Good afternoon, and welcome to the Arrowhead Summer Series of R&D Webinars, Part four. As a reminder, all participants are in a listen-only mode. This event is being recorded, and a replay and a PDF version of the slides will be available on the Arrowhead website following the conclusion of the call. I would now like to turn the call over to your host, Vincent Anzalone, Vice President and Head of Investor Relations. Please go ahead. Thanks so much, Sarah, and thanks, everybody, for joining us today. Before we start, I just wanna make sure that you know that we will be making forward-looking statements, so refer to the risk factors in our SEC filings. And so this is Part four of our summer series of R&D webinars. We started with muscle in May. We had cardiometabolic in June. We did the pulmonary programs in July. Today, we're doing obesity and metabolic. And then next month will be the final installment of the summer series, where we'll cover our growing CNS portfolio. So the goal, and I've said this on each one, so I'll go quickly. But the goals of this summer series is to provide more focused time, so we can cover parts of our pipeline that we just don't get to talk about in depth. We also wanna talk about advances that we're making to the TRiM platform broadly, and that's definitely applicable today, where we'll go over the TRiM platform's ability to get directly to adipose tissue. You can hear directly from the team members that work on these programs day to day, and then finally, get some external perspective from a physician scientist that's an expert in the field. So today, we'll quickly... I'll finish quickly, and then I'll turn it over to Dr. Carel le Roux, who'll go over the obesity space generally, and what's remaining, where there's still unmet need. Eric Bush will cover our Inhibin E program, which we have disclosed previously. Tao Pei will then talk about the TRiM platform and how we're getting directly to adipose tissue. Eric will come back and talk about the newly announced program that we press released earlier today, called ARO-ALK7, which uses that adipose delivery system. James Hamilton will talk about the upcoming clinical trials for both of those drugs, and then I'll give you some key takeaways. Then we'll have some time for Q&A at the end. So I just wanted to introduce Dr. le Roux before we move on. We are very lucky to have him. He's an expert in the field of metabolic medicine and obesity. He's the Chair of Metabolic Medicine at the University College Dublin School of Medicine. And again, we are very fortunate to have him today. So please feel free to ask as many questions of him as you'd like. Well, thank you very much. Thank you. Arrowhead, most if you're investors, you have seen this quite a few times, but Arrowhead is an RNAi therapeutics platform company. We've got a broad pipeline of 14 clinical stage assets that are across therapeutic area. We have a good mix of early, mid, and late-stage programs, and actually one that's approaching commercialization. We hope to launch next year our first commercial product. Our pipeline spans the ultra-rare disease, all the way up to the most highly prevalent cardiovascular disease, including the obesity programs we'll talk about today. All of our programs are built on our proprietary targeted RNAi molecule technology platform. It's designed to induce deep and durable gene silencing using the RNAi mechanism. We feel like Arrowhead is the clear leader in the field of fulfilling the promise of bringing RNAi to where diseases live, not just in the liver, but to several different tissue types throughout the body. And again, today, we'll talk about an additional expansion of that TRiM platform into adipose tissue. And then lastly, we have. We think we have the financial resources to really exploit all of these assets. So here's our platform. Again, it's large and broad, and it covers many different therapeutic areas. You won't see ARO-INHBE or ARO-ALK7 on this pipeline chart, just because we only cover clinical stage assets in our pipeline chart. They will be added shortly. We did mention this in the press release, but our goal is to have regulatory interactions and filings before the end of the year, and start clinical studies for both new programs shortly after that. So now I will turn the call over to Dr. le Roux. Well, thank you very much, and it's a pleasure being here with you. I sort of start with this very famous painting that hangs in the National Gallery in London, and at the time, you may remember that the really smart people, probably similar to the people on this call, at least they understood that the Earth was round. But Copernicus just came with this new science and actually said, "Turns out that your lived experience, the things that you saw every day happening," which was that the sun came up in the east, and it went around and set in the west, and therefore, people assumed that the Earth must be the center of the universe because they saw the sun going around them. And he actually came with the science and showed actually they were 180 degrees wrong because it turned out that the Earth was rotating around the sun. And of course, by knowing the new scientific details, we could interpret our natural world so much better. And I think we had one of these Copernicus moments at the moment because most of us on the call will think that overeating causes the disease of obesity, but what we are now seeing is probably the opposite is true. The disease of obesity causes people to overeat, and it's this new science that brings new opportunities that we would like to explore... Now, I work with lots of different companies, including Arrowhead. And what we have understood is that what you would see on the right-hand side, that's Sisyphus, a Greek character that was thrown in the depths of Hades, and what he had to do is roll this rock up this hill every day. And every day he got to the top, the rock would roll down. And that is what I and many of my specialist colleagues used to do, is we asked people to eat less and move more. And now we understand that was like asking, you know, Sisyphus to roll up this rock because it would just roll down. And what we wanna do now is we want to remove the rock. We want to treat the disease of obesity so that we can actually have better outcomes. But what we've understood is that we need more and different treatments. We, we need more nutritional therapies, more pharmacotherapies, and more surgical therapies, because that is the only way we're going to address this disease. Now, if you look at how successful we have been back to the 1960s, the top line there indicates bariatric surgery. And you could see if you had a gastric bypass in the 1960s, you would lose exactly the same amount of weight that you would lose today. It was much safer to do the operations now than it was back then, so safety has improved dramatically, but efficacy did not improve. And the same with the green line over there, indicated as intensive lifestyle therapy. You could see that if you had an intensive lifestyle approach back in the 1960s, you would lose exactly the same amount of weight that if you have a lifestyle approach with all the apps that you can dream about in 2023 and 2024, you get about 5% weight loss. But what has changed in the last three and four years dramatically is pharmacotherapy, and the fact that it can be scaled, is tremendously valuable. And now we have effective treatments, but what I am seeing in clinic is that the majority of my patients do very well, but there's a large minority that are not responding to the really impressive treatments that we have today. So why is that? You know, in the past, we were arguing that obesity is a disease, but now we actually are taking it one step further and suggesting to you that it's very unlikely that obesity is just one disease. It's much more likely that it's multiple diseases. So if you just think about, you know, on the X-axis there, you have increasing in BMI, and the Y-axis, you have increase in cardiovascular risk. But what you will see are there are outliers. There are people who are discordant, people with much lower levels of obesity, but that have a very high cardiovascular risk, and some patients with very large BMIs, but actually very low cardiovascular risk. So what we are now understanding is that it's probably more than one disease. And we've been able to lead a project in Europe called the IMI SOPHIA project, that we're trying to map patients on a so-called UMAP system, where we were able to dissect and find these different subtypes. We call them people who are discordant for hypertension, for transaminases in the liver, for lipid profiles, for glycemia, but also for inflammation. And by understanding these, both in males and females, what we were able to do is look at the risk, and you can see that your risks are dramatically different. For example, if you are in a patient group that are discordant for inflammation, and therefore, understanding, the different diseases allows us to understand that we need more treatments. Now, here I'm showing you the STEP 1 extension study. This is with semaglutide. And first of all, you can see the average weight loss is dramatic, you know, 16% with semaglutide. But you would also see exactly what happens when people discontinue the treatment, and that happens at 68 weeks, where people then become ravenously hungry and regain their weight. And that's a major problem that we have at the moment, is to actually increase the stay time of these medications. They are very good, but like all medications, they only work if people take them. And the side effects of the medications is one of the reasons why our stay time is not as good. So we need to improve that. We need to improve the side effect profiles. There's lots of work in that space. But it also means that if we can get different mechanisms, and different treatments with lower side effect profiles, that can also improve our stay time, because it's only when we do that, that we can have dramatic long-term health benefits. And here what you're seeing is the GLP-1 classes and their therapy, persistence or so-called stay time. And you can see dramatically how it changes, you know, within, you know, at 180 days, you know, already down to about 50%. And this is something that we need to work on. So stay time is important, and part of that is driven by side effect profiles that we need to continuously, improve. Because what happens if you can continue the medication, and here's again, I'm showing you the STEP 5 study with semaglutide as an example. So if you can continue the treatments, what you can see is you can maintain the benefit. But look now over to the right-hand side. What you can see in those bar graphs is that more than a third of patients will achieve more than 20% weight loss, and we call them the super responders. But now look on the left-hand side of that, and what you will see, even people treated with semaglutide, it's about 25% of patients that lose less than 5% of their weight. Okay? So we have responders and non-responders. And very important to say, it is not the smart people who listen to me that lose a lot of weight, or the people that don't listen, that don't lose weight. It is biology.... So what we now need to do is, a lot of patients are coming to us, starting the medication, doing very well, but other people looking exactly like them with the same levels of motivation are coming, starting these really good treatments and not losing any weight. Again, more evidence and reason why we need different treatments in the system to help those patients. And, of course, the adverse events that we are seeing here, and I'm showing you tirzepatide, a drug that's a very well-tolerated, really great drug. But you can see, we still see a substantial number of patients, you know, who have adverse events that's leading to discontinuation in the clinical trials. Now, just remember, you know, I run a lot of these trials, and we bend over backwards to keep people in clinical trials. We are far more successful in clinical trials than in clinical practice because we have more resources at our disposal. But you can see, despite our best efforts, people discontinue the treatment because of side effects. So this is a well-tolerated drug. It's a good drug, but you can see despite that, there are patients that can't tolerate the medication in the long term. Now, one of the issues that we are really grappling with at the minute is that when we get people to lose a substantial amount of weight, we see that most of it is adipocytes, so fat mass, but we also see some lean muscle mass loss. Here I'm showing you both for semaglutide as well as for tirzepatide. So what we are trying to understand is how can we get maximum adipocyte loss and fat mass loss, but actually maintain the muscle mass? Because if we can do that, we can further improve functionality, and that is what drives patients' quality of life, and that is also what provides value to patients. That's the value proposition for people having these medications in the long term. It turns out weight loss isn't enough of a value proposition to continue the medication. You actually have to have health gains, and certainly functional gains is part of that discussion. So how about targeting a completely different mechanisms? Because, you know, for example, semaglutide, tirzepatide, you know, a lot of the gut hormone classes of medication are targeting the subcortical areas of the brain, very effective place to target. You can see there are some people that have a disease that is not situated in that area. Can we target adipocytes, because that is also central to metabolic disease, and we're going to hear more about that on the call today. Let me summarize and suggest to you that, you know, 500 years ago, this is a typical painting from Botticelli, depicting Dante's Inferno. You'll remember, Dante depicted the seven mortal sins, and two of these sins, one was sloth and another one was gluttony. Therefore, European thinking was driven by this idea that, you know, to be sinful is a willful act, and therefore, we thought that obesity was a choice. That's why we even had, you know, terms like behavior therapy, teaching people how to behave. Now we just understand it as a biological disease that we can approach from a biological angle, and when we give biological treatments, we get biological results. It's completely transformed the way you and I think about obesity, because now all we do is we treat it like a chronic disease that it is, and that's why we're so much more effective at doing that. Allow me to conclude and suggest to you that the future of obesity care will include chronic treatments that's aimed at health gain, not weight loss. Recognizing the biological basis of the disease will allow us to treat it that much better. But we need more and different treatments to address the subtypes of this disease if we're going to be successful. I'm handing back to Eric, and I'm happy to take some questions later. Thank you, Dr. le Roux. Very nice setup for us here. So I'm happy to give a brief update today on ARO-INHBE. This is our first clinical program in obesity. And we'll be talking in some broad themes this morning about a couple different aspects of emerging themes in obesity. And I just wanna pause and highlight, you know, the power of human genetics to uncover novel therapeutic targets and pathways that have not previously been appreciated and may very well be best fitted and suited for novel and emerging therapeutic modalities like RNA interference. So the key pathway that we'll be talking about here first is a new pathway that's been described in recent years that connects the liver to adipose depots to regulate energy homeostasis. So the gene, inhibin subunit beta E or Inhibin E, is expressed primarily in liver tissue, in hepatocytes, a cell type that we can deliver siRNA to very effectively. So in settings of excess caloric intake and increased triglycerides, this gene responds, and creates a protein, a product from that gene, which is Activin E. It's a dimer, and it is secreted by the liver and moves into circulation. It's referred to as Activin E. It's a potent hepatokine. And the cognate receptor for Activin E is ALK7. And ALK7, as we'll hear about later, is a TGF-beta superfamily member that's primarily expressed in adipocytes.... and signaling through the ALK7 receptor in response to Activin E ligand has a number of broad effects, but most prominently, suppression of lipolysis in adipose tissue, which can drive adipose hypertrophy and increasing visceral adiposity and insulin resistance. So as I mentioned, this is a genetically validated target, and this has emerged from a number of human GWAS studies in recent years, demonstrating that rare heterozygous putative loss-of-function variants at this locus, Inhibin E, are clearly associated with reduced abdominal fat. Here, we're looking at waist-to-hip ratio in the main figure, and then looking off to the right, also, these loss-of-function variants of Inhibin E are associated with lower risk of metabolic disease, such as coronary heart disease and type two diabetes. So strongly validating this hepatocyte target in these indications. So moving back to sort of preclinical models and how we've thought about this and studied it, context here for background, the INHBE knockout mice have been studied on high-fat diet, as you might expect, fairly rigorously. And these animals exhibit reduced body weight gain and increased lipolysis when placed on a high-fat diet. So if you look in this graph, animals over 16 weeks here in black on the high-fat diet, wild-type controls, they gain substantial weight. And the dark blue line right underneath that, these are the INHBE knockout mice that gain weight at a slower rate relative to their wild-type controls. So moving on from there, the concept here for ARO-INHBE is relatively straightforward. We can make GalNAc conjugated siRNAs optimized to silence Inhibin E mRNA in hepatocytes and deliver very effectively. And consequent to delivery, we silence circulating Activin E hepatokine, and downstream of that, silence activation of the ALK7 receptor on adipocytes, thus restoring lipolysis and consequently reducing adipocyte hypertrophy and adiposity. So back to preclinical work with hepatic INHBE silencing. Our typical MO in this respect is to make a tool trigger to the rodent Inhibin E gene, administer this to animals of a model of diet-induced obesity, and try to phenocopy what's known in the knockout mice. So that's what's done here. So this is an Inhibin E siRNA tool trigger as a GalNAc tool conjugate for liver delivery. A word about this animal model of diet-induced obesity, this mouse model of diet-induced obesity. This is an intervention model where animals have been placed on a high-fat diet for 10-14 weeks, so they already have enhanced increased body mass before they, we incept siRNA treatment. So what you're looking at here is the next 16 weeks of treatment on therapy. So what we found here is that mice on this high-fat diet treated with the Inhibin E siRNA, we got very deep suppression of Inhibin E mRNA in the liver, as you see on the right, greater than 90% knockdown. If you look at the body weight change graphs on the left, we see that animals receiving the Inhibin E siRNA regimen had nearly a 20% suppression in body weight gain relative to the vehicle controls. So, moving onto a body composition analysis by DEXA scan, some of you may be familiar with this assessment. Looking to the right, we see representative images of these obese mice on saline control or Inhibin E siRNA regimen. In red, we are imaging adipose tissue, and in blue, you are imaging lean muscle mass. And it... hopefully, it's apparent from these images that animals receiving Inhibin E liver silencing regimen had substantial reductions in adipose tissue gain. That's seen by quantitative analysis on the left, approximately a 22% reduction in fat mass accumulation with Inhibin E siRNA. And I wanna highlight that and it should hopefully be obvious in the images as well, that this was not accompanied by a change in lean muscle mass. And we'll touch on this later, but it should be clear that in terms of quality of weight loss, it's important where that weight loss comes from. And certainly, incretin mimetics as standard of care, that weight loss is coming both from fat and lean muscle mass, which isn't terribly desirable. And in this case, certainly phenocopying what's been shown in knockouts, that the lean muscle mass is not affected. In fact, it is slightly increased. Moving on to an assessment of glycemic control. We carried out glucose tolerance tests in animals, in the obese animals receiving Inhibin E siRNA, and we saw a trend, a modest reduction in glucose area under the curve, suggesting a modest improvement in glycemic control. These animals receiving Inhibin E siRNA to silence liver Inhibin E, on the high-fat diet, were also treated with catecholamine to stimulate lipolysis, in this case, a beta-3 adrenergic agonist. And if you look at the two right-hand panels, the catecholamine infusion increases expression of a wide variety of lipolytic genes in various fat depots. What we see across the board in all these lipolytic genes is that Activin E silencing in the liver resulted in an enhanced lipolytic gene upregulation in inguinal and perigonadal fat depots, suggestive of increased lipid mobilization. Downstream of that, looking for evidence of increased oxidation of the free fatty acids, we see increases in ketones, in this case, beta-hydroxybutyrate. So questions about, you know, increased lipid mobilization, we wanted to look and make sure or evaluate whether that increased lipid mobilization had any impact on liver fat. In fact, we did see in H&E stains on the right, there was less liver fat accumulation in animals receiving Activin E silencing relative to saline controls. So no evidence of steatosis. Trends to reductions in liver triglycerides and liver fat composition by DEXA scans. And then, finally, one last slide introducing our ARO-INHBE candidate. These were lean, cyno monkeys that received 2 dose levels of ARO-INHBE by subcutaneous injection on the first day of study and 4 weeks later. And what we're following here is serial blood draw to assess target engagement, in this case, Activin E silencing at the protein level in serum. And what we can see at the highest dose level here, at 4.5 milligrams per kilogram, a nearly 80% reduction in circulating serum Activin E, and that persists for a few months post-cessation of dosing, with a trend to recovery 2 months post-dose. With that, I'm going to turn it over to Tao Pei, my colleague, who will tell us a little bit about the adipose platform. Thank you, Eric. So next, we'll switch gears to talk about our new TRiM platform for delivery of RNA therapies to adipose tissue. The reason why we're interested in adipose tissue, there are two main reasons. As mentioned earlier, one key reason is that adipose is therapeutically relevant to metabolic disease. Another reason why we're interested in adipose is that we believe it is a super tissue for RNA therapy that will allow deep and long-lasting gene silencing effect, similar to what we have observed in liver. We have seen huge success of RNA therapy in liver so far, and there are some interesting similarities between liver and adipose. Hepatocyte is a major cell type in liver, while adipocyte is a major cell type in adipose. Hepatocyte has 6 months to a year lifespan. Adipocyte has a lifespan of several years. Therefore, if we can deliver siRNA to adipocyte, we can expect deep and long-lasting RNA silencing effect there. At Arrowhead, we have developed a TRiM platform to bring potential RNA therapies to adipocyte in adipose tissue. On the top right corner is our TRiM adipose platform. It's a dual lipid siRNA conjugate, with one lipid ligand covalently linked to the five-prime end of sense strand, and the second lipid attached to the three-prime end of sense strand. Given the nature of adipose as lipid storage, we want to take advantage of the lipid uptake pathway to deliver a lipid siRNA conjugate to adipocyte. Here, on the left, we use adipocyte-specific gene, adiponectin or Adipoq here, to demonstrate gene knockdown in different adipose tissue in mouse using our TRiM conjugate. With as little as 0.75 single subcutaneous dose, we can achieve 80% knockdown of adiponectin messenger RNA in mouse after 3 weeks post-dosing. A single 3 MPK subQ dose, we can improve the knockdown to 95% over adiponectin messenger RNA in mouse iWAT and pWAT. iWAT is inguinal white adipose tissue, part of subcutaneous fat here, and pWAT is perigonadal white adipose tissue, part of visceral fat. Since adiponectin protein is also secreted into blood circulation, we can monitor protein reduction in serum. Here, we are able to achieve over 90% serum protein knockdown at all three dose levels, 0.75 MPK, 1.5 MPK, and 3 MPK, after a single subcutaneous administration of our TRiM adipose conjugate. Furthermore, we also find good correlation between mRNA knockdown in adipose tissue on the left, and a protein knockdown in serum on the right. A closer look at the microscope and the RNAscope confirms the siRNA delivery and depletion of the target gene in adipocyte. At the top, we can see the red-colored siRNA is delivered to the adipocyte. At the bottom, we can see the brown-colored adiponectin messenger RNA in adipocyte is pretty much all wiped out two weeks after a single subQ dose of 3 MPK of our TRiM adipose conjugate. We also test our TRiM adipose platform in duration studies in mouse. At a single 2 MPK dose, the blue-colored subQ dose maintains 90% knockdown of serum protein for six weeks, and a minimum 75% knockdown for 10 weeks. The green-colored IV dose increase the duration to 10 weeks for 90% knockdown and 16 weeks or 4 months for minimum 75% knockdown of serum adiponectin protein in mouse. Next, let's review the selectivity of our TRiM adipose platform. The platform has systemic distribution with greatest accumulation in liver, lung, and spleen among peripheral tissues. However, despite peripheral tissue accumulation, we only observe significant RNA silencing effect in adipose tissue. Here, we use SOD1 target siRNA to assess the functional tissue selectivity of our TRiM adipose platform. As a tool gene, SOD1 is ubiquitously expressed in multiple tissues and cell types. At therapeutically relevant dose, we only observe moderate to little knockdown in peripheral tissues, including liver, lung, and spleen. At the same time, we still maintain high 70s-85% knockdown in iWAT and pWAT in mouse. Overall, the data indicate that our TRiM adipose platform has a very good functional tissue selectivity. Moving on to higher species, non-human primate, we continue to observe deep and durable knockdown of serum adiponectin protein. At a single 1.5 MPK subcutaneous dose, about 70%-90% knockdown is achieved at 1 month post-dosing, and a minimum 75% knockdown is maintained for 3 months using our TRiM adipose conjugate. Increasing the dose to 5 MPK single subcutaneous dose, we can improve the max knockdown to 98% and extend the duration to 9 months, with minimum 75% knockdown of serum adiponectin. Finally, a yearly dosing regimen is feasible when we switch to IV dosing and increase the dose level to 10 MPK. Here, we are able to achieve 99% max knockdown and maintain 75% knockdown or higher over 16 months after a single 10 MPK IV dose. That's way over a year of duration. Last, but also very important, our TRiM adipose platform also demonstrates very good safety profile in rat. In the non-GLP exploratory tox study, the rats are dosed up to 120 MPK at day 1 and day 15, and follow with necropsy at day 16 and day 29. No mortality is observed during the study, and no noteworthy clinical observation or body weight changes compared to vehicle group. There are minimal findings in clin chem, hematology, and coagulation. In histopathology, no test article-related adverse effect is found. In summary, our TRiM adipose platform has demonstrated great efficacy and durable knockdown of the target gene and protein in mouse and in non-human primate. The platform also shows good functional tissue selectivity in mouse and a good safety profile in rat. So next, my colleague, Eric, will present our first adipose program toward obesity indications. Thank you, Tao. So obviously, I'm very excited to present some preclinical pharmacology data on ARO-ALK7, our first clinical program to utilize this new and exciting adipocyte delivery platform. So, this figure should be familiar. I just showed you this pathway. Again, this crucial liver to adipose tissue communication axis that has recently been defined. And again, going back to the power of human genetics to really look for what human loss of function data are teaching us about novel targets and pathways, in recent years, there have also been genetic GWAS studies demonstrating that heterozygous loss of function alleles of ALK7 are also this receptor are also associated with lower risks of obesity and type 2 diabetes. I guess that shouldn't necessarily come as a surprise. Let's go back to this cartoon and talk a little bit about not this one ligand, but the ALK7 receptor itself. ALK7 is a TGF-beta superfamily receptor that is preferentially expressed in adipocytes. In order to successfully drug this, you need to be able to hit it where it lives, which again, is in adipose tissue. Activin E, of course, as I told you, is an important ligand for this receptor. But critically, there are other ligands that interact with the ALK7 receptor on adipose tissue, including other ligands that have been linked to metabolic disease and obesity, such as GDF3, GDF11, other activins, and so forth. As I mentioned again, just to remind you, ALK7 signaling broadly suppresses lipolysis and shifting the balance to lipid deposition and an increase in adipocyte size. So conceptually, the approach to developing a drug here targeting ALK7 is straightforward. We utilize the new adipocyte targeting platform that Tao just described, and created a highly specific and potent siRNA to deliver to adipocytes and silence ALK7 mRNA and ALK7 receptor expression on those adipocytes. And that silencing should restore lipolysis and reduce adipocyte hypertrophy and visceral adiposity. So going back to sort of preclinical context here, of course, the ALK7 knockout mice have been studied, and in fact, the adipocyte-specific ALK7 knockout mice have been studied in diet-induced obesity models. In looking in the left-hand panel, you can see in that middle line that adipocyte-specific knockout mice, placed on a high-fat diet, do indeed gain weight at a reduced rate relative to wild-type controls. Same effect on body composition is observed here, just like with Activin E. This is weight loss that occurs primarily in fat mass. No evidence of lean muscle mass being impacted with adipocyte-specific knockout on high-fat diet. Notably, in this particular study, they looked at oral glucose tolerance and saw no impact on insulin sensitivity when ALK7 was knocked out in adipose tissue. Back to our sort of standard operating procedure here, trying to phenocopy the knockout mice with a tool trigger against ALK7, directed to adipose tissue. Again, these were—it was a high-fat diet model, diet-induced obesity. Mice were placed on a high-fat diet for approximately 10 weeks or more, to increase body mass, and then incept a regimen of ALK7 siRNA treatment to knock down ALK7 in adipose depots. And that's shown in the upper right-hand panel, with 80% reduction in ALK7 mRNA in the inguinal adipose, about 40% reduction in perigonadal adipose depots. But back to the left-hand panel here, looking at body weight change, over the 16 weeks on drug, saline control animals continued to gain weight, and animals on the ALK7 silencing regimen had approximately a nearly 40% suppression in body weight gain relative to controls. Now, importantly, we know this results from RNA interference at the ALK7 mRNA, because we are able to do a very simple chemical change to that ALK7 tool trigger, a minor chemical modification to prevent that siRNA from incorporation into the RISC silencing complex. That control, shown in red, is unable to silence ALK7 mRNA, but in any other way, it's the same as that tool trigger, and as you see, that had no impact on changing body weight gain in this model. So looking at body composition, again, representative images by DEXA on the right, the obese mice with saline treatment, high accumulation of red fat mass. Looking at the blue lean muscle mass, it should be clear, there were reductions in fat mass on the left. Quantified, that was a 50% reduction over the course of this study, and I want to highlight again, lean mass, muscle mass, was completely spared, while the complete loss of weight gain appeared to come from the fat mass itself. Mice on the ALK7 siRNA, on the high-fat diet, were also stimulated with catecholamines to look at lipid mobilization impacts. As with Inhibin E, we saw enhanced upregulation of a panel of lipolytic genes in both adipose depots, shown on the right, suggestive of increased lipid mobilization. And then again, looking downstream to evidence of fatty acid oxidation, we do see a doubling of ketones, beta-hydroxybutyrate levels substantially increased. So again, with this evidence of increased lipid mobilization, we wanted to rule out or look at the potential liver steatosis, and we saw the same thing. Looking at H&E on the right, high-fat diet animals treated with the ALK7 siRNA, in fact, had less liver fat accumulation than control animals, and this was correlated with a significant 67% decrease in liver triglycerides. And then finally, one graph I want to spend a little bit of time on is, of course, Arrowhead is very interested in studying this new platform and target in the context of existing standard of care, namely, incretin mimetic therapeutics, both alone and in combination. So let me sort of walk you back and forth, and apologies, I don't have a laser pointer, so I'm gonna direct you back and forth between these two panels. But if we look on the left, again, we have our standard diet-induced obesity mouse model, where in this case, the mice were on a high-fat diet for 14 weeks prior to inception of therapy. You can see the saline control animals continued to gain weight, adding an additional 20% body weight, whereas animals with ALK7 regimen on board to silence adipose ALK7, we saw a reduced body weight gain in the green line. And looking to the right, as I showed you before, in that second bar, that was all coming from the fat mass, so no change in lean muscle mass. So moving back to the body weight change graph on the left, we looked at tirzepatide, one of the cornerstone standard of care drugs, administered here at a full pharmacologic dose of 0.2 mgs per kg daily. If you look at the blue line, you can see a steep and significant reduction in body weight over the first couple of weeks on drug, and we know this is due to reduced food consumption, and that's generally maintained over the course of the following 16 weeks. So that's not a surprise. But looking to the right, at the middle blue bar in the upper panel, yes, of course, that's we see reductions in fat mass, but I'd again direct your eye to the bar below on lean mass. There's also a substantial reduction in lean muscle mass. So this body weight change is coming from both of those. So that this really reads on quality of that weight loss. So moving back to the left-hand panel, again, I'll focus your attention on the red line, where we looked at a subtherapeutic dose level of tirzepatide. So this was a third of the dose daily, so at 0.07 mg per kg daily. Hopefully, you can appreciate that those animals did indeed lose weight fairly rapidly over the first few weeks on drug, sort of an intermediate level of change in body weight, but that was not preserved at that drug level. In fact, from five weeks on, they begin to gain weight back and trend back towards baseline. So, if you look to the right, again, on body composition analysis, yes, there was in that red bar, the fourth bar from the left, fat mass was indeed reduced, not to the same level as the higher dose, but look and see that the lean muscle mass was also similarly, similarly impacted to the lean muscle mass, so a significant effect on muscle. Back again to the left, we combined this subtherapeutic dose of tirzepatide with our ALK-7 regimen, and hopefully, you can appreciate there that when combining those two regimens together, we recaptured a full pharmacologic signal on body weight change, as a full dose of tirzepatide. And then back to body composition, in the fourth graph or the fourth column, fat mass reduction was the same as a full dose of tirzepatide, but notably with a significantly reduced impact on lean muscle mass. And then one last slide here on our ARO-ALK7 clinical candidate. These are studies done in lean non-human primates. In the left-hand panel, these animals received a single 3 mg per kg subcutaneous injection of ARO-ALK7. And then we carried out serial adipose tissue biopsies over the following months. And hopefully, what you can appreciate there is that we saw rapid reduction in adipose ALK7 mRNA, deep silencing that persisted out to at least 4 months post-dose, with potentially some recovery beyond that. We have additional studies ongoing in non-human primates. One example is the study on the right, which is ongoing. I only have 8-week data to share with you. It's a dose-response study. You know, again, hopefully, you can appreciate that much lower dose levels, as low as 0.75 mg/kg, are also mediating quite substantial reductions in ALK7 mRNA and adipose tissue in these lean primates. So with that, I'll turn it over to James, who will talk us through some of the clinical trial designs for both of these programs. Great. Thanks, Eric. So first, we'll start with the ARO-INHBE phase I/IIa study. This will be a clinical trial in healthy volunteers with obesity, at least initially, so BMI greater than 30. We will start with single escalating doses and then include several cohorts on the right, the 2-B, 3-B, and 4-B cohorts, where we will investigate two doses given on days 1 and 29 of ARO-INHBE... We plan to run a similar study with ARO-ALK7, again, starting in healthy volunteers with obesity. The only difference in this design is that these volunteers will undergo baseline adipose biopsies, and then we'll measure post-dose biopsies in both the single and the multiple ascending dose cohorts on days 29 and end of study for the single ascending dose, and days 57 and 169 for the multiple ascending dose. This will allow us to measure a gene target knockdown in the tissue of interest. With both of these molecules, we then plan to study as part of the in the same two studies, the effects of ARO-INHBE in individuals with obesity in combination with tirzepatide. So we will look at two different doses of tirzepatide in combination with ARO-INHBE to see the effects of the combination at the two separate dose levels on the various biomarkers as well as body weight. And then at the bottom, the 5C cohort, we'll look at the effects of the combination of tirzepatide with ARO-INHBE in patients with obesity as well as type two diabetes. Similarly, for ARO-ALK7, we will duplicate these three cohorts in obese patients at 2 different dose levels, and then also a cohort of obese patients with type 2 diabetes. Again, the only difference here versus the ARO-INHBE study being that these patients will all undergo pre-dose and post-dose adipose biopsies. And then finally, the primary and secondary endpoints will be pretty standard for phase 1 study, then the pharmacologic endpoints will be slightly different between the ARO-INHBE study and the ARO-ALK7 study. In the ARO-INHBE study, we will evaluate serum Activin E levels as a biomarker of gene target silencing in the liver. And then in the ALK7 program, again, we will measure adipose knockdown of the gene target using biopsies. Then otherwise, the pharmacologic endpoints will be similar. We'll look at changes in weight, changes in waist circumference, changes in body composition based on MRI, and on that same MRI, we will be able to evaluate changes in liver fat. And then we have a fairly extensive panel of metabolic parameters, lipid parameters, and glycemic control parameters that we'll measure in the patients and the healthy volunteers with obesity in both studies. And so with that, I'll hand things back to Vince. Thanks so much, James, and thanks to the entire panel. There's a lot of really good information today. Okay, so what have we learned? And what's important to Arrowhead? So it is clear, and Dr. le Roux talked about this, and I think it's clear from our experience with the successful agents that obesity is not one disease, it's multiple diseases. And in addition, it increases the risk of serious downstream metabolic diseases like diabetes and heart disease, stroke, and more. And we think, and at least the data so far and other agents has proven this out, that reducing fat mass may ultimately improve patient outcomes in the long run, and potentially dramatically. That's the goal. Second, the... It has become clear, and this has not been historically true, that this is not a market, a pharmacotherapy market, driven by aesthetics or weight loss. That's the weight loss is basically a marker for what we expect long-term health outcomes to benefit. And that, again, that's the long-term goal of obesity and metabolic disease therapies, to improve long-term health outcomes. And one important part is that payers in the health system agree with this. And that's been a big question in this space for a long time, is if you have effective therapies that are safe, that are well-tolerated, and that can have dramatic levels of weight loss, will they be reimbursed? And will payers here, commercial payers here in the US, and then also, around the world, will they reimburse this product and pay for it? And I think that it's become clear that that is true. Next, we believe, and again, Dr. le Roux is an expert in this, and so we defer to his opinion on this. But new therapies have, over the last handful of years, made an enormous impact in this space. And where the opportunities still lie is in novel new mechanisms, second, in therapies that can better maintain lean mass and importantly, improve body composition, and third, therapies that can address the gastrointestinal AEs that we see in clinical studies. And then, even more starkly, once these therapies are used long-term, how many patients are really staying on the GLP-1s long term? So we believe that the genetics and the biology of these pathways support the idea that Inhibin E, the gene, and the Activin E ligand, and the ALK7 receptor pathway are active here, and it's something that we should explore inhibiting that pathway. And I think that, you know, an important thing to think about here, the basic idea is that we're doing two ARO-INHBE is turning off the gene that sends the message to the body to store more fat. And then, ARO- ALK7 is turning off the way that fat tissue receives that message. So we're kind of trying to do the same thing in two different ways. I think there's a lot of good precedent with pharmacotherapy, with this basic strategy. If you look to monoclonal antibodies, you think about when you're designing an antibody, do you want to address the ligand or the receptor? And with the ligand, you have an antibody that's a trap. You trap the ligand, or you have an antibody that's a blockade on the receptor. That's the same idea with this, is what's going to be the more effective way to get to this signaling? And I think that we have a way to address both, and we'll learn which is the more effective way shortly. And again, as we've seen, the preclinical data have been really very promising for both of these programs. And I hope that it shows that we tried to do the same studies head-to-head just to see if there was one clear advantage here. And I think that both of them are both very compelling, and the upcoming clinical studies will show, you know, where both of these fit. And I think that, you know, but Arrowhead as a company, we think that we are first - we will be first in class in the clinic for both of these. And as with all of our programs, our goal is to be best in class as well. And this is near term. You know, these are... You're just hearing about these data now, but these are not early programs. We're in the final stages of preclinical development, and our plan is to file CTAs before the end of the year and to start clinical studies for both of these shortly thereafter. And James had indicated, these first-in-man studies, they're not simple safety studies. We're going to learn a lot in these first-in-human studies. We're looking at single doses, we're looking at multiple doses in an obese population, and we're also looking at combination therapy with tirzepatide. So there, there's a lot of data that's going to come out of both of these programs over the next 12 months or so. So with that, again, I want to thank all the panelists, and we are going to open up the call to some questions. So give me a moment as I compile some of those questions. Okay, as if anybody has seen our prior R&D webinars, we're going to get way, way more questions than we'll be able to get to, but I'll try to take as many as possible. So the first question comes from Patrick Trucchio at H.C. Wainwright. The question is: We understand that part of weight loss achieved with GLP-1 agonist is coming from loss of lean mass, but do we understand which type of adipose tissue is driving the fat loss? And I guess I'll ask our team first, and then turn it to Dr. le Roux as well. Yeah, I guess, I can jump in here. Thanks, Vince. So, obviously, I'll make sure Dr. le Roux has a chance to weigh in as well. But, you know, our understanding of GLP-1s from the studies that have been done suggest that weight loss or the fat mass loss comes from all adipose depots. Now, some studies have shown that, some but not all, have shown that visceral adipose depots, which we know are the ones closely associated with metabolic derangements and the metabolic syndrome, may be more affected than subcutaneous depots, but that hasn't been shown in all the studies. You know, I think looking, you know, tying this back to ARO-INHBE and ARO-ALK7, you know, one of the striking things from the genetic data that Eric had described is that measures of visceral adiposity seem to be more affected in these patients with predicted loss-of-function mutations. And that's looking both at surrogates of visceral adiposity, including waist-to-hip ratio, as well as MRI measures of visceral adiposity, and looking at gluteofemoral adiposity. So, maybe that's... I'll pass it to Dr. le Roux for his thoughts as well. No, I agree with all of that. But just to add that it also depends on when you look at the weight loss. So the initial weight loss, you effectively get most of the fat loss from the liver, then visceral fat, and then subcutaneous. But once you actually become stable, you reach the plateau, you generally revert back to the ratio of subcutaneous to visceral fat that you had before you started. So initially, you lose mostly organ fat, then visceral fat, then subcutaneous fat. So you have to just make sure when you actually are looking at that. Thanks very much. Next question comes from Andrea Tan at Goldman Sachs: Mechanistically, is targeting ALK7 receptor or Activin E ligand a better approach to modulate this pathway? Well, I don't think we- Go ahead, James. I don't think we know that yet, and that's one of the reasons to study both of them in the clinic. You know, targeting Inhibin E is very specific for that one gene product, Inhibin E and Activin E. And targeting the ALK7 receptor will block its ability to bind not just the Activin E ligand, but also other ligands that may be binding to ALK7. So there may be a broader effect by targeting ALK7. Eric, what do you think? Yeah, no, I'd agree with that. I mean, empirically, we're gonna have to work this out. This is a new pathway that's been recently uncovered. I think we're guided at the core by the human genetics and reassured by the human genetics, and we intend to answer the question based on the human genetics. Thank you. Next question comes from Jason Gerberry at Bank of America. Given the mechanism of both approaches are independent of food intake, how do you think about the risks trial subjects adopt a more liberal diet and consumption that negates fat loss benefit? I guess I will turn that to Dr. le Roux to see what has been your experience in clinical trials of other agents. Yeah, so, you know, I'm yet to meet a person that wants to have the disease of obesity. So, you know, we have this idea that people will just let go and... But actually, that's the benefit of actually framing it as a disease. It's a little bit like when you tell somebody for the first time that they have type one diabetes, and you're gonna treat them with insulin, they don't rush off to the candy store to get some more sugar intake. You know, they understand this is a serious disease, they take control of it. And I think with these medications, you know, you allow people control, and that is the one thing that people want more than anything. Now, once they have control of the disease, then we can amplify the health benefits by better diets and better exercise programs. So I think that is the benefit of treating, and I think finally, I would say that's the two concepts that we talk about. One is the disease of obesity, and the second is the cultural desire for thinness. So people who want to look different when they look in a mirror, and typically payers won't pay for that. But payers will pay for people to actually have health gains, and that's where these medications would be focused on. Thank you. Next question comes from Brendan Smith at TD Cowen. How do you expect the dosing interval data to translate from mice to humans? Do you expect 3-, 6-, 9-, or 12-month dosing in humans will be possible? So I'll let the clinical. Yeah, I'd be careful on, yeah, the mouse is just a tool trigger, right, James? So. Yeah, I, we tend to—when we set dose intervals in the clinical trials, we'd look at the cyno model more. And of course, our other GalNAc programs, where we typically are able to dose no less frequently than Q3 month. And we typically gain a little bit of duration and depth when we go from the monkey into the clinic. You know, I think we'd be looking at maybe somewhere in the Q3 to Q6 month duration for Inhibin E. For ALK7, that could be longer, based on the monkey data, but I think that's something we'll have to sort out in phase 1, what the duration looks like after a single dose. Thank you. There's a related question to that. This is from Maury Raycroft at Jefferies. What knockdown in biopsy tissue do you think you need to achieve? I'm assuming he means ALK7. Where would you get the biopsies from? Yeah, so we're finalizing the biopsy protocol now. I think we're looking at sites, abdominal sites, sites on the back as well, and potentially, the thigh as potential biopsy sites. And then, the question of how much knockdown do you need, I don't think it's totally been established. Eric, what, based on the human genetic data, what are you thinking? Yeah, human genetics, again, we're triangulating, but certainly the putative loss of function data that we were citing there with protection against obesity, these are, these are heterozygotes, right? And so you're... You know, dosage may vary a bit. So, you know, we anticipate less than, you know, certainly less than deep knockdown may be sufficient. So, Probably better, yeah, better than 50% would- Yeah would be the minimum threshold. Yep. I think we'd be- Yep -targeting something more like 80%. Yeah. Thank you. Next question is from Mayank Mamtani of B. Riley Securities for Dr. le Roux. What obesity disease subpopulations where you see more need for CVD disease management that you aren't seeing well addressed by existing therapies where obviously they don't get good lipid management? Yeah, so that's the real challenge for us, is that, you know, I've seen thousands of patients with obesity, and I have no ability to predict which patients will respond to treatment A or treatment B. So effectively, what we are doing at the moment is we are using a trial of therapy of 3 months, or we call it a diagnostic phase, where we would start a treatment, and we will be able to predict long-term outcome by the way people respond in the first 3 months. So what I think will happen in the future, is that we will start our treatments, and at 3 months, make a decision if somebody is responding or not responding, and change until such a time as we get better diagnostics. But I think the more critical question now is that at the moment, we don't have patient choice. And once you actually start explaining to patients about different mechanisms, then you actually find that people actually buy into, you know, different treatments. And what we do in our clinical practice is we provide, we empower the patients to make those choices. But if they don't respond to the treatment, we know there's something else to go to. Now, at the moment, we are a bit, you know, we don't have that much else to go to, and that's why we need more treatments so that we can offer that to patients. So ultimately, we will get better diagnostics to help us decide which patients will respond to treatment A or treatment B. But until that time, we can tell within 3 months how patients respond. Thank you. This is a question from Will Pickering at Bernstein. What are some pros and cons of this pathway versus myostatin and/or Activin A? Eric or Ziming? I can- So, for myostatin, and the obvious benefit is increased lean mass, but the fat mass decrease is relatively mild. So for ALK7, and Activin E, and we clearly show pretty robust decrease in the fat mass and preserved lean mass. How about for Activin A, any, any thoughts on advantages or disadvantages with that target? It's more of a muscle target, I think, right? That's correct. So for Activin A, we have pre-clinical data to support that actually the muscle Activin A inhibition alone show less robust effects than myostatin. So, they are in the same family, but there are subtle differences. Thank you. Next question from Ted Tenthoff at Piper Sandler. What tox might you expect or be aware of? I would, I, I would actually say we don't expect that, but what, what we would be aware or looking for, from the ligand inhibitor, I'm assuming he means, and from ALK7 target biology. So what are we on the lookout from a tox standpoint here? Yeah, I think, like you said, Vince, based on our experience in non-GLP and GLP tox, what we've have available to date, we wouldn't expect anything. But I think whenever you modulate these types of pathways, looking for any type of adverse changes in either lipid parameters or measures of glycemic control are probably important things to look at. So, you know, blood sugar, A1C, what's happening to triglycerides, LDL cholesterol, that sort of thing. What's happening to liver fat, that's one of the reasons why we included that in our clinical trial as an exploratory endpoint, we measured liver fat. It'll be interesting to see if liver fat goes down, but what we really don't, we really care about it, is it not going up. So, I think that's probably the best answer I can give at this time. Thank you. Next question is from Ellie Merle at UBS. Activin E influences the cardiovascular system, including heart function and vascular biology. How do you think about potential risks for cardiovascular dysfunctions such as hypertension or impaired regulation of vascular tone and heart function? Ziming or Eric, do you want to take a first shot at that? Well, let me take first shot. So, from genetic evidence and preclinical evidence, we have not found any data that inhibition of Activin E will negatively affect blood pressure, cardiovascular disease. So, of course, we need to keep close eye on it, but so far, there's no flag. Yes, even through our exploratory toxicology studies and that, yes. Thank you. Next question from Mani Foroohar at Leerink. After initiating phase I studies, what would be the timeline to be to the first data readout? Can we think of this as a 2025 event? And what should we expect to be included in the first data set for each? I'll take a first pass at that, and then, James, you can fill in the holes. So as we mentioned, our goal is to get the CTAs filed before the end of the year, and start the clinical studies shortly thereafter. Now, the clinical studies are designed to get lots of answers, in kind of a, you know, again, with single-dose monotherapy, multiple dose monotherapy, and then also in combination with tirzepatide. So we will learn a lot more in this study than your typical first-in-man study. So James, you want to kind of fill in timelines on this, assuming we get these up and running early in 2025? Yeah. I think that these should be pretty straightforward to enroll both studies. So, yeah, I think by, you know, second half of 2025, something like that, we should be in a position where we can start to share the biomarker data as well as some of the weight loss data, imaging data. Thank you. Next question is from Jay Olson at Oppenheimer: "What clinical benefits would be driven by preservation of lean muscle mass, and what clinical endpoints would you use to measure those benefits?" And I would actually first ask Dr. le Roux that. What would you expect? You did mention that, that that's one of the, one of the big to-dos for pharmacotherapy, is find ways to, to maintain and preserve lean mass. What are, what are the downstream benefits of that? Yeah. So ultimately, the downstream benefit will be improvement in function. So the amount of mass that people carry is not that critical, but what they can do with it is really important. And therefore, what we are currently focusing on is that when people do lose muscle mass, what's the quality of the muscle afterwards? And we know that if we treat obesity, we reduce inflammation, and the muscle mass therefore actually improves in quality, even though there's less of it. Now, in this situation, where you would actually reduce adipocytes, you will also reduce adipocyte inside the muscle. So most of us, maybe on the weekend, had a nice rib eye steak, and you would remember that there was actually some fat cells inside the muscle. Now, if you're going to target adipocytes, you're also going to reduce that. So you're going to improve the quality of the muscle in this instance, while not losing lean mass. And that's, that's gonna be an advantage. So it's not going to be about measuring the amount of muscle. It's going to measure the quality of muscle by testing the function and whether or not that's on a six-minute walk test or a sit- to- stand test, that's where, there's currently a lot of discussion, in how we are going to standardize those measurements going forward. Thank you. And we only have time for one more question, and I will pick one that I think both Dr. le Roux and the panel will have an opinion on. So this is from Maury Raycroft at Jefferies, and I will paraphrase this. So where would this be used? And actually, I'll first pose that question to Dr. le Roux. So provided we have one or both of these agents that have a clinical profile that's similar or matches what we've seen pre-clinically, where would these agents fit in the current standard of care? Maintenance therapy, upstream, downstream, in combination. How do you see these fitting? First of all, I think we need to get double-digit weight loss. If we get 10% weight loss, you know, you have a ballgame. Now, if you get 15% weight loss, as is suggested, you know, 15%-20% weight loss, as is suggested by the phase I or the animal data, then what you will have, it could either be a first-line treatment or it can act as in combination with another medication that already, you know, you have in play. Think about how we treat hypertension. You know, you may start with an ACE inhibitor, but you will add in a second-line agent if you don't have full control. But other patients may start with a calcium antagonist, for example, and add in an ACE inhibitor. So, I think this has the potential for both a first-line agent, but certainly, and in a combination. Because remember, at the moment, obesity is the only chronic disease that we don't yet have a target for. So we talk about percentage weight loss as if that's a target, but we don't talk about percentage hemoglobin A1C reduction or percentage millimeters of mercury for blood pressure. We talk about treating to target, and I think that is what's gonna happen in the next one or two years in obesity medicine, is we're gonna work out what those targets are, and therefore, I think combination therapies are going to be far more common than they are at the moment. Then maybe, James, if you can talk a bit about our strategy for clinical development. Yeah, I think as we lined laid out in the slides, I mean, we wanna understand how the drugs work as monotherapies, but also in combination. Just as Dr. le Roux had mentioned, I mean, we're considering both of those pathways as paths for further development post-phase I, but we kind of need to see the data first to make a call. Thank you. And again, thanks to the entire panel, especially Dr. le Roux, for joining us today. It was very, very helpful. I appreciate it. And to everybody out at home, thanks so much for spending the time, and we will see you next month at the final installment of the summer series, where we talk about our CNS platform. Thank you.