Hi, everyone. My name is Maury Raycroft. I'm one of the biotech analysts at Jefferies. I'd like to welcome Chris Anzalone, the CEO of Arrowhead. Thanks so much for joining us today, Chris, and congrats on the FCS approval yesterday. Thanks very much. It's a pleasure to be here, as always, and thanks for having us. We're going to do a fireside chat format. To start off, for those who are new to the story, maybe provide an overview of the company, and then for FCS, talk about the commercial opportunity there based on your market research, KOL feedback, and also what Ionis has reported for their first nine months of TrinCol's launch. Great. Again, thank you. We are an RNAi company. We are a bit unique in that we are technology-focused rather than disease-area-focused. We have built the set of platforms that allow us to bring RNAi to a number of different cell types, in fact, seven. We have five clinical programs that are representative of what we have, clinical programs in five of those cell types. In fact, by the end of this year, we'll have 20 individual drug candidates in clinical studies. We are quite broad. Our model is dependent upon doing some partnering and holding on to some assets ourselves and developing and commercializing ourselves. We are making a concerted play in cardiometabolic, and I define that broadly. Plozasiran, now Redemplo, which we'll talk about, is one of those. Zodasiran is an ANGPTL3 inhibitor that can treat HOFH. We're in a phase III study there. We will have a dimer or a bispecific that will be treating patients in the next month or so. This is designed to lower both LDL and triglycerides via lowering PCSK9 and ApoC3. We'll know probably the middle of next year how well that's translating. We have obesity assets as well. Together, cardiometabolic is really at the core of what we are doing, at least internally and commercially. We've got other call options that are interesting. Let's see what our CNS platform looks like. We'll be treating Alzheimer's patients or healthy volunteers first, but then Alzheimer's patients with our ARO-MAPT candidate that is administered via simple subcutaneous injection. We should have some data there in the summertime. That could be a place where we also decide to expand into other franchises. The point is, we've got a very broad offering, and we've got a technology that's increasingly validated and allows us to go where disease is. Plozasiran, now Redemplo, is the lead for that. As you mentioned, we just got yesterday, we're approved by the FDA to treat FCS patients. That is a small population. The idea here is to lower ApoC3 and thereby lower triglycerides for this population. That should translate into lowering the risk of pancreatitis. That is our first market. We expect to expand into severe hypertriglyceridemia market sometime soon. We have ongoing phase III studies there that will allow us, I think, to expand the label into severe hypertriglyceridemia. That all of a sudden expands the market substantially. There's about 3.5 million people with severe hypertriglyceridemia as defined by triglycerides above 500. Within that, we think the high-risk population, about 750,000 - 1 million or so people, are the core of that market, at least initially. That is going to be our focus in SHTG. We will see if we can step down as we are in the market for some time. Got it. Yeah, that's a great intro and setup for FCS and then moving into these bigger indications. Maybe talk about pricing for the drug at $60,000. How do you expect this pricing to impact reimbursement and market access for FCS patients relative to Ionis's higher-priced drug? Do you expect earlier or preferred formulary? Sure. Yeah, let's talk about that. We are in the FCS market because we have a good drug in Redemplo. There are patients, there are FCS patients who need that drug. We need to get our commercial folks into the field, communicating with physicians and payers. It is an important market for us. The economic driver of Redemplo is really in the SHTG market. Everything we can do, anything we can do to make sure we get the correct price for that is important. It is lowering triglycerides. Unfortunately, triglycerides are on a standard lipid panel. People have this sort of knee-jerk reaction that it is a cardiovascular drug and therefore needs to be priced in the $10,000-$20,000 range. We think that is absolutely wrong. This is a pancreatitis drug. Given what it can do for those high-risk patients who are at substantial risk of pancreatitis because of elevated triglycerides in that population, we think it's more analogous to a MASH drug or to a severe asthma drug. We need to make sure that the payers understand that, the providers understand that. We jumped in, we're jumping into the FCS market with an SHTG price. We call this one Redemplo pricing. We are not going to ask different patients to pay different amounts for the same drug. As you say, the annual WAC price is $60,000. We think that's the appropriate price for SHTG. In particular, what we're talking about there is not the broad 3.5 million or so people with triglycerides above 500. It is those high-risk individuals with triglycerides above 800 or so with or without a history of pancreatitis. It's important that we keep those patients from getting their first episode of pancreatitis because we know that future episodes can be more severe and certainly more numerous once you have one episode of pancreatitis. Look, this to us felt like the right strategy. Let's get into market quickly with FCS. Let's treat these patients who need to be treated. Let's start working with payers immediately so they start to understand the value of this drug long-term in the SHTG market. It's just not simple for them, right? There has never really been a good way of lowering triglycerides substantially in a well-tolerated fashion. It is not part of their normal actuarials. This takes education on the payer side, but also on the provider side. We'll be doing that while we're treating FCS patients to help, again, payers understand that this is certainly an important drug for these patients who have increased risk of pancreatitis. For an acute pancreatitis event, I guess, how much could that cost the system? Yeah. That can certainly be greater than $60,000, can even be $100,000. That often, often will require hospital stays, and so multiple days in the ICU. This is an expensive condition. Also, there are human costs to this because it's not like it's an asymptomatic disease that every once in a while will lead to pancreatitis. These patients have recurrent abdominal pain. They've got brain fog. Many of them can't work. There's a ton of lost productivity in addition to the direct medical costs. Yeah. And so you're coming in at this $60,000 flat price. You think payers are going to be on board with it. And this is for the more high-risk population. But Ionis is going after a broader population where they said they could have stepped on pricing to $10,000-$20,000. And so what's going to enable a doctor to make the right decision on which drug they should use? Yeah. Look, I have no control over how they're going to price their drug. We view this looking at our own drug and what that offers to these patients and to healthcare systems, frankly. That is why we think $60,000 is correct. Look, this is finally, FCS patients have opportunities to treat this condition. Shortly, SHTG patients will have an opportunity to treat this condition. They'll have a choice. That's a good thing. Redemplo is now approved. Tryngolza with Ionis is on the market. Physicians have choices, and that's a good thing for patients. We think the choices here are relatively clear, right? It's not easy to, it's very difficult, in fact, to compare two different drugs across different clinical studies. You can look at their phase III data and our phase III data, and it's fairly clear, right? We are dosed once a quarter. They're dosed once a month. We showed about an 80% reduction of triglycerides from baseline. They showed 30%-40% in their FCS phase III. We didn't see any hypersensitivity. They saw some because it's an ASO. We didn't see any antidrug antibodies. I think 40% of those patients or so had antidrug antibodies. They had around a 20% rate of non-responder. We didn't have any non-responders. All patients had triglycerides lower. It's good for patients to have choices, but we think the choice is relatively clear. Having said all that, it's important that there are two players there, right? Less so for the FCS market, but certainly for the SHTG market because this is a build market. There have been no therapies really to treat this condition in the past. You could take fish oils, take fibrates. Those might lower triglycerides in the 20%-30% range or so, but doesn't really move the needle. Two companies can build this market better than one company. I think it's better for patients and for the overall industry for two of us to be out there. Got it. Makes sense. Let's talk about the broader opportunity. You've got three phase III studies ongoing, the Shasta III, Shasta IV for SHTG, and then MIR3 for mixed dyslipidemia. Top lines for all three of these studies are expected middle of next year. Can you talk about the patient baseline profiles relative to Ionis? We know these trials are overpowered for triglyceride reduction, but given the variability in placebo responses, what could the expectations for placebo response be? Sure. We will have, I think we're publishing the baseline data at a conference in the first week of December. It's escaping me what conference that is. I want to say December 3, 4, or 5, something like that. Those data will be out there. What we've said publicly in the past is that the baseline characteristics were similar. Look, Ionis showed really good data in core and core II. The fact that they did see an improvement in pancreatitis risk was a very important thing for the industry. That's the first time, to my knowledge, it's the first time anyone has shown a relationship between lowering triglycerides and a decrease in risk of pancreatitis in the SHTG market. That's a very important thing for payers to see and for physicians to see and for patients to see. That was great for the field, and I was happy to see that. I don't know what our Shasta III and IV combined will show in terms of pancreatitis rate. If history is prologue, we would expect at least as good triglyceride reduction as what Ionis has seen. I think we've got a very good chance of seeing also an improvement in pancreatitis risk. We have belt and suspenders here. We also have Shasta V that is designed to show an improvement in pancreatitis. It is enrolling those high-risk patients that I mentioned, those patients with triglycerides above 800 and history of pancreatitis. This really is the core of the initial market, at least within SHTG. Even if we were not to show an improvement in pancreatitis in III and IV, V is designed to show that. We feel quite good that we will have that on our label at some point. If you see the improvement in Shasta III and IV, would you discontinue Shasta V? Yeah, it's a good question. We'll have to take a look at the data. We are certainly open to that. If that answers all the questions and we don't see any additional value in Shasta V, sure, we'd be happy to discontinue that. It doesn't make sense for us to make that decision now until those data come in around the summertime. What's the status of that study? Any status update for Shasta V? Yeah, it's moving. We have been bringing a number of sites online. That is progressing. Yep. Got it. Okay. For the acute pancreatitis events, do you have an estimate for your study on what that could look like based on your triglyceride reduction? I guess any modeling that you've done there? We have done that modeling. Can you comment on it? Yeah, look, we are looking forward to seeing what those data look like. I don't know what they're going to show, but we have a drug that works, that appears to work in all people and lower triglycerides substantially in all people. I think we've got a good shot. Got it. There's been debate on how the AP events are adjudicated. Ionis is using gold standard criteria based on Atlanta classification by an independent CRO. Presumably, you're doing the same thing. Are there potential differences in how you're documenting the AP cases? Yeah, it's a good question. Historically, we were using the gold standard, the Atlanta criteria. For our Palisade phase III study in FCS patients, the pancreatitis events were adjudicated based on that. By the way, we did see a statistically significant improvement in pancreatitis risk when you combined our two doses, 25 and 50. We saw it even with the most stringent adjudication criteria there are. Having said that, we saw what Ionis was doing, and they had a broader criteria that included not only pancreatitis, but possible and probable pancreatitis. Regulators seemed to be okay with that. It didn't make any sense for us to stick with the stricter criteria. We have harmonized that. We are using essentially the same criteria as Ionis. We expect to see more events now in III and IV and V, Shasta III, IV, and V than we would have if we would have kept the more stringent Atlanta criteria. Got it. Is that something you had to get alignment with FDA on, or? No. I don't think we had those discussions. The Atlanta classification was simple because that was standard. We were watching how the regulators would react to the Ionis criteria. They believed that that was a valid criteria. So we're using it. Got it. Maybe comment on safety. At AHA, we got mixed views on the increased hepatic fat in the A1C that Ionis is showing. What's your take on the risk-benefit profile? Our safety profile so far has been quite clean. We do see in some diabetic patients slight increases in A1C. That's just physiology. When these patients are all of a sudden metabolizing triglycerides, the sugar can be shunted into gluconeogenesis. Diabetic patients may need to alter their medication. We were nonplussed by that because it's manageable. Physicians have been nonplussed by that. Regulators have been nonplussed by that. Payers have been nonplussed by that. We're comfortable with that. Beyond that, again, we didn't see any hypersensitivity. We didn't see any thrombocytopenia. We didn't see any antidrug antibodies. We saw very limited injection site reactions. We didn't see any drug-related transaminase excursions to speak of. We are quite happy with our safety profile. My expectation is that will continue into the larger Shasta III, Shasta IV, MIR3, Shasta V studies. We know this modality well. We know our molecules quite well. I expect that to continue. We'll see if that hepatic steatosis finding with Ionis is going to be a problem for them. We don't have much data there. We have small numbers in a prior study where we looked at that. We didn't see any increase in liver fat at this 25 mg dose, the dose we're taking to market. We're not expecting to see it. I don't know if it's drug-related. It doesn't sound like it. I think it may be ASO-related because also remember that Ionis had an ANGPTL3 program that was showing an increase in liver fat. I think that program is no longer operating. We also have an ANGPTL3 program we call Zodasiran. People asked us around that time, do you see an increase in liver fat? Not only did we not see an increase, we saw a decrease in liver fat. That could be just a byproduct of ASO. We'll know that sometime in the middle of next year. As you mentioned, I think a subset of our patients, we are looking at liver fat content. Got it. Maybe just back to FCS, if we just talk about the immediate launch plans and just what you're going to share in earnings updates for the launch as you go. What kind of metrics are? Yeah. We'll have an earnings call, I guess, next week. We do not expect on that call to give any guidance on what the revenue looks like. We really want to get a quarter or so under our belt to see how our launch is going before we start to make any guidance on that. Got it. Okay. Yeah, maybe for SHTG, just talk about how big the market opportunity could be. You talked about number of patients, but I guess anything else on just with your profile, what kind of uptake you anticipate getting there? Yeah, look, we think that's a sleeper. It is a historically underdiagnosed market. We know that in large part because there's been nothing to treat these patients. That happens all the time in biotech, right? That all of a sudden, when a condition has a treatment, it is more properly diagnosed. We think that's going to be the case. Even so, we think there are three and a half million or so people with severe hypertriglyceridemia. These are people with trigs above 500. We think that's the broad market that we will launch into in SHTG. However, the core market that we're focused on is that high-risk population, those people with triglycerides above 800 or 880 and history of pancreatitis. We think there's 750,000 or so of those, maybe up to a million. That's really our core market. When you think about our TAM, think of it based in that much more narrow market. That allows us, I think, to build out a smaller sales force than one that would be addressing all three and a half million or so. Having said all that, look, I think that this is a good drug. I think this drug can certainly help those high-risk folks who are at great risk of pancreatitis in the near term. I think longer term, it could be that we will step into those less severe markets. That is not really our focus right now. The focus right now is helping those folks who really need this relief. Got it. Maybe shifting gears, talk about the dimer, the PCSK9 ApoC3, and just what the strategy is there. Sure. How cool is that molecule? It's incredible, I think. It is a dimer or bispecific, depending upon how you want to categorize it. It is designed to reduce expression of both PCSK9 and ApoC3 with the goal of lowering LDL cholesterol and triglycerides. We think this is a potentially transformational drug in ASCVD. What we're talking about with Redemplo is the very high level of triglycerides. The primary risk there is pancreatitis. That's why we call that a pancreatitis drug. That's where that sits. However, there is this population. It's very large. We think around 20 million people in the United States with increased LDL and increased triglycerides that are at heightened risk of ASCVD. Everyone knows that elevated LDL levels increase risks of ASCVD. There is increasing data indicating, suggesting that remnant cholesterol is at least as atherogenic as LDL cholesterol. There's not been a good way to lower that substantially. Now we will have this, I think, relatively complete medicine that can lower both risk factors and really squeeze out an awful lot of ASCVD risk. As I said, that's a 20 million or so person market in the United States. It's never been prospectively studied. We are in this very interesting situation where I think we will know if we have a drug in six or eight months. We know how our RNA molecules deal with safety. Now we'll just see how well this dimer translates from animals to humans. In animals, we saw good knockdown in both PCSK9 and ApoC3, therefore both LDL and triglycerides. We'll see how well it translates. I think there is a relatively low risk on this drug's ability to do those things and to do it in a well-tolerated fashion. I think the risk is the stoichiometry. Let's see if we get good enough knockdown in both LDL and triglycerides to make sense. We'll know that, as I said, I think in the summertime. Got it. So potentially data summer next year. Yeah, it won't be complete data, but we will have data in patients, in mixed hyperlipidemia patients. Got it. Okay. At AHA, there's a lot of interest in ANGPTL3 as a target too. You've got a phase III program, which I think is underappreciated in HOFH. Maybe provide a status update on that and talk about the synergy between ANGPTL3 and PCSK9 and how that can influence a bigger picture strategy. Sure. We do have an ANGPTL3 program. It's called Zodasiran. We are in a phase III study in HOFH patients. My expectation is that that should be fully enrolled sometime in the first half of 2026. It's a year-long study. Done sometime in the first half of 2027. We will file shortly thereafter. That could be a 2028 launch. That dovetails well with Redemplo. It's going to be the same physician network that we're calling on for Zodasiran as we are with Redemplo. Our incremental commercial costs are very low by adding Zodasiran into the bag. Yet we have exposure to some additional revenue. Now, it's a small market, HOFH patients, because we're not going after HEFH. We're going after only HOFH. It's a small number of patients. Given our phase II data, I think I'm going to get these numbers wrong, but I'm going to say we've treated around 17, somewhere around 15 or 17 HOFH patients in phase II studies, phase II and phase I studies. It appears to, Zodasiran appears to lower LDL in a very similar fashion as the antibodies. We expect our activity to be comparable, but with the added benefit of a simple sub-Q injection once a quarter rather than an IV infusion once a month. We think there's market share to be taken. Got it. We've only got a minute left, so we're going to do a rapid fire on a couple of programs. For obesity, you're going to have data by the end of this year. Just maybe briefly set expectations. Yeah. I'm not going to set expectations. We've got these two programs, ARO-INHBE and ARO-ALK7, that are both addressing two ends of the same pathway, this activin E pathway. We're really excited about these. The animal data were stunning. The physiological rationale is strong. ARO-INHBE is addressing the liver, and ARO-ALK7 is addressing the receptor in adipose. We are looking forward to seeing how these translate from animals to humans. We will have incomplete data sometime by the end of the year or around that time. I think you've got two bites of the apple. You'll have some data around the end of the year and then a more complete data set sometime in the first half of 2026. We are trying to schedule this webinar right now. Between travel and the holidays, it may bleed into early January. We'll see. Sometime around the end of the year to early part of 2026, we'll have some data. Got it. There is a lot of interest in the Sarepta partner programs. Maybe provide a status update there. Sure. Yeah. DUX4 and DM1, we think those are great drugs. Those are where we continue to dose patients. We are still operating those studies. I don't know if Sarepta is guided to when they're going to release data, but we continue to operate in both those. We are on track to trigger a $200 million milestone based on DM1 dosing by the end of this year. We look forward to getting those data out. We think those are important drugs into important diseases. Okay. Maybe in closing, you've got a lot going on at the company. Maybe just highlight key catalysts through 2026 that investors should be focused on. We have big 2026. It is led by our launch of Redemplo in FCS. Let's see how that goes. It is an important drug that I think does important things to this patient population. That is important. Second, I think we will have early MAPT data. This is our Alzheimer's drug that is administered via simple sub-Q injection sometime in the summertime. Should that translate from animals to humans well, that is a disruptive program. Not only the target and the disease we are going after, but also it could serve to de-risk that whole platform. The idea of getting into the brain with oligos via sub-Q injection is important. Summer for that. Also summer for dimer data. I think we will know if we have a drug in the summertime with the ApoC3, PCSK9 dimer. Of course, Shasta III and IV are going to read out in the summertime. We'll see what those look like for our eventual SNDA and SHTG. That's all I can think of in the next eight months. We have an important eight months ahead of us. Got it. Okay. Thanks so much for joining us today, Chris. Thank you.