My name is Maury Raycroft, and I'm one of the biotech analysts at Jefferies. I'm happy to introduce and welcome James Hamilton, the CMO, and Daniel Apel, CFO of Arrowhead Pharmaceuticals. This is a fireside chat. Thanks so much for joining us today. Thanks. A pleasure to be here. Of course. Maybe for those who are new to this story, if you guys can provide a one-minute intro to your programs at Arrowhead. Sure. Happy to take that. Just for folks new to the story, high level, I think most people know we're an siRNA therapeutics company. We don't do anything else, just siRNA drugs. No gene therapy or gene editing, at least not yet. We've been focused on a platform we call TRiM, stands for Targeted RNAi Molecule. We've utilized this platform, which from our standpoint, is one of the most productive discovery and development platforms of any biotech our size. We've leveraged this platform to put 20 clinical candidates into various stages of clinical trials now. As you might expect with a platform that's been that productive, we can't keep everything, so we do tend to partner off some assets, keep some wholly owned assets. Some of the partnered assets include olpasiran, which is partnered with Amgen, fazirsiran, partnered with Takeda. We have two molecules, one for hepatitis B and one for MASH, both partnered with GSK, and then a broad discovery collaboration with Sarepta, and then most recently, a discovery collaboration with Novartis. On the wholly owned side, we have REDEMPLO, which was recently approved for familial chylomicronemia syndrome and is in phase III for severe hypertriglyceridemia. Coming up just behind that, also in phase III, is zodasiran for homozygous familial hypercholesterolemia. Some of the earlier wholly owned programs include ARO-ALK7 and ARO-INHBE, both for obesity. Maybe there's a MASH indication there also. A little earlier is ARO-MAPT, which targets the MAPT gene. That's the gene that codes for tau protein that's involved in Alzheimer's disease and other tauopathies. That's our 30,000-foot view of the company. Great. Yeah, it's a good overview of the company. A lot of interest in plozasiran in the SHTG studies with pivotal data coming up. Maybe just clarifying, when do you expect the last patient, last visit to be completed? Should we expect the top line in July or potentially later in the third quarter? Yeah. So far so good. Everything's on track there. We should have the last patients coming in over the next month or so. We've been saying all along Q3 for data, so I think we're going to stick with that in terms of guidance. I think there's too many things that could still happen in terms of getting a late AP event that needs adjudicated or a late SAE to narrow that down to a specific month. Everything's on track now, I think, and we're planning on Q3 for data. Got it. Okay. There's also a lot of interest in AP, the acute pancreatitis, and I think people want to know if you can achieve stat sig on the APM point. The trial's blinded, but can you share your internal monitoring, what that tells you about total AP events accrued across both arms? Are you confident you've crossed that minimum threshold of having greater than or equal to nine total events needed? Yeah. What we've said all along is, and we remain cautiously optimistic about our ability to hit on AP. We think that if we have at least nine or so events, with an event rate similar to what the CORE and CORE2 studies show, we should have around 80% power, and of course, any more events than that just increases our power. We feel pretty good, but we're still blinded, so we'll see in Q3 where things land. Got it. I guess, can you say if the events are tracking, or any more specifics around that? I think we can't give any more specific guidance other than we haven't seen anything sort of wildly out of our range of expectations. Got it. Are you contemplating any stats plans changes to potentially include crossover data and AP analysis if needed? No plans of changing our SAP or our statistical analysis. We've planned all along to pool these studies, so pooling the AP data from SHASTA-3 and SHASTA-4, and no change in that regard. Yeah, I don't anticipate any changes going forward. Got it. For just the event rate trends versus original assumptions, so based on what you said, is it fair to assume that the trends are as expected, or could they potentially be a little bit faster? No, I think they're generally as expected. Again, we haven't seen anything wildly outside of our expectations based on what others have presented in terms of event rate. Yeah. Okay. There's inherent patient variability related to fasting triglycerides at baseline versus screening. What are your expectations for control arm performance and overall placebo-adjusted treatment effects on triglyceride reduction? Does it matter if placebo triglycerides came in lower than expected due to diet or et cetera? Yeah, in terms of expectation for the placebo group. I think in triglyceride studies, you do see a trend downwards in the placebo group as some patients are able to go on a diet and stay on that diet. We saw a little of that early on, just going from screening to baseline. If you look at the screening values and then the baseline value, which includes day one and the average of the last screening visit, we get a little bit of a decline. That's probably patients going on diet and being strict about their diet. My guess is there's probably a little bit of a reversion to the mean as people struggle to stay on a low-calorie diet over the course of a year. A 10% decline in the placebo group wouldn't surprise me. That's probably my expectations. We'll see. Our baseline triglyceride values for the combined SHASTA-3 and SHASTA-4 are about 860. That's a pretty good baseline to work with. If you remember, in SHASTA-2, our baseline values were more around 600, and we still saw about a 70% reduction in triglycerides. I feel pretty confident about 860. As far as things that we worry about, that's not one of them. Got it. Okay. Ionis, their olezarsen sBLA PDUFA is coming up on June 30th. What are your expectations on what their label can look like, especially as it relates to any claims on AP benefit? Yeah, I don't know. I think they'll get approved, and I think they'll probably get AP in the label. Hard to say where that'll show up, if it'll just be mentioned in section 14 or somewhere else. I thought the CORE and CORE2 data looked really good and really convincing, particularly the AP data. Yeah. Okay. On safety, you've highlighted you don't see hypersensitivity reactions, liver fat increases, and no thrombocytopenia. What are your latest thoughts on whether these are on-target APOC3 class effects, or are they unique to plozasiran's RNAi modality versus Ionis' ASO? Are you collecting liver fat data in SHASTA-3 and SHASTA-4? The hypersensitivity and the thrombocytopenia, we don't see. That, I think, is more an ASO class effect, particularly the thrombocytopenia that's been reported with various other ASO molecules beyond olezarsen. Same with the hypersensitivity, more of an ASO class effect. We're not seeing much of that at all with the siRNAs. This question around liver fat, I think we'll have to wait and see. We did not see that, the increase in liver fat in our SHASTA-2 phase II study at the 25-milligram go-to-market dose. We saw a 2% absolute increase from baseline at the 50-milligram dose, at a higher dose that we're not using any longer. Contrast that to what Ionis saw, which was about a 2%-4% dose-dependent increase in liver fat. My take is that maybe there's a combination of on-target versus off-target. If you remember, the ASOs, this finding has been noted before with ASOs, specifically with vupanorsen, which targeted ANGPTL3. That molecule demonstrated a dose-dependent increase in ALTs and liver fat. We'll see. I think we're hopeful that we don't see an increase in liver fat. That being said, if we did see something consistent with what Ionis saw, I think we're both in the same boat. I'm also not sure how clinically significant that increase in liver fat really is. Got it. Yeah, that makes sense. Yeah, what do you hear from your doctors on the liver fat increase and just whether they're concerned about that? Yeah. What we hear when we talk to KOLs is exactly that in the setting of no other biomarker changes, so no increase in ALTs or worsening of FibroScan or something else, that it's pretty innocuous and something that they'd be fine taking that trade-off if it could keep their pancreatitis patients out of the hospital. When you report your SHTG data, will you have some sort of an update on liver fat as well? Yes, we should. Yeah. Okay. For REDEMPLO and FCS, the launch is going well, trending better versus Ionis at a similar launch time point. With the prescription run rate hitting about 30 per week, how much represents pent-up demand versus sustainable steady-state patient identification? I'll take that. It's true, if you look at the first full commercial quarter of sales, we are trending better. That's when you normalize for price and look at it sort of a unit basis. I wouldn't over-index on that. These are ultra-rare indications, small numbers. It is true, and part of that is the commercial end engaged commercial team we have. In terms of the demand, we saw a little bit of a pent-up demand from, call it the EAP switch and some switchers from TRYNGOLZA. Most of it is new to class, and we're seeing sort of a linear progression there in terms of uptick in demand, perhaps with a little bit of an acceleration in the last month or so. Got it. Okay. You're not providing more specifics on patient numbers at this point? No. Okay. What are your expectations on how patients naive to the APOC3 class and patients switching from TRYNGOLZA will evolve this year? What type of feedback are you getting from prescribers, and how will they choose between REDEMPLO and TRYNGOLZA? Yeah. I think I mentioned the linear growth that we're having. I think our expectation is that largely continues, mostly naive. We'll get some contribution from switchers. TRYNGOLZA is a good product, obviously. They did have a subset of non-responders, around 20% of their BALANCE trial. There are always going to be people that don't tolerate it well or have some sort of frustration. We will continue to see switches, but mostly naive to class is what we're expecting. In terms of prescriber choice, physicians will have their choices. Some will try both molecules. We've obviously stated we think we have the superior molecule, and reference our knockdown and our potency, not just with the triglycerides, but if you just take it back up a step with APOC3 overall, you see much greater knockdown. More potent, convenient dosing with the three-month schedule versus every single month. Importantly, no warnings, no precautions, or no contraindications. We'll let that sort of speak for itself there. Got it. Okay. That's helpful. What's been the feedback from payers since you took a price cut last month with your WAC to $45,000 versus $60,000 prior? Does that meaningfully accelerate formulary decision making, and could there be any more adjustments on pricing? Yeah, no. The feedback's been very positive. I think TRYNGOLZA came out at $600,000. We came out at $60,000. They very much welcomed that. When TRYNGOLZA went down to $40, I think us moving down to $45 gave a clear statement that we view ourselves as a premium product, and we'll still do that. It removes any kind of uncertainty that the payers had in terms of how do we have to react to get them to view it as cost comparable. Our research indicates if we're within 15%-20%, we're viewed as cost comparable from the payer standpoint. That's what we move to, maintaining that sort of premium price, but being within the 15%-20%. Yep. Let's see. Sorry. Has it meaningfully accelerated formulary decision making? I would say it certainly has helped, again, by removing that uncertainty. We're very much on track with the payer discussions. We're obviously approved for genetic and clinical. They've been very open to discussions of putting in policies that are aligned to our label as opposed to putting in things like diagnostics, score intros, and whatnot. Very happy with those discussions and they're proceeding very well. Got it. Okay. For your obesity program, so let's shift gears to that. You had an updated EASL recently. Maybe just go through the key takes on the experience so far and what data should we expect second half of this year across your ARO-INHBE and ALK-7 cohorts for both monotherapy and the GLP combo cohorts? Yeah, I can take that one. At EASL, we focused on INHBE, and that presentation was really more focused on the liver fat. As a monotherapy with ARO-INHBE, we're seeing about a 40% reduction in liver fat from baseline in patients with hepatic steatosis at baseline. We do see a monotherapy pathway there for ARO-INHBE as a MASH drug. We're also still looking at ARO-INHBE in combination with GLP-1s, particularly in the diabetics for additional weight loss, and we've continued to see some additional weight loss in the diabetic population with that combination therapy versus the GLP-1 alone. ALK-7 is probably what we'll focus on mostly in the second half of the year. We may have some updates on ARO-INHBE as well, but we're due for ALK-7, primarily focusing on body composition changes, weight loss changes, combination, and monotherapy. Stay tuned there. I think so far we've only talked about some of the visceral fat reductions and knockdown with ARO-ALK7, and we'll have more data by end of the year with regards to changes in body composition. Got it. That's helpful. From my understanding, the last time you commented on the number of patients in this study, it was January. You said there was about 192 patients. How many additional patients have been dosed since then? Can you talk about just new dosing regimens, maintenance schedules, or GLP-1 dose combinations that are being explored beyond the initial tirzepatide combo data? Yep. Yeah, both of those studies are fully enrolled now, both ARO-ALK7 and ARO-INHBE. That puts us at, I think, right around 240 total patients, and that's aggregate of monotherapy in combination with tirzepatide. We did add some cohorts to the ARO-INHBE study. Let's see, we added four cohorts. We increased the size of the cohort that was looking at 400 mg ARO-INHBE plus 5 mg of tirzepatide. We also wanted to look at a higher dose, 600 mg ARO-INHBE plus 5 mg of tirzepatide. Those both go for a full year, we should get more longitudinal data out of those new cohorts. We added a 600 mg monotherapy cohort in Type 2 Diabetics, which is one gap we felt like we had, that there was no Type 2 Diabetic monotherapy cohort. We'll get a good look at those patients at a high dose. We added a high-dose tirzepatide cohort. We'll do 400 mg ARO-INHBE with 15 mg of tirzepatide. We'll see how many patients can get up to 15 mg. The idea is to see if we still see an additive effect in the diabetics with a higher dose of tirzepatide using the combination regimen. For any of these cohorts, do you have options to do maintenance assessment where you basically stop the GLP-1? We could. It's not built in right now, but that would be an easy amendment to make. They would've been on drug for a long time. I think that'd be an interesting opportunity to see what happens when you remove the GLP-1. Yeah. Yeah. Right. Okay. I guess when would you make that decision? Could that be something that happens this year? Probably next year. Like I said, we're going to follow those for a year, probably mid to late 2027. There's a lot of focus on these programs for seeing weight loss and comparing that to other programs in this space. I don't know if that's the best benchmark, but how are you setting expectations around weight loss for monotherapy versus combo? Is greater than 15% the right benchmark for monotherapy and greater than 25% for combo? Are those correct, or? Yeah, for monotherapy, we're still just following the guidelines of a 5% change, 5% decline in overall body weight over one year. It's not clear what the hurdle to get over is for combination therapy. We've been hearing an additional 5% on top of GLP-1 therapy at one year, or less weight loss if there's some additional clinical benefit, like an improvement in A1C or something like that. I think those are all still things we have to sort out with FDA. I don't think we're alone there. It sounds like there's a lot of other companies that are wanting to do GLP-1 combination therapies that need to sort out what's the hurdle to get over, what additional weight loss needs to be seen. I think it's something the whole field will have to sort out in the coming years. For the update second half of this year, what could you show on body composition and visceral fat reduction and lean mass gain or preservation? Do you think that could differentiate versus GLP-1s? Yeah, potentially. I think we're still of the mind that we're likely going to combine and not compete with GLP-1. We're really not trying to make that comparison, but looking for additional, either improvement in body composition in the form of fat loss, visceral fat loss, or total fat loss, or some improvement or retention of lean mass. I think the visceral fat loss that we've seen in the mid-teens and even progressing to 20% in some of the cohorts at the later time points, that seems pretty good to us. I think if we can maintain that, we feel confident with that level of visceral fat reduction. Then on the lean mass preservation, any lean mass preservation, I think on top of the GLP-1s would be a welcome improvement. Is there a certain threshold for A1C that you'd want to see in your studies? Yeah, I don't think we've thought of a threshold for lowering A1C. We certainly don't want to see a worsening of A1C. If you could see a 0.2% or 0.25% reduction, that'd be helpful. I don't think it's required to get approval. Got it. Okay. You said that you plan to meet with FDA mid-year. What are the potential outcomes and scenarios for phase IIb studies planned, and do you envision any type of streamlined regulatory path to approval given FDA's recent guidance for a single pivotal being sufficient? On the latter question, probably not. I think that this is going to be a pretty standard path to approval for either the MASH indication or the weight loss indication. We'll see if there's any opportunities to shorten things. We're having some of those conversations, getting feedback from FDA right now specific to ARO-INHBE, that will help guide what the phase II plans look like. We still plan to have a phase II study submitted and up and running by end of this year. Got it. Okay. You mentioned interest in other obesity targets that could be unlocked by being able to target adipose tissue, including ones that could have neuro or CNS effects. Where are you at with those programs, and is your ongoing preclinical work exploratory at this point, or do you feel like you have potential to make some big breakthroughs on these targets? Yeah, we do have quite a few additional targets. Some in the adipocyte, some, as you mentioned, in the CNS also. A handful of those have made it into the preclinical development pathway. We're doing GLP tox and all the things we'd need to file an IND or a CTA, and I think one of those will probably get at least filed to start phase I by end of this year. Got it. Anything more on those targets that you're saying? For the MAPT data, which I'm going to talk about that next, but will seeing the knockdown there with the subcu injection, does that help de-risk these potential obesity targets? Yeah. Well, on the new targets, I think we're holding it a little closer to the vest on disclosing targets. I think when we mention a target, the next day, there's like five other companies that have been working on the same target. We're not talking about preclinical targets or sharing data on those programs as much as we used to. When we submit the IND or the CTA, I think the world will learn what the targets are. Sorry, what was the second part of the question? For the MAPT data later this year with the subcu injection to get a CNS target, does that help de-risk the obesity? Yeah, I don't know that it helps the MAPT program. That's a different platform. The ARO-MAPT uses a transferrin-targeted Fab, whereas the obesity platform uses a small molecule lipid that targets the adipocyte. I do think the MAPT platform will be significantly de-risked depending on what the data show. Regardless of how important tau is for Alzheimer's disease, I think if we can show good knockdown with that subcu administered platform, that is huge for the platform, right? There's a lot of other CNS targets out there that we can go after, and just showing the ability to knock down gene targets in the CNS with a subcu route, that would be huge for us. As you might imagine, we have lots of other pre-clinical programs that we're working on now that rely on that platform. Yeah, I do think it'll be de-risking for the CNS platform. Okay. Maybe before we dive into MAPT, just one more question for obesity. For INHBE, would you guys keep that in-house? You're showing some great data there with liver fat reduction. You've out licensed another MASH program. Could it make sense to out license INHBE as well? Yeah. I think for the time being, the plan is at least through phase II to keep that wholly owned. Got it. Okay. For MAPT for CNS, we had the Biogen phase II data that technically failed, but there were sufficient positive cognitive trends on multiple measures to advance the asset into a phase III study. What was your impression on the data? Do those data reinforce or change your views on what's needed targeting tau production with a RNA approach, RNAi approach? Yeah, I thought generally that it was supportive of the tau hypothesis. It didn't negate the concept that knocking down MAPT to reduce tau levels could be a therapeutic route for Alzheimer's or for other tauopathies. There weren't a lot of data disclosed, so I guess we'll see, I think in July, we'll get a look at the detailed data. Maybe the most encouraging aspect was that they are moving into phase III, and so Biogen presumably has seen all the data, and they're willing to make that investment in a large phase III program based on what they've seen. I think that's generally supportive for all of the other programs targeting tau, including ours. Got it. For knockdown for your program in this data update later this year, what do you want to see there in the healthy volunteers? You talked about how this de-risks the platform. What could next steps be after you do this update later this year? Yeah, the update later this year will be healthy volunteer data, primarily looking at safety, of course, then knockdown in the healthies. The Ionis knockdown data that's been shown was in patients, in Alzheimer's patients. They were seeing about 50% - 60% total tau knockdown in the CSF. We're in healthy volunteers. I think we should be able to reach something equivalent, 50%, 60%. That'd be the hurdle we'd like to get over. We are also enrolling patients in this study. Those cohorts just got started. I think we've got some of the first few patients in screening now. It probably won't have patient data until next year. The update this year will focus on healthy volunteers' safety and knockdown. Got it. Okay. That's helpful. You've got a unique dimer for APOC3 PCSK9 that you're going to report data on in third quarter of this year. What could initial success look like for this program, and how quickly could you move this into a pivotal? For the dimer, that's an exciting program for us. We're doing a phase I study that's in patients with mixed hyperlipidemia, so they have the condition that we'd be ultimately looking to treat. I think if we can get total ApoB reductions of, call it 40% in that range, that we'd feel competitive with just the other PCSK9 inhibitors that are out there. We should have inclisiran-like effects on PCSK9, and of course, we have the APOC3 component to hit the triglycerides. I'd expect some additive reduction in ApoB when you combine those two mechanisms, but I'd feel pretty good with 40% or better. In terms of where that program's headed, the current study is just a single and a multiple escalating dose trial in the mixed hyperlipidemia patients. We'll probably do some phase II work maybe as part of this study, just add a part three that would dose patients for a year or so. Beyond that, it's probably at some point will involve an outcome study in the mixed hyperlipidemia patients. Of course, we want to sort out long-term safety and figure out the right dose before we get to that outcome study, but we want to get there as fast as possible. Maybe we learn more about that next year. I think so, yep. Okay. We do plan to update later this year, Q3, as you mentioned, with the Dimer. Right. Okay. We're out of time. Maybe in closing up, if you want to just comment on any potential BD activities, key catalysts ahead, and then cash runway. No BD activities that we're planning, so we're not planning to out license anything or anything of that nature. Nothing to disclose. Catalysts, I think James touched upon all of them, SHASTA-3, SHASTA-4 readout. We'll get the data on the Dimer, some data on the MAPT and the CSF. Zodasiran, we're hoping to get full enrollment for that program later this year. The additional data on obesity, I don't know if, James, if you have anything to add to that as well. I think that covers it. Those are the main catalysts coming up. Got it. Thanks so much for joining us today. Thanks for having us.