Hi, everyone. My name is Maury Raycroft, and I'm one of the biotech analysts at Jefferies. I'd like to welcome our guests today, Vince Anzalone, Vice President in IR, and Bruce Given, Chief Medical Scientist of Arrowhead. Thanks so much for joining us today. Thanks. Thank you, Maury. We're going to do fireside chat format. So maybe for those who are new to this story, if you can give a one-minute intro to your platform and programs. Sure. So that was a harder 1-minute thing today than it was a handful of years ago. We are a rapidly growing RNAi therapeutics company. We have a proprietary platform called TRiM, or Targeted RNAi Molecule. It's a delivery platform that allows us to get delivery to multiple different cell types in the body. Our current clinical pipeline is 14 different individual programs. 10 of those are wholly owned, 4 of those are with partners, and our drugs are across therapeutic area. We have cardiometabolic programs, pulmonary, muscle, ultimately CNS, and others that are important to our program. And I think that, you know, it's important to recognize that we have a good diversity throughout our pipeline, both with respect to therapeutic area, but also with stage. We have multiple early clinical programs, and then now 3 to almost 4, phase 3 programs. We just had, and we'll talk about this in a moment, but we, we just gave our first top-line data release for our first phase 3 program in plozasiran, which I think is a really big event for us as a company, for any growing clinical-stage biotech company, is to have your first phase 3 readout, and that was a successful readout that met the primary endpoint and statistical significance on all key secondary endpoints. So that was a really exciting event for us. Yeah. Much congrats on that update, and that's a great overview as well of the pipeline and what you guys are doing. And you mentioned the FCS program. So the two late-stage cardiometabolic assets are APOC3 and ANG3, and you just had the top-line data for FCS, and we're going to see the full data at your June twenty-fifth R&D event. One of the key differences versus Ionis is that you enrolled both genetically and clinically confirmed FCS patients. Can you comment on whether the triglyceride reduction was similar or different in these two patient populations? Yeah, so, Maury, we don't, you know, we don't have that final data yet. We only have the top-line data. Having said that, you know, we had, you know, over 90% reduction in APOC3, which, you know, just being so close to 100%, it can't be very different between those two. And likewise, we had 80% reduction in triglyceride from baseline. So again, it's just mathematically not possible for there to be a huge difference. And, you know, we had limited data, less than 10 patients from phase I and phase II with patients with genetic FCS, and frankly, they hadn't looked any different either. So we went in expecting not to see a difference, and now mathematically, I think it'd be very hard for there to be any sort of significant difference. So I think it's unlikely that we're going to really see something there. Got it. That makes sense. Interestingly, the study also hit stat sig on reducing acute pancreatitis events. We thought this was an important result, given that the small sample size and Ionis didn't show stat sig difference on this measure. Do you expect this to be in the label, and are there any other differences you expect to see in the label versus Ionis? So, you know, labeling, of course, is always, you know, up to the FDA, and I'm always careful not to front-run the FDA. What's important here is that, you know, this was a pre-specified, multiplicity-controlled endpoint, and we beat it. We were statistically significant. That doesn't guarantee, of course, that it'll go into the package insert. Small study, you know, small number of events, but, you know, enough events that we were able to show statistical significance between placebo and active. So whether it winds up into the label or not, I have no doubt that it'll wind up, you know, clear in the publication of the data, for instance. And it's a very important, you know, endpoint, clearly for, you know, for FCS. Got it. Yeah, maybe talk about the significance of reducing pancreatitis and how that reads through to the longer-term plan for APOC3. Yeah, well, you know, that is the dreaded complication of FCS, and it is the key, you know, motivator for treatment for payers and for physicians and for patients. You know, so it's, it's extremely important in this disease. It is the dominant thing, and pancreatitis can be fatal. You know, so it's, it's a big, it's a very big deal. And, it's not a surprise, but it, it's one of a hoped-for endpoint in such a small study. Got it. Makes sense. And one underappreciated aspect is the potential market opportunity for this first commercial program in FCS. What is your current thinking based on market research and KOL feedback on the addressable patients in the United States? ... Sure, I'll take that. So we kind of view plozasiran, and we'll talk about the zodasiran, our second cardiometabolic program, separately. But we view plozasiran as having this really interesting commercial, potential commercial dynamic, where there is a rare population, and that's, you know, the genetically confirmed FCS. There's a slightly larger, but still rare population, which is the phenotypic FCS. And then there's a larger population with SHTG, severe hypertriglyceridemia, and Bruce can talk about our phase III studies there later. And then also an even larger potential ASCVD population on top of that. And, you know, in broad strokes, and this is oversimplifying it, but if we were to do clinical studies in all of those populations, they would roughly read out in that same order. You know, the rare first, the kind of moderate opportunity second, and then the ASCVD third, which allows us, as an emerging commercial company, to build out commercial infrastructure in the US and potentially globally over time, and in kind of a staged fashion. So your question about the actual size, you know, and again, these are broad numbers, but think about this general ballpark. FCS and then phenotypic FCS, maybe 1,000 to 5,000 to 10,000, somewhere in that ballpark of patients. Not all of those will be diagnosed, not all of those will be eligible for care. Those that are eligible for care, not all will, the physicians will want to treat with an ApoC-III inhibitor, and of those, not all will want to choose plozasiran. So there's kind of, you know, cuts that get you down to that addressable population. The epidemiology says that there might be 80,000 or so patients that have trigs above 880 and a history of pancreatitis, maybe 800,000 or so with 880 and above, without a documented history of pancreatitis. And then, when you talk about the larger SHTG, which is defined as trigs over 500, it's somewhere in that 2-3 million patient ballpark. Now, again, the further down that continuum you go, the more cuts there are for, you know, reducing the addressable population. But we think that even in SHTG, and I think, you know, for this audience, you know, this is a really underappreciated commercial opportunity, the trigs of 500 and above. You know, we see, again, it depends on data, and it depends on reimbursement and uptake, but we see a potential multibillion-dollar opportunity just with SHTG. Now, I would say our commercial work and our payer and our physician outreach looks like the, you know, on that continuum of 500 and above, the higher it is, the more willing physicians are to treat. So when you get above 880, it's very clear. When you're approaching 880, it's less clear but still relatively clear. When you're getting down to 500, you know, there, it is not 100% clear that this largely asymptomatic disease will be treated that consistently. And so we've kind of built in those assumptions for our commercial build-out in the future. But again, you know, I want to hammer this home, that I do think that the commercial opportunity for SHTG alone is a widely misunderstood and underappreciated opportunity, that we hope to, you know, be helping people to get to where we are, you know, in between now and when we're launching. Got it. And assuming you get approved for FCS, what are your thoughts, latest thoughts on pricing strategy at launch and as you expand into these, larger patient populations? And then what's a good, proxy launch to think about? We know that there's Wegovy in the EU, but there's probably better, proxies out there. How, what do you think about that? Yeah, I think I'm always reluctant to talk about, you know, pricing 'cause there's so much that goes into that. You know, the data, the opportunity, the label, and then the negotiations with payers. So I would say, in general terms, this is an orphan disease, and we think the value, potential value of the product, you know, based on data, would warrant orphan pricing. I don't want to put numbers around it. And then, you know, the second complication is that, as you mentioned, Ionis, the olezarsen product, they have a phase III readout, and I believe they have filed or are in the process of filing. And so they're, you know, a couple quarters or so maybe ahead of us. And so our commercial strategy likely will have to adjust to where they launch. And so, you know, I think that's FCS in both genetic and phenotypic. For SHTG, we are far too early to be predicting what pricing or reimbursement would be or market access around the world. We need to see data, and we need to see what the landscape looks like at that time. Got it. And, had a clarification question for, the two phase IIIs, the SHASTA-3 and SHASTA-4 studies, for SHTG. Both of those studies are very similar in scope. Just wondering if you can remind me if the FDA insisted on having, two phase IIIs for approval here. Yeah, they wanted to. And, you know, the size of the program is not driven by powering for efficacy. It's driven just by, you know, ICH guidelines on how many patients, you know, they want in an indication like this, you know, treated for a year in placebo-controlled trials. So there's actually SHASTA-3, SHASTA-4, and SHASTA-9, and SHASTA-9 is in patients with mixed hyperlipidemia, and it's just simply to build the safety database for, you know, that we'll need not only, you know, for the FDA, but also for EMA, for instance. Probably, you know, the Japanese as well will want to, you know, ICH guidelines. So I think in the end, you know, SHASTA-3 and SHASTA-4 are very, very similar. They're wildly overpowered for efficacy... So really, they're just there for safety, you know, building up the safety database. Got it. And then you've got the SHASTA-5 study, which is for the high-risk patients with acute pancreatitis. How will all of this come together when you file for approval? Is it gonna be one sBLA that includes all of these studies in it, or how is that gonna work? So actually, the SHASTA-5, you know, the pancreatitis study, is more for payers than for regulatory authorities. So I don't consider SHASTA-5 to be on the critical path for regulatory filings. That doesn't mean that it won't go in. If it finishes on time. Well, on time is the wrong word. In time, if it finishes in time, for sure, we would include it. But if it doesn't finish in time, it won't hold up the filings from my perspective. You know, so but, you know, it. So I don't think it's in the way of regulatory approval, but I do think it's very important, you know, potentially for payers, especially in Europe, but even in the US. And even with the fact that the PALISADE was statistically significant, you know, for pancreatitis, I mean, that helps. But I think, you know, the European authorities are, you know, pretty tough, you know, and you know, to get, you know, the kind of approvals and reimbursement that we would want to actually be successful in the market, we think, you know, SHASTA-5 is an important study. Got it. Makes sense. You mentioned time, I guess, how are you thinking about timelines for getting these, the SHASTA studies fully enrolled and getting to top-line data? Right. So SHASTA-3, 4, and 9 are already enrolling. Our expectation is that we'll complete enrolling next year. The last patient in has a year of treatment, you know, which means that we anticipate, you know, having those studies clinically complete in 2026. And, you know, depending on when enrollment ends in 2025, that will determine, you know, whether or not we'll have top-line data in 2026 or not. My suspicion is that we will, but I wouldn't take that as guidance. That's just, you know, an R&D guy's thinking. And then, you know, we'll file, you know, a few months after obviously completing those, and, you know, so, you know, potential approvals, you know, probably in 2028. Got it. Okay. Yeah, it's helpful. So another update recently was the New England Journal of Medicine publications, which was two publications, and then also the commentary as well. So congrats on that. What are your latest thoughts on the CVOT study in respect to size and scope, and whether APOC3 and ANGPTL3 can potentially be worked into a single streamlined study? In the commentary, it alluded to potentially having that type of study design, so wondering if there's any more on that you could say. You want that? Sure, I'll take that. So here's what I'll say, for cardiometabolic broadly, but plozasiran in particular. The strength of the data in those programs and in that program warrants that we move as fast as we can to make that a commercial product, and all that that entails, including doing the outreach and the work with regulators, which we are going to do shortly, and we just have those data a couple of days ago, and so it's hot off the press. So our goal now is to interact with regulators here in the U.S., and then, you know, ultimately, we'll look beyond to figure out the fastest way to get this filed and reviewed, and approved, and launched in FCS. The second main goal for that program is to get SHTG fully enrolled, as Bruce mentioned. Our hope is that that's in 2025, and then again, do the same thing and move as rapidly as we can to get that filed, and reviewed, and approved, and launched. And then the third is, as you mentioned, the potential cardiovascular outcome study and the ASCVD opportunity. There's a few steps for that. The first would be to do a proper analysis of the data and the opportunity, and then the patient population, and then do modeling and see what a study design or designs would look like, and then interact with regulators, and then get a study up and running. We're kind of in that interacting with regulators phase now. So we've done the analysis and the New England papers. If you haven't read them, I'd recommend taking a look 'cause there's a really good discussion of the genetics of both of those targets, ANG and APO, a good discussion of the data. And then lastly, you know, what do we do? You know, what do we do with these? And so the design work has flowed from all of that, and then now we're kind of in the regulatory interaction and feasibility stage. So right now, I wouldn't want to give guidance on what it's gonna look like, if we're gonna do it, when we're gonna do it, which asset we're gonna use, and/or sizing. But we are committed to moving those programs forward and having as broad applicability as possible. Now, excuse me. For, you know, a huge company, you know, the making an investment in—or what you think is a good investment with a good probability of a return is an easier proposition. For a smaller company like us, we need to be very careful about capital allocation, and where we source capital to source, even these investment opportunities that we think are really, really attractive for us. And so the feasibility of this can't be done in a vacuum. It has to include that part of it. Where are we gonna find the capital, and how are we gonna allocate the capital across all of those other 10 programs, and then, you know, some of the preclinical programs, too? So we're doing all that work now. You know, this is a really long-winded way of saying there's a lot that's going into this decision, and we wanna make sure we're making the right decision before we communicate the actual end plan with you guys on the street. ... Got it. That makes sense, and you probably can't say much more, but there's discussion around what the cost would be to get these studies run. Can you potentially bookend what that could look like? I guess, what would make sense for Arrowhead to do? Yeah, the cost will drive from the design. And so I wouldn't wanna say cost until we've zeroed it in on a design and sizing, because it can be a huge range. Right. Makes sense. Okay, and then wanted to ask a couple questions about your pulmonary platform, which is moving along as well. You've got the RAGE program, which is also an RNAi program. How does your recent data at ATS inform your phase II plans in asthma patients? And you've mentioned seeing anecdotal signals on on FeNO, but you also noted the screen failure enrollment challenges for these FeNO high patients. So what types of asthma patients will you enroll in the phase II, and how will this phase II design be similar or different versus other asthma phase II studies? So I'll say the general answer, you know, and then Bruce can kind of fill in all the holes here. So with RAGE, we've had really encouraging PD data, both in healthy volunteers and now in patients. And you mentioned ATS. We showed that we can get a high level of knockdown of the RAGE target in lung, again, both in healthy volunteers, and it translates relatively well into patients with mild to moderate asthma. So that's a big win for the platform, you know, but for that program itself as well, and also the duration. You know, we've come to expect, and I think that investors also have come to expect, that RNAi has a couple or a few hallmarks. One, you can get very spec... Or you can get knockdown of one thing. You know, the RNAi is designed to be very precise. You're down-regulating the expression of one particular gene. That's attractive. Second, you have a long duration of effect, which allows for infrequent dosing. In liver, we're looking at, you know, once every three months or less frequent dosing. Now, with our lung program, specifically RAGE, it looks like we can get a long enough duration, which would allow for dosing once every two months, which is a really big change, for that population. But for any inhaled drug, that's an attractive thing. So the next step would be, is there any signal for not only PD, but downstream anti-inflammatory effect? And then you move to a phase II. We were looking at these high FeNO cohorts as kind of that next biomarker of a biomarker kind of thing, 'cause, you know, if you think about RAGE, measuring RAGE knockdown is really just measuring that. Are you knocking down that one gene product? It's not. It's an activity measure, not an efficacy measure at all. And RAGE inhibition can affect many different inflammatory pathways. And, you know, I would recommend you guys all view our R&D webinar for the pulmonary program, which is next month, in July. This month we'll do cardiometabolic, next month will be pulmonary, and part of that will be to go into the complex biology of that RAGE pathway. It down-regulates many different inflammatory pathways. FeNO was really just a measure, an indirect measure, of IL-13-driven inflammation in the lung, and that was, that's the only other thing that's really measurable, in an early clinical study, upstream of a functional benefit for asthma patients. So we have three cohorts, I believe it's three, and as you mentioned, they were enrolling a little slower than we had hoped for. Our hope was that we would have enough of that enrolled so that we can give the first readout in Q3, and it looks like we're not gonna have enough patients enrolled to do that Q3 readout. But that was not a gating item for a phase II design. Phase II, we needed to have tox, we needed to have chronic tox, we needed to have the dose response relatively well characterized and the dose interval, and then we have to do some design work and patient population selection for the phase II. We're in that last phase now, where we're doing that design work and patient selection, and then also, as similar to with cardiometabolic, we're doing the regulatory interaction, to make sure that this design ideas that we have are okay with regulators. So the FeNO readout, it might be one quarter, maybe two quarters, we don't know yet when how long we're gonna. It'll be before we have those data. But we didn't wanna slow down the phase II for that, because again, it wasn't gating for a phase II startup, which we hope will be sometime around the end of the year or so. Got it, so- I mean, we don't even know if it's important. That's right ... for RAGE, you know, let alone, you know, how long it's gonna take to get that, and we just didn't wanna hold up any longer. I mean, we clearly know now that we have target engagement. We know the dose response for the target engagement, so we know what our clinical dose, and we've confirmed that the dose response is the same in asthma as it is in normal volunteers. So, you know, we have everything we need. So to wait around for, you know, for a readout on something that we don't even know is important or not, you know, just didn't make any sense to us, and that's why we're going ahead and moving forward now, rather than waiting for something that we wouldn't necessarily know how to interpret anyway. Got- ... positive or negative, it wouldn't matter, you know, we wouldn't really know whether it was gonna be predictive of activity. So phase II will be designed to actually, you know, look for, you know, clinical activity. Got it. Okay, makes sense. And is there a certain... Is it a matter of finding the right patients with the right amount of FeNO at baseline, or is that part of it? For phase II? Yeah. No, I doubt that FeNO will have anything to do with it. Okay. You know, it just, ... I don't know that it matters. That was part of the limiting factor for accrual in this Phase 1- Right. for the high FeNO cohort. So they needed, patients needed to come in with a certain, with asthma, with FeNO above, I believe it was 35, with blood eosinophils above 200, I believe it was. And, you know, if you think about it, this is a, it's an early clinical study without a therapeutic intent. So, you know, it's just two doses, and there's competition with other approved agents in asthma, other clinical studies that may have a therapeutic intent. So it was just, it was more challenging to get patients in than we originally anticipated. Got it. Okay, we're pretty much out of time, but I'm gonna do two rapid-fire questions. For MUC5AC and MMP7, is there gonna be... Are you gonna have a data update at the Pulmonary R&D Day for those? We haven't said when we'll do that. Okay. I think we will have some target engagement data for both of those this year. We haven't gotten more specific than that. Got it. Are you guys saying, when Takeda, when the phase 3 study for AATD could hit that 100-110 patients needed? No, we have to defer to Takeda on that, unfortunately. So I believe the first patient in was April or so of last year, something like that. You know, and so we will, we'll defer to them on guidance. Okay. And then maybe to close out, I wanted you to comment on just the manufacturing capabilities, how that differentiates you from other RNAi players. And then for financing strategy, I don't know if there's anything more on that you're saying. And then just what are the key catalysts ahead that investors should be focused on? Three-part question. Let me take the last two first. So the key catalysts are we will have, I think, important catalysts across the pipeline, over the next 12-18 months. Full FCS data, hopefully, full enrollment in the SHTG plozasiran study, clarity on the cardiovascular outcome study, readouts for all three of our pulmonary programs, RAGE, MUC5AC, MMP7, our muscle programs. We've just had a muscle R&D webinar about a week or two ago, so DUX4 for FSHD and DM1 for our... for DM1. Those should have readouts over the next 12-18 months, which I think could be impactful. And, you know, I guess if we're including next year, our first commercial launch, you know, provided everything goes to plan, of plozasiran, in the FCS population. Now, again, I... That that I think is a really critical thing for us to get right, as a growing company, and really changes our profile, I think, in, you know, in the minds of investors, when we can actually become a commercial company, build out infrastructure, start to get commercial revenue, and build that, you know, that capability. Got it. Okay. Thank you very much for taking the time and joining us today. Thank you.