. We have a question for the physicians on the panel here. curious doctors, can you walk us through how you think about the acute pancreatitis effects that we are seeing here in the SHASTA-3, SHASTA-4. And how that fares against or -- and how would that ultimately impact your decision-making if both options become available today?

I'd be happy to start over [indiscernible]. For me right now, that this is such a huge unmet medically. There's just a huge market out there for patients that need this treatment. So I'm actually not thinking of competitors between the 2 companies. I'm thinking of the 2 companies to let could work together with the same strategy for all the clinicians to find as many as possible of these patients. There's so many of them out there. So I actually see that as a big bank there's 2 different companies that will try to make clinicians find right patients and refer them to doctors that see these touch [indiscernible]. Gerald, what's your point?

Yes, I totally agree. I mean, I think when there are to really good products, there's a feed forward mechanism and everyone can be a winner. I mean there are advantages in the direction of poseseran in terms of we have not seen a deterioration in the effect, the liver enzyme changes are very good. The HVAC is not statistically significant. So at the end of the day, it's the clinical consultation around specialty choice. I mean I'd rather have an injection for every 3 months really rather than every month for a start, and you want to inject themselves every month. But there will be people who would like a short-term injection in terms of they got fair and side effects and reversibility. There are -- we have 1 continued clinical situations where that would be indicated. But I would have thought the less frequent injection site reactions from the fact that these injections are not there no injection site reactions at , which is extraordinary actually would put disaster and in an advantage point really, but there are sort of something different. And that ultimately depends on how the doctor Monte and what patients perspective is on this. and then the price of the 2 products. as well as yes, that's a difficult one. Let's have another question.

Thanks, Brian. Tara, do we have another question ready?

So our next question comes from Mike Ulz of Morgan Stanley.

Congrats on the data as well. Maybe another question for the 2 physicians just when plozasran potentially comes available next year? Are you going to be targeting your high-risk patients initially primarily? Or would you might go more broad into the mild and moderations as well?

I can start. Borge Nordestgaard. I mean what you see it's again, it depends on the price because it was very inexpensive many, many more patients would have. But what I do see historically is that when some new drug coming to the market than manifestations tend to be somewhat conservative. So they will always start with the highest risk patients, the ones with the highest flip will be 1 thing, but certainly also the 1 for acute pancreatitis. But that experience to grow and the price is right, a lot of patients will be offered this type because there's really nothing we can do for them today.

Yes, I would agree with that. I mean, come back to the price clinical practice, we like to restratify everywhere you go, ConryHub disease, pneumonias irritant. So people aren't going to be restated by and it would be significantly easier. I mean, I don't want to talk too much about the cost-effectiveness really to actually fund something where the risk is higher. That's they'll try to contender. But clinical practice is step. So the first thing patients will enter guidline -- the ACC AHA guideline recommended diet carfibrates and the tribes will drop. We'll have to go through the -- it's the resiting that has persisted Carispecific innovation track literate to which you will have to follow that line. I mean the study is excellent in showing the effectiveness of very good background carriers. So that will have to be part of for.

Our next question comes from Maury Raycroft at Jefferies.