Everyone, and thank you for joining us at TD Cowen's 2025 Treatment Advances in Obesity Summit. I'm Joe Thome, one of the Senior Biotech Analysts here on the team at TD Cowen, and it is my pleasure to have with me today Dr. James Hamilton, who is the Chief Medical Officer and Head of Research and Development of Arrowhead Pharmaceuticals. Thanks for joining us. Maybe before we get into some of the specific programs, it might be helpful just to level set and kick off the discussion with just a brief overview of Arrowhead's recent progress and accomplishments. Obviously, we saw the update on the Sarepta partnership this morning, which is great to see. Maybe what should investors be expecting into the end of the year and into 2026? We can kind of go from there. Yeah, sure. Happy to cover all of that. Thanks for having me. Thanks for the invitation to present today. In terms of what we have going forward, end of this year into next year, of course, I'm sure everybody saw the recent first approval of Redemplo in FCS. O ur quarterly call is tomorrow. We'll give some updates on launch progress around Redemplo. In addition to that, specific to the obesity space, we do still plan to provide an update and release some data from our INHBE and ALK7 programs over that time frame. Probably like first week in January is what we're looking at now, just because of the holidays and some scheduling conflicts. In addition to the obesity releases, we'll be initiating our DIMER phase I, the APOC3 PCSK9 DIMER phase I. We have filed that study and should be dosing probably early next year. There's some slowdown around the holidays at some of the sites, but I'd anticipate we'll have the first patient in early next year, probably January. Beyond that, we've already filed with our ARO-MAPT program to get that phase I up and going. I should have that study launched around the same time frame, end of this year, early next year for ARO-MAPT. That's broadly I think what investors can anticipate over the next month or so, month to two months. Great. Maybe for the focus of the day, we'll start on the obesity programs and then we'll dive into some of the others as the session goes on. Maybe, what do you and Arrowhead view as sort of the largest unmet need in the treatment of obesity? Obviously, we've come a long way with the GLP-1s, but maybe if you could just go into your approach to studying obesity and where you think that are kind of the open space is. Sure. Yeah, I think that there's still ample unmet need and a lot of various pockets of maybe niche opportunity, but we still think there's unmet need in terms of generating a larger magnitude of weight loss in combination with GLPs, preferentially fat mass loss and sparing lean tissue. I think that is one of the areas of opportunity that are out there. We think that there may be an opportunity for therapeutics that potentially induce less weight loss than the GLPs, maybe more like 7%-10% of body weight, but with a preferential tolerability profile. W ithout some of the GI side effects and an easy-to-administer Q4 month or Q3 to Q6 month dosing regimen would be attractive. Beyond that, there's probably some subpopulations that may be resistant to GLPs and thinking of diabetics specifically, where they just tend to not lose as much weight on the GLP-1 agonists compared to the non-diabetics. There may be some opportunity to combine or use novel therapeutic approaches in some of these subpopulations. We're an siRNA company, so we're looking for gene targets either in the adipocytes or in the hepatocytes or other metabolically active tissues, where we can silence a gene and achieve any of those goals, right? Address any of those opportunities. Great. Maybe we'll start with the INHBE program, because that was the first one of the two programs into the clinic. Maybe just broadly, can you talk a little bit about INHBE's role? What happens when it's dysregulated, and kind of where is it primarily expressed and its role I guess broadly in weight loss and obviously with dysregulation, potentially obesity? Sure. This is a really interesting target for us. I know there's others that are also looking at this target as well. INHBE is the gene that codes for the protein Activin E. T his protein is primarily expressed by the hepatocyte in the liver, although there's some other sites of expression, maybe a little bit of expression in the pancreas and some other sites as well. It appears to be part of a regulatory system for fat storage in the adipocyte. In the setting of excessive caloric intake or an excess amount of calories, the liver expresses Activin E. It secretes this into the blood. This is a signaling mechanism. The Activin E binds to ALK7 on the adipocyte, which downregulates lipolysis. It is downregulating the mobilization of fat, and promoting storage of fat by the adipocytes. In the setting, as you mentioned, there's settings where you can get this excess dysregulated and that occurs in the presence of an excess of calories. Also, we've seen this seemed to occur in the presence of type 2 diabetes. Others have shown this, but we've seen some of this, that there are higher levels of Activin E expression in the type 2 diabetics versus the non-diabetics. In those two settings, the Activin E signaling can become dysregulated and excessive. The theory is that we can intercept that signal, and silence the expression at the hepatocyte or by knocking down ALK7 in the adipocyte and that could prevent some of that fat storage. Great. Maybe can you talk a little bit about some of the preclinical data that you've seen with INHBE, and kind of how you got confidence moving this specific program into the clinic? Most of the preclinical data that we have is, we've done a lot of work in this DIO or diet-induced obesity mouse model, where the mice are put on a high-calorie diet and they progressively gain weight. We treat them with either a control, either saline control or a scrambled RNA versus the INHBE siRNA. We're knocking down the INHBE gene in these animals, usually with a tool trigger that's specific to the mouse. What we've seen is a differential in the amount of weight gain by about 20% with INHBE, in the animals that are treated with the siRNA versus the control animals. That's after being on the diet for about 16 weeks. We've also done some work in the same model in combination with the GLP-1s, specifically tirzepatide, showing additive weight loss when we combine the siRNA with the GLPs and also showing the ability to achieve the same weight loss with a lower dose of the GLP in those animals. Importantly, the weight loss that we're seeing in these animals appears to be almost entirely fat. They preserve lean mass, but they lose or gain less fat mass than the control animals. That's the primary animal models that we've worked with. We've done some work in lean cynos and monkeys, but those are primarily just knockdown studies, confirming knockdown of the target in the animals. We haven't done any obese cyno studies yet. Okay, perfect. Maybe we'll go into the phase I A, I B, two kind of combo study that's ongoing right now. Maybe if you could just give us a little bit of an update as to kind of where you're at within the study. When we do see that initial data set, what is the company kind of guiding for? There's the SAD cohorts, and then you kind of move on to some combo tirzepatide in sort of the healthy obese volunteers and then some type 2 diabetic patients. Maybe if you could just help us kind of understand the progress, and what we should be expecting in terms of amount of data that can be shared. Sure. As you mentioned, we start with single and multiple escalating doses in otherwise healthy obese volunteers. These are individuals with a BMI greater than 30, but they're otherwise healthy, non-diabetic, do not have a lot of other medical problems. We look at four dose levels in the SAD cohorts. We start at 50, we go to 50, 100, 200, and 400. In the MAD, we look at just 100, 200, and 400. Those two doses are spaced by 28 days. They give drug on day one and day 29 and then follow knockdown out through, I think we go through six months in the MAD studies. There are six per cohort in the SAD, 12 per cohort in the MAD. The combo studies, this is ARO-INHBE on top of tirzepatide. We look at three dose levels in the non-diabetic combos, 100, 200, and 400, 12 per cohort in each of those. In the type 2 diabetic multi-dose arms, it's the same dose levels, so 100, 200, and 400 also there. The study is nearly fully enrolled. We have almost all the healthy volunteer or the obese healthy volunteer cohorts. Those are full. The combo cohorts are almost full. I think we're still waiting to enroll the last few diabetics into the multi-dose combo arms. We should have a good amount of data at this coming release from all the cohorts. The most substantial data will be from just those SAD and MAD healthy volunteer cohorts. The study has moved along nicely. In terms of what we are looking at, of course it's a phase I study primarily, so s afety is the primary. We do really want to get a good look at the biomarker knockdown. We can measure Activin E in the blood. Want to see a good dose response there, want to maximize knockdown. Everyone enrolled gets an MRI at baseline, and then two post-dose MRIs. We'll get a real detailed look at different compartments of fat storage. We'll be able to see changes in visceral fat, changes in subcutaneous fat storage, of course total fat versus lean mass storage. We'll also get a good look at the liver and see if there's any changes in liver fat, either up or down in terms of liver fat. Should be a pretty robust data release here coming up. When you think about sort of the bar for moving candidates forward, and this can be for INHBE or ALK7, obviously you just indicated a lot of different measures. It seems like there are a lot of different ways to win outside of just overall weight reduction. You mentioned the tolerability profile, and obviously the quality of weight loss. I guess, how do you make that decision on what sort of an ideal profile to move forward into phase III? Do you have sort of internal metrics or target product profiles that you're thinking about that you can share? Sure, y eah. For this study, our view has been, and we've said this I think publicly a few times, from an efficacy standpoint, we view this as a hypothesis-generating study, right? That we're casting a wide net, looking at a lot of different metrics here and we'll see what moves. We do think that some level of weight loss is either in combination or as a monotherapy would be needed to move this forward, but we don't have a definitive cutoff. We want to see what the study shows. If there's a signal somewhere that looks interesting, we would expand either certain cohorts of this study to confirm that signal or run a confirmatory phase II to confirm that signal. That's kind of how we're viewing this study. Okay, perfect. You did indicate earlier that there are some other companies looking at INHBE. I think Wave obviously had maybe some early data. I guess, how do you view your program versus maybe some of the others in terms of, obviously the data will show how these stack up, but I guess just at face level, any differentiating features that you want to highlight? Yeah, I think that this program, the Arrowhead program, was in the clinic first. I think we've got a little bit just time-wise, of a lead there and have made a lot of progress not only in the healthy volunteers, but enrolling some of these subpopulations and looking at combo therapy. I have a lot of confidence in our ability to design, and bring into phase I potent siRNA sequences and triggers that should induce siRNA. I think that could be a potential advantage for us. I mean, otherwise, right, it's kind of the same concept that everybody's looking at using an siRNA approach to knock down INHBE. Our chemistry here is no different than our other GalNAc chemistries. I mean, there's not a new technology being employed here. It's pretty plain vanilla GalNAc approach. Maybe if we could compare and contrast the ALK7 approach versus the INHBE, because obviously different kind of tissue targeting. I guess, can you walk us through a little bit, how the mechanisms are different between the two targets? I guess when you extrapolate that back to what you've done preclinically, any sort of main differences there outside of the diet-induced obesity model in mice? Right, y eah. Both of these are hitting the same axis, right? One hits the liver signal and the other hits the receptor for that signal. We chose to take these both into phase I for a couple of reasons. The GalNAc technology was tried and true. The sort of safety profile of that platform, I think generally people are confident with and understand any kind of class effects with the GalNAc siRNA. We felt good that we'd be able to use that technology to knock down the target. In contrast, the ALK7 program uses a novel delivery platform that's designed to target a receptor on the surface of the adipocyte that facilitates delivery into that cell type. That's a novel technology. This is first in human for that technology, so there's a little bit more risk there. We thought we'd study both of them. One is a little bit maybe more pedestrian from a technology standpoint, but consistent. We've been able to consistently knock down targets with the GalNAc siRNAs, whereas the ALK7 adipocyte- targeted technology is newer. The preclinical data with ALK7 targeting look really interesting. The duration that we've seen in monkeys is probably amenable to every six-month dosing. I would say every three months at the least, but you could probably get every six months out of ALK7 knockdown in the adipocyte. That differential in fat mass in the DIO model was more like 40% in the siRNA-treated animals versus the controls. That equated to like a 50% difference in fat mass between those two groups, with no lean mass loss. It might be that ALK7 knockdown is a more potent way to go after this axis than INHBE. To me, that always made sense because there's other ligands that bind to ALK7, whereas Activin E is just one of those ligands. Hitting the receptor, you might have more of an effect versus hitting the ligand, but w e'll see. That's why we wanted to study them both. I guess theoretically, is there a patient population where you think one of these mechanisms, I guess," makes sense more," because of that kind of differential targeting that you just mentioned or are these both going to be good for all types of patients? Yeah, I can't think of a patient population where one would be more advantageous than the other. I think we'll just have to see how the data play out, and if there's any differentiators that boil to the surface when we have all the data. Perfect. Maybe can you just update us on kind of how this trial is progressing? I guess one started in the clinic a little bit after I think the INHBE program. Just curious how this one's progressing, and any differences overall in sort of the trial conduct? It looked pretty similar, but anything you want to call out? That's right. These are almost identical trial designs. The only difference is that in the ALK7 study, there's no direct serum measurable biomarker. We do adipose biopsies pre-dose and then a couple of time points post-dose, just to measure mRNA knockdown. We also measure duration. That's the intent of doing multiple biopsies post-dose. We can get a good idea of duration of effect. Otherwise, the studies are really identical with that same obese healthy volunteer population, and then the non-diabetic and diabetic combo cohorts. ALK7 was about two quarters behind INHBE. We just nominated the INHBE lead candidate first, and then ALK7 came afterwards. We're about through the healthy volunteers in both the SAD and the MAD healthy volunteers with ALK7, and we've started enrolling the combo cohorts. I think in terms of data, we'll have mostly knockdown mostly PD data and some safety data from this study. Okay, perfect. I guess just maybe last question on the obesity side of things, because I want to make sure we touch on some of the other programs. Obviously, with sort of the early data releases, when do you think you'll have enough kind of patient follow-up to decide, I'm moving forward into next steps? Are we going to have everything that you need in sort of early January, or is this going to be kind of a developing story in 2026? How do we think about that? Yeah, I think it's probably more the latter. I think because we'll need the ALK7 data really, particularly from the combo cohorts to make a call, so I think probably first half of 2026 is when we're really likely to have a critical mass of data from both studies to make a decision about, does one move forward and the other not or do we look to partner one or both of these, or what's the path forward? Okay, perfect. Maybe we'll turn to Redemplo, just given the recent approval. Maybe can you touch a little bit, I guess sort of on your initial launch expectations? Obviously, the pricing paradigm was interesting versus kind of what Ionis has done, where they started high obviously in FCS and then may lower down in SHTG. Anything, I guess, on sort of how you expect the early launch to go, and maybe why did the company pursue that sort of one-price strategy for FCS and then hopefully SHTG once available? Sure. I'm going to punt on the pricing question. I don't want to front-run our commercial team, but they'll give an update tomorrow on the call. I mean, there's been a lot of interest in the molecule, and I think a lot of PIs and investigators who were involved in our studies who are interested in getting patients on the drug. I think we'll give a specific update probably tomorrow afternoon. Sounds good. I guess just as we think about the differentiation versus olezarsen, obviously the dosing convenience, if you can give any sort of indication as to what the initial feedback is on that, not even just the commercial launch, but I guess just in your kind of years of talking to KOLs. At AHA, there was this discussion section talking about hepatic fat content maybe between the different approaches. I guess, do you think that's something that's real, I guess first of all? How will you be thinking about that when you read out the SHTG data later next year? Yeah, happy to hit on both of those. I think that plozasiran can compete very well against olezarsen in terms of magnitude of triglyceride reductions in the FCS population, and also in terms of the labeled safety profile. I think we're in a good place there. The liver fat question is really interesting. My recollection is, Ionis showed about a 2%-4% absolute increase in liver fat in patients with steatosis at baseline. It was dose-dependent, right? The 2% was the low dose, and the 4% was the 80 mg dose. It remains to be seen. We're looking at this in our phase III SHASTA-3 and SHASTA-4 studies. We'll know in Q3 of 2026 how we look. We did look at this in a smaller study, a subpopulation in our SHASTA-2 phase II study and did not see any increase in liver fat at the go-to-market dose, at the 25 mg dose. I mean, it's possible that this could be on target. It doesn't seem like an impossibility, but I think we kind of need to get our phase III data on that to maybe weigh in. The one confounder that I think is interesting on this topic is [buprenorphine], right? That was the ASO against ANGPTL3 that showed an increase in liver fat, whereas two different siRNAs did not show an increase in liver fat. In fact, we and Lilly showed a decrease in liver fat with ANGPTL3 knockdown. I don't know if this is going to be the same scenario with APOC3 knockdown or if it is something that's more on target, but I think we'll see. Maybe just in the last minute we have here, just how is the company setting expectations for SHASTA-3, 4? Obviously, now that we saw the Ionis data, has that changed your expectation for what you want to see in terms of acute pancreatitis risk reduction in these sort of initial studies versus SHASTA-5, o r what are you kind of setting the expectation as in that data? I think their data was really encouraging that they strongly hit on acute pancreatitis when they pooled the studies. They also hit when they looked at each dose separately at both the 50 and the 80. It seems like there was a strong effect there. I mean, I have not seen our data yet. I do not want to set any expectations just because I have not seen anything, but I thought that their data was really encouraging in terms of supporting the triglyceride reduction in that population can prevent acute pancreatitis. Great. Unfortunately, we're at time, and unfortunately, we didn't get to get a lot of the other pipeline programs as well, but definitely a lot to expect from Arrowhead in 2026. We look forward to it, and hope everyone tunes into the earnings call tomorrow evening as well. Thanks for joining us. Yeah. Thanks for having me, Joe.