Good morning and back to final day of the 2024 Global Biopharma Conference here in Miami. I am Mani Foroohar, Senior Managing Director and Senior Analyst, Genetic Medicines, and I'm very fortunate to be hosting Vince Anzalone from Arrowhead Pharmaceuticals. Vince, how does it feel to be possibly the only person at this conference who flew here for worse weather? Yeah, it's a long flight over here, and actually it's beautiful right now. We were having a whole bunch of rain in California this year, so this is actually nice. I think we'll take the rain. I think we'll take it. Yeah, we need it. Joking aside, obviously Arrowhead's pipeline has expanded across tissue types in the last several years, most especially last year and this year, and we started talking about early clinical data, in the pulmonary pipeline, adding on to the work we're seeing in cardiometabolic, etc. So let's start with what is the most complex part of the pipeline in terms of late-stage sophisticated trials, in cardiometabolic. How are you thinking about launch timing for ARO-C3, asset selection, and what the right patient population for ARO-C3 is? Yeah, so we felt like that was an easier question, about a year ago, and even six months ago. It started to become a lot more complicated, which is a good problem because we feel like there's not a bad choice. Both plozasiran, which targets APOC3, and zodasiran which targets ANGPTL3, has had phenomenal data at phase II across many different lipid and lipoprotein parameters. So we feel like there's not a bad answer. What has made it more complicated, is this emerging story on the link between remnant cholesterol and cardiovascular disease, or cardiovascular risk. So there's been a lot of publications about that, and some of them actually, believe that the correlation is tighter, than even LDL was way back in the day. and it's not something that has been movable, with other, mechanisms. And so we historically have thought of the APOC3 program. Plozasiran is primarily a triglyceride-targeted program, and then zodasiran is more LDL-targeted. But it's actually become a lot more complicated than that. So just to review, the APOC3 program, plozasiran, we are in one phase III study now for a rare disease called FCS, or Familial Chylomicronemia Syndrome. It's patients who have a series of genetic mutations, some known, some unknown, that cause them not to be able to metabolize triglycerides in the blood. And so they accumulate these enormously high levels. So the normal level is 150 mg per deciliter. These patients can be in the thousands. And it causes, again, severely elevated triglycerides, leading to bouts of acute pancreatitis and hospitalization and, in the very severe cases, death. And it's not a disease that's had any really available treatment that moves the needle. So our phase III study called PALISADE is in 75 patients. It's about half split between genetically confirmed and then phenotypic FCS. That's a, you know, it's an interesting distinction because, as I said, there's a series of genetic mutations that are called, you know, genetically confirmed FCS, and then some that are unknown. We, at the advice of FDA, have enrolled patients on both sides. I think it was 40 and 35, so 40 genetically confirmed, 35 phenotypic FCS. Phenotypic would, we had defined it in the study as, trigs over 880 with a history of pancreatitis in a certain amount of time. So that study, excuse me, is going to have the final patient final visit in May, and so we should have a dataset called a couple months after that. We likely will top-line that and then present the full dataset later in the year. That enables us to start the NDA process and hopefully get that filed right around the end of 2024, which sets us up potentially, if the data continue to be good, for a launch of our first drug in 2025. And that's an important thing for a growing company like us. We've been at RNAi for many, many years, and we have a lot of really interesting assets. But this is kind of a big step, you know, where we take that next step in growth for the company and become commercial. And so that's really what we're focused on right now. The next step for plozasiran after FCS is the severe hypertriglyceridemia population, or SHTG. So where we are there is that we have our current plan is to have three separate phase III studies for SHTG, and we'll call them SHASTA- 3, SHASTA- 4, and SHASTA- 5. SHASTA-3 and SHASTA-4 are essentially carbon copies of each other, the same study doing the same thing with the same endpoint in a different set of patients. So we have two well-controlled studies, and each of those will be, you know, or together, those will be somewhere in the 700 or so patient range. The primary endpoint that is triglyceride lowering after one year, and we have split out patients that are at high risk of acute pancreatitis into the SHASTA- 5 study. We think that gives us the best opportunity to potentially show a signal in the reduction of risk of pancreatitis, which I think is important for payers. In the U.S., it will be somewhat important, but ex-U.S., it's critical in some geographies to show that end clinical benefit. Because in the end, you know, triglycerides are a bad actor for a number of reasons, but the goal of therapy in this population is to reduce or eliminate, frankly, the risk of having acute pancreatitis. So those studies we have filed, the protocols with FDA, and so our hope is that in the next quarter or so we can get those up and running. We have also done some changes to the monitoring plan and geographies that will be included in that study over the last couple months that we think accelerate the potential or accelerate the path to full enrollment. So our hope is that these changes have shaved potentially up to a year off the enrollment time. So that would be the next step for the plozasiran product, is to expand into SHTG, which I think is an underappreciated disease and certainly an underappreciated market, I think, from an investor standpoint. There's potentially 4 million or so patients who have trigs above 500 and potentially up to 1 million with trigs above 880 and maybe in the 100,000 range with 880 and a history of pancreatitis. And so I think that there's a couple things that have to happen. There has to be disease awareness work that goes on. There has to be a better understanding of what triglycerides do and how they affect patients downstream. And then there's just the blocking and tackling of clinical trial work that we have to do. We have to execute as tightly as we possibly can over the coming years to get those phase IIIs done. And then, as you mentioned earlier, and as we started to talk about, there's the large opportunity of atherosclerotic cardiovascular disease. And that is still an open question for us about which way we go and how we design a study that has the highest probability of showing a benefit for reducing the risk of cardiovascular events. And so where we are with that is that we have, well, we maybe call it, you know, a few months ago, we had almost completed the process of designing a phase III CVOT for plozasiran. And that is when, as I mentioned earlier, we started reassessing the idea of remnant cholesterol being a predictor of cardiovascular events. And so now we've essentially done a modified version of phase III design for zodasiran for the ANGPTL3 program. We've done the modeling. We've looked at the patient population, what the background event rate would be for various patient populations, and then looked at what we think the effect size would be for each molecule in those populations, and then looked at what the statistics would be. We run the statistics to figure out sizing of clinical trials and then how long it would take us to accrue the studies, the cost of them, and then ultimately the end commercial market of all the different scenarios, whether one is successful or the other is not or both are successful or neither. So we're kind of doing that heavy lifting now. I would say we are very much towards the end of that process. We should have some guidance publicly, call it over the next quarter or two, about how we're going to do that. So I think that's an important decision. We are a small but growing company, and so making the decision to make that investment in time and in resources and in capital is a critical thing for us to do. We don't want to go into this lightly. We want to make sure that we have done an exhaustive analysis of every possibility to make sure that when we decide to make that investment, that we are 100% committed to that. So apropos of making those decisions, obviously when you're thinking about cardiometabolic disease, pulmonary disease, when you're thinking about some of the more rare liver diseases, Alpha-1 Antitrypsin-Associated Deficiency, etc., which is a little bit of a pulmonary and liver component, as you think of these very different indications, how do you think about the profile of the Chief Medical Officer for each indication? And to what extent does an individual new leader who's going to be responsible for the cardiometabolic business have to be in place to properly run a global CVOT? Yeah, that's a good question. I agree that when we're talking about these large, expensive, late-stage studies that have a lot of moving parts, we need to make sure that at the leadership level, we have domain expertise there. So that's what we're committed to doing this year, is recruiting the proper senior leader for cardiometabolic, somebody who's run large, late-stage, likely CVOT studies and has been involved with the filing of successful NDAs and understands the ins and outs of that. That's critical. Now, when we were an earlier stage company, I think that it was more important to have generalist leaders at the CMO level because we're in so many different therapeutic areas. We needed that. Now that our late-stage development is so hyper-focused on cardiometabolic, we need that domain expertise. We have a really good team at the medical director level. But again, we brought back Bruce Given, who was our prior head of R&D for nine years or so on an interim basis to help us with this kind of transition. Now, he's continued to be an advisor to the company since he retired in 2020. And so he's intimately aware of our products. He was actually head of R&D when we selected and did all the preclinical work and the early clinical work for plozasiran and zodasiran. So those are part of what he brought to Arrowhead. He also has a history of running R&D as well as running sales and marketing. And so he understands that bridge, which has been very helpful in the short term. But what he's here to do is make sure that the start of the phase III studies is efficient, that when we're ready to get the SHTG and then ultimately the CVOT study started, that we've thought about every design element to make sure that there's no inefficiency or there's never a way to eliminate it, but reduce the inefficiency and the waste that sometimes happens with large clinical studies. And this is the time to make those decisions. Once it's going, it's like an aircraft carrier. It takes a lot. It's very slow to turn. Right now, it's very fast. And so we're making a lot of critical design decisions that we think are going to be helpful long term. But once, Bruce will be here as long as necessary. But our goal is to bring in some domain expertise in cardiometabolic. I think that's important. Now, we've only talked about plozasiran essentially, but our cardiometabolic pipeline includes zodasiran, which we will be starting phase III studies in HoFH and then potentially high-risk HeFH. And then, as you mentioned earlier, we are looking at the possibility of that being an asset for a cardiovascular outcome study. And then just behind those two assets, we have two new programs that hopefully will have CTAs this year for both of them. One is against the target INHBE. It's an obesity target. And then another obesity metabolic disease target that is actually using our adipose delivery platform. We haven't disclosed what the target on that is, but our hope is that we'll have a CTA for that towards the end of this year as well. And so I think our cardiometabolic pipeline is starting to round out, which is important when we're approaching commercial because it doesn't make a lot of sense to build a commercial sales force to support one, but to support two or three or potentially four complementary programs. I think it makes us a lot more confident in the build-out of commercial. And I think it's important. We talked about this very recently, and we'll certainly let everybody know when we have timing on this. But our hope is that we can do something publicly on this cardiometabolic pipeline to kind of round it out and talk about the new programs that we have that we haven't disclosed any data on that look really, frankly, very, very interesting and I think also are enormously underappreciated at the investor level, frankly, because we haven't talked about any of the data yet. Our hope is that over the coming months, we'll be able to provide more information about why we're excited about those two new assets. So looking forward to that. But on what we have disclosed thus far, I think one of the challenges of the cardiometabolic space is obviously there's a huge pool of potential preventable events. The causality and the driver contribution of each biomarker is a little nuanced by patient population. So when you think about APOC3, ANGPTL3, LPA, Lp(a), I guess, that's typically spoken about, when you think about these different targets, how do you parse out each opportunity and where each one falls in the pipeline? Because there's a universe of patients for whom there's meaningful overlap. And overlying this, of course, is the broad targeting LDL, which is the great success story in cardiometabolic disease, but certainly doesn't get the job done. So how do we think about the patient populations for each of these targets? Yeah, it's a very challenging question. We have 13 minutes here, and I'll give you a two-minute answer, which is going to be totally insufficient. But the truth is that even after LDL is well-controlled, there's still an enormous cardiovascular disease risk, a residual risk of cardiovascular disease. So it's been kind of the field's goal to identify what's driving that. And I think that there's so much clinical data out there from all of these large cardiovascular outcome studies that there's a lot of really good work at the academic level and at the physician level, and there's so much published information out there. Now, there haven't been agents that have been able to reduce triglycerides and reduce LDL and reduce remnant cholesterol and increase HDL and kind of change this whole lipid and lipoprotein profile to the way that APOC3 and ANGPTL3 can. So it's impossible to say, to know for certainty, what's going to happen in a large patient population and how you select the patient population for that. But I think that the growing body of research is supportive that changing the lipid profiles from the way they looked before, they have APOC3 inhibitors or ANGPTL3 inhibitors, to add the way they look after. And then fast forward that patient two, three, four, five, 10 years, I think that it is not a non-controversial statement to say that the patient with the lipid profile post APOC3 or ANGPTL3 inhibition is dramatically superior as far as the risk of cardiovascular disease goes than prior to. Now, your question, or the crux of your question is a really good one. How do you identify the patients that are at the highest probability of showing a signal? That's what I talked about earlier. We're doing a lot of that modeling work, which includes, excuse me, all of the data that we have access to from prior clinical studies and all of the published research that's emerging on remnant cholesterol and VLDL to inform that process. But the truth is, you kind of need to take a leap at a certain point. Where we are now is, I mentioned this at the outset, and I can't stress this enough, that we really feel like there is not a bad decision here. It's just which decision is right for us as a company. We are towards the end of that process. We will talk about that a good bit more over the next quarter or two because it's something that's consuming a lot of our effort. As I said before, we're bringing in experts in the field who have done this work and have thought about this and have done research and have published on this for a number of years. So we feel like we have a good handle on the biology. We have the best folks that are advising us on this. Now we just need to make that decision. When we talk about disclosing the new assets that you talked about earlier, giving some clarity on asset selection, etc., for ARO-C3, and also some of the more nuances of included geographies, etc., as well as the potential introduction maybe this year of a new leader for that emerging business unit, is it reasonable for us to assume that would be an event that looks kind of like the R&D analyst day last year? Is this something you do around a conference? What's the right venue to give what's sort of a collective universe of cardiometabolic updates? Well, I think there's certainly going to be a series of updates throughout the year. The new assets on their own are really interesting. And so I think that we can spend a lot of time on those by themselves. We like to do an R&D day sometime in the May, June, July time frame every year. Now, the content of that changes throughout the year or, I mean, year to year. Sometimes it's an overall portfolio review. Sometimes it's about discovery. Sometimes it's about certain assets. But I think that what we want to do for the remainder of the year is do kind of a series of these things. Some will be in person. Some will be webcast. I think that the accessibility of webcast events is much greater than in-person events. And also, bite-size one-hour events are easier to consume than a four- to five-hour R&D day. And so we have all of those considerations. As I said, we don't have a certain date in mind for this or the content. But I think that we want to get this out there because I think it's very underappreciated at this point. Great. We focused on the cardiopulmonary side of the conversation here. But obviously, there's a lot of excitement, somewhat earlier stage, to be fair, about the pulmonary platform. Saw some early data last year. What are we going to get this year from across those assets? And at what point do we start seeing a more tightened indication selection and sort of patient population definition for the various targets in the pulmonary portfolio? Yeah. So you mentioned we have good data so far on that. We were thrilled to see that the platform, the pulmonary delivery platform that uses our TRiM technology, seems to be doing exactly what we hoped it would do, which is get efficient delivery to pulmonary epithelial cells and then get a high level of knockdown that has an RNAi-like curve or shape of the curve. And what I mean by that is that if you look at the liver, not just in our hands, but in others that have done RNAi, the big benefit is the kinetics of inhibition of the target. So if you can get a critical mass of these siRNA molecules into your target cell and then load it into RISC, you start to get you see knockdown. The kinetics of it is it might take a couple to a few weeks to reach maximal knockdown. But when it gets there, it's just clamped. It's a flat curve with liver for a number of months. And we never knew if you could actually see that same profile in extrahepatic cells. I mean, but the biology is the same. Cells don't care. The RNAi mechanism is conserved across different cell types. So we assumed it would be that way, but we just don't know. And so what we saw last year and into this year is that in a healthy volunteer population, after two doses, two inhaled doses separated by four weeks in the ARO-RAGE program, that we could get 90%+ knockdown of the target that persisted for two months or so. And that was really exciting. We are now dosing in our actually, I think we've finished the dosing in three cohorts with mild to moderate asthma. So those data will be talking about over the next couple of months or so. We should have final data on that, I would say, coming in the next month or so. So that's important because then we can see not only does that process or the knockdown translate from different preclinical species into healthy volunteers, but we can also get delivery into an inflamed asthmatic lung and get knockdown that hopefully matches what we saw in healthy volunteers. Then the next step after that for validation, not just for the platform, but the product, is in a more severe population. So patients with high baseline FeNO, high baseline eosinophils, do we see the same kinetics of PD? And are there any signals that we're getting an anti-inflammatory effect? And so your question about patient population selection, we're really just focused now on identifying PD and making sure that the product does what it's designed to do. Our initial thoughts for ARO-RAGE, at least, is that we'll focus on severe asthma. We think that that's a population that we think that we can have a benefit in. And the good thing about ARO-RAGE as a target is it's kind of upstream in that inflammatory cascade. And so theoretically, and based on the biology, we might be able to have a potent anti-inflammatory effect in Type 2 and non-Type 2 patients. And so we think the profile could be potentially similar to tezepelumab in that respect, which has been a very successful product. We think that the convenience of a once-every-two-month nebulized drug is an attractive thing for patients. And also, as I mentioned before, the kinetics of knockdown and that long tail hopefully make the real-world outcomes attractive. So we're excited about that. The other two early-stage programs in pulmonary, ARO-MUC5AC, that's targeting mucoobstructive disease. And so at this point, we think that there's open space in COPD, which is very underserved. And similar to ARO-RAGE, we're focused now just on identifying PD, so selecting a dose and the dose interval before we start to do patient population selection for phase II studies. And then the third program is ARO-MMP7, which targets IPF. And that, I think, is an enormously undertreated and unmet need. And we're going about IPF with a different mechanism in a different way than two approved products. So MMP7 has kind of a pro-fibrotic. The idea is that we can reduce the progression of pulmonary fibrosis and potentially allow some healing there. That's a great overview. Let's dive into the extended pipeline. Obviously, we've talked about cardiometabolic and pulmonary. But obviously, there's been a lot of discussion around targeting muscle, targeting adipose tissue. What are we going to get this year in terms of further data, evidence of delivery, breadth of applicability as people think about the potential target universe that's available to you with those targeting modalities? So for muscle, we'll start with that because we just presented some data at the MDA conference, preclinical data, about a week ago or so for ARO-DM1, our ARO-DM1 program. That shows that we can get high level of knockdown in muscle and skeletal muscle. Then for models of ARO-DM1, we can get not only DMPK knockdown, but we can get correction of the splicopathies that are pathogenic there. That program just started dosing patients. We've dosed the two sentinel patients in the clinical study. Now we're going to enroll all the rest of the patients in that cohort. It depends on how fast we can accrue. It's possible that we potentially have initial data for that clinical study at the end of the year in early to mid-2025. It's hard to give guidance this early in the program because it's a somewhat rare disease. So I couldn't tell you how long it'll take us to accrue all the patients. I think it's 48 patients, up to 48 patients in that study. The second program targeting muscle is ARO-DUX4 for FSHD. That's pretty close to where ARO-DM1 is. We've activated some clinical sites. So we should be dosing the first patients shortly for that study. I would say same timeline for clinical data there. Hopefully, over the next year or so, we'll have initial data. Then you mentioned adipose. We showed last year at our R&D day some very early preclinical data that shows that after an injection, we can get 90%+ knockdown with about six months of duration after a single dose. I mean, it really looks great. That was not a therapeutic gene target. That was just kind of a tool trigger where we could measure knockdown in the blood. We do have a development candidate that we've nominated that, again, we should hopefully have a CTA call it right around the end of this year. We'll show more data on that particular target and all the work that led up to that nomination this year. Great. And we are exactly two seconds over. Obviously, a lot going on this year, a lot of breadth across the pipeline throughout this year. We're looking forward to seeing those updates. It's going to be an eventful time for Arrowhead. Yep. Yeah, it's exciting. Thank you, Mani. I appreciate you having us. Thanks to the whole Leerink team. Thank you. Pleasure as always.