Great, thanks. Hello, everybody, Luca Issi, Senior Biotech Analyst here at RBC Capital Markets, and today is our great privilege to have Arrowhead Pharmaceuticals with us for a fireside chat. Representing the company, we have Chris Anzalone, Chief Executive Officer. Chris, thanks so much for joining us. How are you doing today? Thanks very much. It's a pleasure to be here. I'm doing great, thanks. That's great. That's great. We have a long list of questions here, but maybe before we ask you about the individual programs, maybe it would be great if you can give us an update, kind of big picture, what progress has the organization made over the last few months, and most importantly, what's ahead here for Arrowhead? Sure. So I think our great challenge is to help people know where they should look. We're doing an awful lot of things right now, and I think we've made an awful lot of progress over the last several quarters in our cardiometabolic vertical. And that's, I think, you know, the primary value driver for us, you know, in the near to midterm. We've got these two drugs or drug candidates, zodasiran and plozasiran. You know, we'll have full readouts of phase II studies shortly, I guess, over the next couple of weeks at a medical conference. But we've, you know, we have treated, you know, gosh, over 1,000 human subjects, and the data have been compelling from both of those drugs. You know, we know that they appear to do what they're intended to do, and, you know, they lower triglycerides and lower other lipid parameters. And so we have made a lot of progress in slotting these into various markets, I guess, over the next several years. And so the first one is going to be FCS. We have a phase III that will read out over the next month or so, for plozasiran. This is a small market. However, the population that we studied was not just genetic FCS patients, but also what we call phenotypic FCS patients. And so these are patients with triglycerides above 880 and a history of pancreatitis. When you combine these two, and we'll see what our label says, but this is the population that we studied, but when you combine these two, it is not, you know, you know, an ultra-orphan, you know, very, very small market. You know, we think there are thousands of those patients, and there's really no good treatment for them right now. You know, there are fibrates, you know, there are fish oils and such, but these, you know, these are generally lowering triglycerides by, you know, 20 to maybe 25% or so. And plozasiran has shown repeatedly across multiple patient populations that we can lower trigs by, you know, by 75%-90%. We can really move the bar, you know, for these patients. You know, for we, my expectation is that we can get most of them below 880, which, I'm sorry, below 500, which is the threshold of that which, you know, can trigger acute pancreatitis. And for some of these patients, we can get them to normal. And so these are you know, this is a really powerful drug candidate, we believe. And so we're looking forward to seeing those data. You know, we think that is a good launching point for us to become a commercial enterprise, and we've spent a lot of time over the last, you know, few quarters, starting to prepare for that. I think that we can file our first NDA in this indication, you know, by the end of the year, and I expect to be commercial, next year. That's just the first, the first, you know, step in this drug. The next step would be severe hypertriglyceridemia. This is a much larger market. We think there's 3-4 million of those patients. We know that the approval endpoint there is simply lowering triglycerides. We expect to do that in spades, and we've started three phase III studies already. They are year-long studies. Well, two of them are year-long studies, and one is event-based. And so we think that we can then expand the label, you know, over the next several years in SHTG. And then ultimately, you know, we've got this opportunity in a very broad market of mixed dyslipidemia, and we're talking to the FDA right now about how we may address that between plozasiran and zodasiran. So that's plozasiran. And so two words on zodasiran. There is some overlap here. It does some of the same things that plozasiran does. It lowers triglycerides, but it also does other things. You know, it lowers remnant cholesterol substantially and a number of other lipid parameters. We are excited about that in small indications such as HoFH, larger indications such as HeFH, and potentially broad populations, you know, such as mixed dyslipidemia. Again, our data there have been compelling. So, you know, it feels to us like these two drugs are a pipeline unto themselves, and that we have set ourselves up for a train of value creation over the next several years, where almost every year we will have an NDA or a supplement to expand those labels. And so that really is the core of our business for the next few years. Now, we'll talk about other platforms we've got as well. We've got the ability to go after, you know, pulmonary diseases, obesity, we can address the CNS. Anyway, a number of other value creators as well in the next several years. Great. Great, great. Great overview. Maybe, obviously, you mentioned how important FCS is. This could be potentially your first commercial product as an organization, so obviously, pivotal moment for, for Arrowhead. Sounds like the database lock for the phase III is kind of any day at this point. Feels to me that Ionis has actually set a pretty high bar, right? In their data, they have shown, they have shown 11 patients- 11 pancreatitis in placebo and only one pancreatitis in the low dose and one pancreatitis in the high dose. How confident are you that you can match or potentially beat that data? Sure. So, so first on, on where we are, the last patient, last visit was a week or two ago. We expect the, the database to be locked in the next couple of weeks, I think, you know, a week or 10 days, something like that. And so we are hopeful to see data, you know, in the next, you know, month or so. Look, I don't know what the data are gonna show, but as I mentioned, we've been in hundreds of patients or healthy volunteers and patients, with plozasiran, and we've seen very consistent results. And so we expect, you know, apoC-III to be, to be crushed. We expect triglycerides to be crushed. We expect a well-tolerated drug with plozasiran. Look, the unknown here is that it's a small, it's a small study. You know, 72, I believe, or so, patients. And so, you know, you never know what you're gonna find in a small study, but at least historically, we've been very consistent, and I think powerful. Now, as it relates to olezarsen, you know, we will see how our data stack up against theirs. Historically, we have deeper and more durable knockdown. We certainly see that with plozasiran, but we see that more broadly, you know, compared to antisense oligos. With plozasiran, we expect quarterly dosing. Olezarsen would be a monthly dosing. I think that's a real benefit. And frankly, you know, in historic data, we've just seen deeper reductions in apoC-III, deeper reductions in triglycerides. And so, you know, my expectation is that we will stack up well against them. But again, you know, we'll see, we'll see, you know, what our data look like compared to them, to theirs. Got it, got it. Super helpful. Can you tell us maybe a little bit about the baseline characteristic in this trial? I believe that actually Ionis has capped the number of patients with no pancreatitis at 35%, so they really made sure that all the patients, the majority of the patients that were enrolled actually had a history of pancreatitis. Are you doing something similar? Do you expect your baseline characteristics in terms of triglycerides at baseline to be similar to theirs, or any, any thoughts there? That's a good question. I don't know the answer to that. I, I would expect the triglycerides to be similar. With respect to pancreatitis, I don't know. You know, about half of our, of the patients we studied were genetic FCS patients, and about half were, again, what we call phenotypic FCS patients, and so these are patients with trigs above 880 and history of pancreatitis. And so at least, at least, at least that half will have a history of pancreatitis. You know, but yeah, again, you know, we'll see where that goes. We are confident, though, that, that, you know, given the historic data, that we will-- that we'll be just crushing triglycerides, and we know that, that, that, that if you can get patients' triglycerides below 500, they substantially the risk of, of acute pancreatitis is, is substantially reduced. And my expectation is that the majority of these patients will get below 500. And again, I think that some of them may even get to normal. Got it. Got it. Super helpful. Maybe last one on this one. I think you mentioned a few times during the conversation that you're including both genetically defined patients with FCS as well as phenotypically defined patients with FCS. Is that good because you're gonna have access to a broader label, or is that bad because you have more variability in phase III? Well, we'll see. You know, I think it is a net positive. Who knows what the label is gonna say? You know, the FDA will tell us. But I can tell you that that's the population that we studied, and we studied it for a reason. You know, we think that there is a large number of patients that need this kind of therapy. It's not just those with, you know, with this known genetic mutation, but it's also folks, you know, that may have different mutations that we're not studying or, but the result is the same, that they have high triglycerides, and they can get acute pancreatitis. You know, I don't care what the reason is. You know, what we care about is helping these people, you know, not have these events of pancreatitis and not have these, you know, the issues of having substantially increased triglycerides. Got it. Got it. Helpful. Assuming the data's compelling, get approved, you're obviously gonna launch the drug. Two questions: One, how you think about pricing in the context of the prevalence, and then two, how are you thinking about the size of the initial commercial organizations? How many salespeople do you anticipate? How many back office people, how many MSL people, like... And maybe in that context, how should we think about your increase in SG&A? Yeah. So, we can certainly handle this commercial force. You know, it's a relatively small market. It's a very small market. And so, you know, we can do that with a limited number of salespeople, a limited number of MSLs, et cetera. With respect to pricing, we haven't really guided on what we're thinking there yet. It will be priced as an ultra orphan. Look, I think we can have, you know, very open and transparent conversations with payers, which is, you know, assuming we get approved here, the conversations will be, "Look, this is a very small market, and so we have to, you know, to charge X in order to make this make sense." But you know, we are very interested in this broader market of SHTG. Again, we think there are 3-4 million of those people, and so, you know, should we be lucky enough to have good data there and to have approval, you know, in that population, we will certainly be lowering the price. It'll be more appropriate for that size of market. But given that my hope is that we'll be addressing the genetic as well as phenotypic FCS market, I think that's not an inconsequential market. I think there's, you know, there are thousands of those people in the United States alone. We will be addressing the U.S. market. I think that we can address Europe ourselves as well. And so I think that could be meaningful from a financial standpoint. And then, you know, once we expand into SHTG, we think that's a multibillion-dollar opportunity there. You know, there are a lot of folks there, and there are not good treatment options right now, and we think we have a compelling treatment option. Super helpful. Probably pushing my luck, but, can you offer, like, a numerical number of how many salespeople you may need? Is that below or above 50? We haven't guided that yet. You know, give us some time, and, you know, let's see what the label says. Well, let's go upstream of that. Let's see what the data says, then let's see what the label says. And then we can go from there. But it's something that we can, we think we can manage ourselves. Okay. Okay, helpful. Pivoting to severe hypertriglyceridemia, obviously, Ionis is capturing the benefit in terms of severe pancreatitis as part of secondary endpoint, versus you decided to actually run a dedicated trial to actually capture the benefits SHASTA-5. Why do you think that's the better approach? You know, so it's not necessary for approval, it does not appear. But you know, we think it's helpful data for payers. And it made sense to do it as a separate study, so it doesn't slow down you know, the enrollment and of SHASTA- 3 and 4, and doesn't slow down our filing in this market. Look, I think SHTG is the sleeper here. You know, I think if people look at the data, they would agree that the plozasiran and zodasiran do what they're intending to do. I think that the people would agree that there are opportunities there. But I think that people don't really appreciate the value of this SHTG market. Again, we think there's 3-4 million people, you know, with triglycerides above 500. We can think about 1 million of those have triglycerides above 880. That's a very large market that is not well served right now. It sort of feels to me... So that's just for SHTG. And then more broadly, I think there's increasing evidence that triglycerides are bad actors. It sort of feels to me, you know, where triglycerides feel to me right now, like where we were with LDL several decades ago, right? You know, there was some idea that LDL was a bad actor. Statins came in and proved it was a bad actor, and all of a sudden, there was an awful lot of good that these companies could do by lowering LDL. I think that we are just on the cusp of that with triglycerides. You know, it's not really been studied well because the world has not had the ability to substantially reduce triglycerides until now, but I think we are just walking into that. And what's exciting to us is that I think we can step into this very large opportunity in a staged approach. FCS first, small market, we can handle that ourselves. Into SHTG, much larger market, we will likely use international partners, at least there, geographical partners there, and then ultimately, potentially, you know, the very broad market of tens of millions of people who are suffering from, you know, mixed dyslipidemia. Got it. Got it. Very helpful. If I recall it correctly, in severe hypertriglyceridemia, there was a little bit of a HbA1c signal. There was a little bit of a worsening in glycemic control in that data set, and if I recall it correctly, that's why you decided not to use the highest dose going forward, but you decided to use the mid dose. Does that keep you up at night? It does not keep me up at night. But it's something we take seriously. Look, what we found in—as we interrogated three different doses of plozasiran, was that the benefit that you see in the middle dose and the high dose were about the same. And so there was, you know, there is no reason to, you know, to give more drug than you need if you get the same benefit at a lower dose. So that was really the driver there. It was not that we were afraid of the higher dose necessarily, but it just appeared that we didn't need it. With respect to the A1c, we have seen in some uncontrolled diabetics some excursions. It doesn't keep us up at night because it, it does not seem to, you know, to be in play in, in those, in those patients who are not diabetic, and those patients who have controlled diabetes. It just means that you got to control your diabetes. And so, and so, you know, we are, you know, we are telling physicians, you know, in, in ongoing studies and future studies: "Look, just, just, you know, watch your diabetic patients and make sure that you maintain control of diabetes. Got it. Got it. Helpful. Maybe pivoting to ANGPTL3. I think a few investors would argue that there's no way you can run a cardiovascular outcome trial by yourself. You do need a partner. How would you push back to that? Yeah, that it's just not true. You know, I think The Medicines Company showed the world that a non-big pharma company can do an outcomes trial. Their challenge was to stay financed while they were doing that. They were essentially a one-drug company, you know, albeit a good drug. We are not that. You know, we are a platform company with a number of different franchises and programs. And so it allows us to bring in, you know, partnering capital to support the cardiometabolic vertical in particular. And I think we'll do that. I think also The Medicines Company has shown that you can do outcome studies in a more efficient manner than Big Pharma has historically done that, and we are exploring what those options are right now with regulators. You know, we'll have more to talk about once we have feedback from regulators. But I think we can do it. You know, people do ask, you know, even let's assume that we can do it, and let's assume we can do it a bit more efficiently than Big Pharma. It's still a big bill, and so the question is: Well, how are we gonna pay for that? And you know, we can pay for that with, you know, by partnering other programs. B, we have existing partnerships that we believe will continue to perform and bring in additional capital going forward. C, we will be commercializing in FCS and SHTG upstream of that. We think that brings in capital because we think those are real markets. We think, you know, those are potentially profitable drugs. And D, I think I'm on D. These are entirely unencumbered assets, plozasiran and zodasiran, and we would, at some point, potentially be interested in partnering geographically. So I think there's capital there as well. All those buckets. And then, of course, you know, we don't have any debt right now. I think we could, at some point, tap the debt markets. I think we have a number of levers that we can pull in order to make sure that we can finance those. You know, these are very valuable assets as far as I'm concerned, so I think that you know, we are clearly incentivized, you know, to make sure that we can push them forward ourselves. Got it. If I could push back a little bit on this one. You mentioned, you know, potential to run a trial relatively efficiently, and the Medicines Company obviously serving as a good comp here. But how are you thinking about the powering of that trial? I understand early days, but especially in the era of GLP-1, where many patients already have a big cardiovascular benefit just because they're gonna be on GLP-1, and they lose weight, do you need maybe an even bigger trial to show a cardiovascular benefit versus what we've seen historically? How are you thinking about all that? So it's a good question. And we know that many of the patients, you know, on that study would, you know, will be on the GLP-1s. We do not believe that it's gonna require a larger study to show benefit. We've been working with our KOLs for, gosh, several quarters now. And I think we have a good idea about what size that should be. Again, we haven't gone into that yet publicly because we are in discussions with the regulators. But the shorter answer is no, I don't think we're talking about a substantially larger study than what you're, than historically we've seen. Okay. Okay, that's helpful. Maybe pivoting along, maybe on RAGE. Can you just talk a little bit about the FeNO data? Obviously, I think we're all waiting for that data. You know, seems like enrollment is going a little bit slower than you're hoping for. Can you maybe tell us how many patients with high FeNO have you enrolled? That's number one. And then two, are you still committed to show us that data? Sure. So we continue to be really excited about ARO-RAGE. You know, I think that is a really exciting drug candidate, but we've seen very good knockdown in healthy volunteers and in patients. And that pathway is a compelling pathway. You know, it's got an awful lot of interest from KOLs. You know, it should be addressing inflammation, you know, in through a number of pathways, and so we're excited about that. Yes, these FeNO cohorts have enrolled a bit more slowly than we expected. You know, we are acquiring an elevated baseline FeNO in, you know, moderate to severe asthmatics, and it just and we are only, I think, in a couple of sites. And so it's taking us a bit longer than expected, but that's too bad. But we are still committed to this, and we are enrolling as quickly as we can. I think that it just got—it's—we've pushed it back by maybe a quarter or so. You know, we'll see how the, you know, how we can continue to enroll. I think the take-home message here is that we don't wanna wait for that. You know, that was never a gating study for us, or next set of cohorts. It was never gating because we believe in this. And so we have designed a phase II study that we expect to start in the fourth quarter. It just didn't make sense for us to wait to see the FeNO data because again, you know, we are committed to this, and we think that there's enough interest, you know, to go into an asthma study as quickly as we can. Got it. Maybe if I can push there, I do feel that this data is so important because this will change the conversations from, like, technological de-risking. You actually have shown evidence of knocking down genes in lung, which is obviously fantastic, both in healthy volunteers as well as patients. But the FeNO data will actually tell us whether you have a drug or not. Yeah. Yeah, it'll be helpful. Yes, yes. So I guess the question is, one, when is the earliest you can show us that data? And two, do you stand by 40% reduction in FeNO being the bogey here for success, given what we've seen from dupilumab and the TSLPs and some of the other molecules? Yeah. So look, I don't know what the bogey is. You know, more is better. You know, here's what's too bad about this. You know, we are addressing a number of inflammatory pathways. FeNO, FeNO is one that we can assess. We're looking for other ways that we can assess other pathways because we think they're all important. We believe in those studies, and so my hope is that we can get you data as quickly as possible, but I just don't know when that's gonna be. Okay. Okay, that's helpful. Maybe let's talk about obesity, given that that's so topical and, you know, obviously, very, very important. You have a very, very modular platform here, so you can go after multiple targets. Can you talk a little bit about inhibin? And we actually had a conversation with a KOL on Friday last week, and she's excited about the target. However, at the same time, a little concerned that, you know, maybe obliterating visceral fats could potentially be dangerous. So, like, where do we draw the line between, yes, we want to remove some of these fats, but we don't want to cross that line and have a detrimental impact? Yeah, yeah, let's take this step by step. You know, I think we're not in a position where we should be concerned about removing all visceral fat. I think, you know, look, we should be so lucky that we have something that can, that will be, you know, that powerful. Here, look, here's what we've seen. We have two assets that we bring into the clinic this year. One is ARO-INHBE against inhibin E, and the other one is an adipose-targeted construct. We've not said what the target is there. We're really excited about both of these. We will have a webinar on obesity in August, and so you'll hear a lot more about this then. You know, talk about the if you look at inhibin E, we think that's a really interesting pathway. What we have seen in animal models is substantial weight loss in animals. You know, not quite as rapid and to the extent that you see with the GLP-1s, but we see good weight loss. What's important here is that the weight loss that we see appears to be almost entirely fat, and we are not losing any lean muscle mass. That's a very important differentiator, I think. Second, it does not appear these animals are eating less food, and so that is a potentially very interesting feature, right? That these animals appear to be eating the same amount of food, but we are somehow ramping up metabolism such that they lose weight, while they're not limiting their intake. That is also a you know a substantial difference compared to the GLP-1s, and we think that that's something that that is you know that is certainly worthy of study. Got it. Super helpful. We're running out of time, but I do want to ask about Lp(a). We're going to see data from Novartis next year, obviously critical for the broader field to actually validate the Lp(a) hypothesis. One, what do you think is the probability that trial will be successful? Two, what do you think is going to be the hazard ratio for that trial? And three, why do you think your molecule is differentiated? Okay, so 1 and 2, I don't know. 3, Amgen has just shown better reduction in Lp than Novartis has. And so, you know, we talked about this with plozasiran versus olezarsen. I expect this to be a feature, you know, almost any time that one of our siRNA drugs goes up against an ASO. I would always expect us to have a better safety profile, deeper knockdown, and a more durable knockdown. I think that's what Amgen has seen. And so, I'm looking forward to seeing those Novartis data. If they are positive, that reads very well on the Amgen drug. I think if they are negative, it doesn't necessarily read against it because I think that, you know, they're seeing substantially better knockdown. And so if Novartis couldn't, you know, was unable to see a real benefit, I think Amgen still could. Super helpful. I have another 300 questions, but no more time. Chris, thanks so much for joining us, and- Thank you ... best of luck for the rest of the conference. Thanks very much. Thank you so much. Yeah. Thanks, everyone, for joining.