Conference Transcript - ARWR 2026-06-03

Maury Raycroft, Analyst — Jefferies

My name is Maury Raycroft, and I'm one of the biotech analysts at Jeffrey's. I'm happy to introduce and welcome James Hamilton, the CMO, and Dan Appal, CFO of Arrowhead Pharmaceuticals. This is a fireside chat. Thanks so much for joining us today.

James Hamilton, Analyst — CMO

Thanks, a pleasure to be here.

Maury Raycroft, Analyst — Jefferies

And maybe for those who are new to this story, if you guys can provide a one-minute intro to your programs at Arrowhead.

James Hamilton, Analyst — CMO

Yeah, sure. Happy to take that. Just for folks new to the story, high level, I think most people know we're an sRNA therapeutics We don't do anything else, just sRNA drugs, no gene therapy or gene editing, at least not yet. And 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 of 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 Opasran, which is partnered with Amgen, Fazer Saran, 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 Holione side, we have Redemplo, which was recently approved for familial chalmicronemia syndrome and is in phase three for severe hypertriglyceridemia. And then coming up just behind that, also in phase three, is Odaceran for homozygous familial hypercholesterolemia. Some of the earlier wholly owned programs include AeroAlk7 and AeroInhibony, both for obesity, maybe there's a MASH indication there also. And then a little earlier is AeroMapT, which targets the MAPT gene, that's the gene that codes for tau protein that's involved in Alzheimer's disease and other tauopathies. So that's kind of our, you know, 30,000-foot view of the company.

Maury Raycroft, Analyst — Jefferies

Great. Yeah, it's a good overview of the company. And a lot of interest in plozasterin and the SHT studies with pivotal data coming up. Maybe just clarifying, when do you expect the last patient, last visit to be completed, and then should we expect the top line in July or potentially later in third quarter?

James Hamilton, Analyst — CMO

Yeah, so so far so good. Everything's on track there. 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 gonna stick with that in terms of guidance. I think it's just, you know, 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. So everything's on track now, I think, and we're planning on on q3 for for data got it okay and there's also a lot of interest in ap

Maury Raycroft, Analyst — Jefferies

the acute pancreatitis and i think people are want to know if you can achieve stat sig on the apm point the trial is blinded uh but can you share your internal monitoring what that tells you about total ap events accrued across both arms and are you confident you've crossed that that minimum threshold of having greater than or equal to nine total events needed?

James Hamilton, Analyst — CMO

Yep, yeah, what we've said all along is, and we remain optimistic, cautiously optimistic about our ability to hit on AP. We think that if we have at least nine or so events, that with an event rate similar to what the core and core two studies show, we should have around 80% power, and of course, any more events than that just increases our power so we feel pretty good and but you know we're still blinded so we'll see in Q3 where things land got it and I guess can you say if

Maury Raycroft, Analyst — Jefferies

the events are tracking any more specifics around that yeah I think we

James Hamilton, Analyst — CMO

can't give any more specific guidance other than you know we haven't seen

Maury Raycroft, Analyst — Jefferies

anything sort of wildly out of our range of expectations got it and are you Are you contemplating any stats plans, changes to potentially include crossover data and AP analysis if needed?

James Hamilton, Analyst — CMO

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. So, yeah, I don't anticipate any changes going forward.

Maury Raycroft, Analyst — Jefferies

got it and um for the 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

James Hamilton, Analyst — CMO

faster no i think they're generally as expected again i haven't seen um we haven't seen anything wildly outside of our expectations based on what others have presented in terms of event rate so

Maury Raycroft, Analyst — Jefferies

Yeah, okay. And 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?

James Hamilton, Analyst — CMO

Yeah, in terms of expectation for the placebo group, you know, 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. But, you know, 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. So, you know, 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. So, you know, I feel pretty confident about 860. As far as things that we worry about,

Maury Raycroft, Analyst — Jefferies

that's not one of them. Got it. Okay. And IONIS, their Olazarsen, 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?

James Hamilton, Analyst — CMO

Yeah, I don't know. I mean, I think they'll get approved. 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 mean, I thought the core and core two data looked really good and really convincing, particularly the AP data.

Maury Raycroft, Analyst — Jefferies

Yeah, yeah, okay. And 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 Plisacerin's RNAi modality versus Ionis' ASO? And are you collecting liver fat data in shots to three and four?

James Hamilton, Analyst — CMO

So 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 olezarsin. Same with the hypersensitivity, more of an ASO class effect. We're not seeing much of that at all with the S-RNAs. This question around liver fat, I think we'll have to wait and see. You know, we did not see that, the increase in liver fat in our Shasta II 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. And, you know, contrast that to what Iona saw, which was about a 2% to 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 Vupinorsin, which targeted ANG-PTL3. That molecule demonstrated a dose-dependent increase in ALTs and liver fat. So we'll see. I mean, I think, you know, we're hopeful that we don't see an increase in liver fat. That being said, if we did see something consistent with what Iona saw, I think we're both in the same boat. And I'm also not sure how clinically significant that increase in liver fat really is.

Maury Raycroft, Analyst — Jefferies

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?

James Hamilton, Analyst — CMO

Yeah, what we hear when we talk to KOLs is exactly that, 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 is – they'd be fine taking that tradeoff if it could keep their pancreatitis patients out of the hospital.

Maury Raycroft, Analyst — Jefferies

And when you report your SHTG data, will you have some sort of an update on liver fat as well? Yes, we should. Okay. And for Redempla 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?

Christopher Anzalone, CEO

Yeah, so I'll take that. So it's true, we are, you know, 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 sort of a unit basis. But I wouldn't over-index on that. These are, you know, ultra-rare indications, small numbers. But it is true, and part of that is the commercial and engaged commercial team we have. In terms of the demand, I mean, we saw a little bit of a pent-up demand from, you know, call it the eap switch and some switches from tringosa but most of it is new to class and you know we're seeing sort of a linear uh linear progression there in terms of a pick uptick in demand perhaps with a little bit of an acceleration in the last uh last month or so got it okay um

Maury Raycroft, Analyst — Jefferies

and so you're not providing more specifics on like patient numbers at this point uh no Okay. And what are your expectations on how patients naive to the APOC3 class and patients switching from Tringolza will evolve this year? What type of feedback are you getting from prescribers, and how will they choose between Rodumplo and Tringolza?

Christopher Anzalone, CEO

Yeah. So I think we mentioned the linear, kind of linear growth that we're having. I think our expectation is that it largely continues. Mostly naive. We'll get some contribution from switchers. And, you know, Trugosa is a good product, obviously, and so, but they did have a, you know, a subset of non-responders, around 20% of their balanced trial. And then there are always going to be people that don't tolerate it well or have some sort of frustration. So we will continue to see switches, but mostly, you know, naive, naive to class is what we're expecting. In terms of prescriber choice you know physicians will have their choices some will try both molecules we've obviously stated we we think we have the superior molecule and you know 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 so more potent convenient dosing with the three three-month schedule versus every every single month and importantly sort of no warnings, no precautions, or no contraindications. So we'll let that sort of

Maury Raycroft, Analyst — Jefferies

speak for itself there. Got it. Okay, that's helpful. And 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? Is that meaningfully accelerated formulary decision-making, and could there be any more adjustments on pricing? Yeah, no. So

Christopher Anzalone, CEO

So the feedback has been very positive. I think Tringosa came out at 600,000, we came out at 60,000. They very much welcomed that. When Tringosa 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. But it removes any kind of uncertainty that the pairs 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 or 20 percent reviewed as cost comparable from the pair pair standpoint so that's what we we move to you know maintaining that sort of premium price but being within the 15 to 20 percent and as it mean sorry has immediately accelerated formulary decision-making I would say it's been certainly has helped again by removing that uncertainty we're very much on track with the pair discussions. You know, they've been very open to, we're obviously approved for genetic and clinical, they've been very open to discussions of, you know, putting in policies that are aligned to our label as opposed to putting things like diagnostic scoring tools and whatnot. So very happy with those discussions and the proceeding very well. Got it. Okay. And

Maury Raycroft, Analyst — Jefferies

And for your obesity program, so let's shift gears to that. You had an update at EASL recently. Maybe just go through the key takes on the experience so far, and what data should we expect second and a half of this year across your inhibiting and L7 cohorts for both monotherapy and the glyph combo cohorts?

James Hamilton, Analyst — CMO

Yeah, I can take that one. So at EASL, we focused on inhibiting, and that presentation was really more focused on the liver fat. But as a monotherapy with aero-inhibony, we're seeing about a 40% reduction in liver fat from baseline in patients with hepatic steatosis at baseline. So we do see a monotherapy pathway there for aero-inhibony as a MASH drug. We're also still looking at aero-inhibony 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. ALK7 is probably what we'll focus on mostly in the second half of the year. We may have some updates on Aero and Hiboney as well, but we're due for ALK7, primarily focusing on body composition changes, weight loss changes, combination and monotherapy so stay tuned there I think so far we've only talked about some of the visceral fat reductions and knockdown with elk 7 and we'll get we'll have more data by end of the year with regards to changes in

Maury Raycroft, Analyst — Jefferies

body composition got it that's all full and for my understanding the last time you commented on the number of patients in this study it was January you said there's about 192 patients. How many additional patients have been dosed since then? And can you talk about just new dosing regimens, maintenance schedules, or GLP-1 dose combinations that are being explored beyond the initial presuppetide combo data? Yep. Yeah. So both of those studies

James Hamilton, Analyst — CMO

are fully enrolled now, both Aero-ALC7 and Aero-Inhibony. And so that puts us at, I think, right around 240 total patients, and that's an aggregate of monotherapy in combination with terzepatide. And then we did add some cohorts to the Aero and Hiboney study. Let's see, we added four cohorts. We increased the size of the cohort that was looking at 400 milligrams in Hiboney plus five milligrams of terzepatide. We also wanted to look at a higher dose, 600 milligrams inhibony plus five milligrams of terzepatide those both go for a full year so we should get you know more longitudinal data out of those new cohorts we added a 600 milligram monotherapy cohort in type 2 diabetics which is one kind of gap we felt like we had that there was no type 2 diabetic monotherapy cohort so we'll get a good look at those patients at at a high dose and then we added a high dose terzepatide cohort so we'll do 400 milligrams aero inhibiny with 15 milligrams of terzepatide and we'll see how many patients can can get up to 15 milligrams but the idea is to see if we still see a an additive effect in the diabetics with a higher dose of terzepatide using the combination regimen for any of these cohorts you have options to do

Maury Raycroft, Analyst — Jefferies

maintenance assessment where you basically stop the clip one we could it's not built in right now

James Hamilton, Analyst — CMO

but that would be an easy amendment to make and they would have been on drug for a long time so i think you know that'd be an interesting opportunity to see what happens when you take

Maury Raycroft, Analyst — Jefferies

the the glip remove the glip yeah yeah right um okay and yeah i guess when would you make that decision could that some be something that happens this year probably next year i mean like i said

James Hamilton, Analyst — CMO

we're going to follow those for a year and so yet probably mid to late 27 and so there's a lot of

Maury Raycroft, Analyst — Jefferies

focus on these programs or uh 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 for right benchmark for monotherapy being greater than 25 percent for combo is that those correct or yeah i mean for monotherapy we're

James Hamilton, Analyst — CMO

still just following the uh the guidelines of a five percent change five percent decline in overall body weight over a year it's not clear what the the hurdle to get over is for combination therapy we've been hearing an additional five percent on top of gop1 therapy at one year or less weight loss if there's some additional clinical benefit like an improvement in a1c or something like that but i think those are all still things we have to sort out with uh with fda and i don't think we're alone there it sounds like there's a lot of other companies that are wanting to do gop1 combination therapies that kind of need to sort out what uh what's the what's the hurdle to get over what additional weight loss needs to be seen so i think it's something the whole field will

Maury Raycroft, Analyst — Jefferies

have to sort out in the coming years for the update second half of this year um what could you show on body composition and visceral fat reduction and lean mass gain or preservation that and do you think that could differentiate versus uh versus clip ones yeah potentially i

James Hamilton, Analyst — CMO

mean i think we're still of the mind that we're likely going to combine and not compete with GLP-1, so 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 mean, 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 that will we feel confident with that that level of visceral fat reduction and then on the lean fat preservation or the lean mass preservation you know any lean mass preservation i think on top of the uh the glip ones would would be a welcome improvement is there a certain threshold for a1c that you'd want to see your studies? Well, I don't think, 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. You know, if you could see a 0.2 percent or 0.25 percent reduction, that'd be helpful, but I don't think it's required to get

Maury Raycroft, Analyst — Jefferies

approval. Got it. Okay, and you said that you plan to meet with FDA mid-year. What are the potential outcomes and scenarios for phase 2b studies planned and do you envision any type of streamlined regulatory path to approval given fda's recent guidance for a single pivotal being

James Hamilton, Analyst — CMO

sufficient yeah on the the latter question i'd probably not i mean 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 and getting feedback from FDA right now specific to inhibiting and so that will help guide what what the phase two plans look like we still plan to have a phase two study submitted and up and running by by end of this

Maury Raycroft, Analyst — Jefferies

year got it okay and you've 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

James Hamilton, Analyst — CMO

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, and a handful of those have made it into the preclinical development pathway. So, you know, we're doing GOP talks 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

Maury Raycroft, Analyst — Jefferies

filed to start phase one by end of this year. Got it. And anything more on those targets that you're saying? And for the MAP-T data, which I'm going to talk about that next, but we'll seeing the knockdown there with the sub-Q injection, does that help de-risk these potential obesity targets?

James Hamilton, Analyst — CMO

Yeah, well, on the new targets, I think, you know, we're holding it a little closer to the vest on disclosing targets. I think, you know, when we mention a target the next day, there's like five other companies that have been working on the same target. So we're not talking about preclinical targets or, you know, sharing data on those programs as much as we used to. So when we submit the IND or the CTA, I think the world will learn what the targets are. And, sorry, what was the second part of the question?

Maury Raycroft, Analyst — Jefferies

For the MAP-T data later this year with the sub-Q injection to get a CNS target, does that help de-risk the obesity program?

James Hamilton, Analyst — CMO

Yeah, I don't know that it helps de-risk the MAP-T program. So that's a different platform. The AeroMAP-T uses a transferrin-targeted FAB, whereas the obesity platform uses a small molecule lipid that targets the adipocyte. I do think the MAP-T platform will be significantly de-risked depending on what the data show. I mean, regardless of how important tau is for Alzheimer's disease, I think if we can show good knockdown with that sub-q administered platform, that is huge for the platform, right? Because 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 sub-q route. that would be huge for us because as you might imagine we have lots of other preclinical programs that we're working on now that rely on that platform so yeah I do think it'll be de-risking for the the CNS platform okay okay and then

Maury Raycroft, Analyst — Jefferies

yeah maybe before we dive into map T just one more question for obesity for inhibiting would you guys keep that in house you're showing some great data there with the liver fat reduction you've out-licensed another mash program. Could it make sense to out-license

James Hamilton, Analyst — CMO

inhibiting as well? Yeah, I think for the time being, the plan is at least through phase two to keep that wholly owned. Got it. Okay.

Maury Raycroft, Analyst — Jefferies

And for MAP-T for CNS, so we had the Biogen phase two data that technically failed, but there were sufficient positive cognitive trends on multiple measures to advance the asset into a phase three study. What was your impression on the data? and did those data reinforce or change your views on what's needed targeting tau production with a RNA approach, RNAi approach?

James Hamilton, Analyst — CMO

I thought generally that it was supportive of the tau hypothesis. It didn't negate the concept that knocking down MAP-T to reduce tau levels could be a therapeutic route for Alzheimer's or for other tauopathies. I mean, 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're moving into phase three, and so Biogen presumably has seen all the data, and they're willing to make that investment in a large phase three program based on what they've seen. So I think that's generally supportive for all of the other programs targeting tau, including ours.

Maury Raycroft, Analyst — Jefferies

Got it. And for knockdown for your program in this data update later this year, what do you want to see there in the healthy volunteers? And you talked about how this de-risked the platform. I guess what could next steps be after you did this update later this year?

James Hamilton, Analyst — CMO

Yeah, the update later this year will be healthy volunteer data, primarily looking at safety, of course, and then knockdown in the healthies. The IONIS knockdown data that's been shown was in patients, in Alzheimer's patients, and they were seeing about 50% to 60% total tau knockdown in the CSF. We're in healthy volunteers, but I think we should be able to reach something equivalent, 50%, 60%. That would 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. But, yeah, the update this year will focus on healthy volunteers, safety, and knockdown.

Maury Raycroft, Analyst — Jefferies

Got it. That's helpful. And you've got a unique dimer for APOC3, PCSK9. They are going to report data on in the third quarter of this year. What could initial success look like for this program, and how quickly could you move this into a pivotal?

James Hamilton, Analyst — CMO

Yeah, for the dimer, I mean, that's an exciting program for us. We're doing a phase one 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 percent in that range, that we'd feel competitive with just the other PCSK9 inhibitors that are out there. we should have, you know, incliceran-like effects on PCSK9, and, of course, we have the APOC3 component to hit the triglycerides. So I'd expect some additive reduction in APOB when you combine those two mechanisms, but I'd feel pretty good with 40% or better. And then in terms of where that program's headed, you know, the current study is just a single and a multiple escalating dose trial in the mixed hyperlipidemia patients. We'll probably do some phase two work maybe as part of this study, just add a part three that would, you know, dose patients for a year or so. But beyond that, it's probably, at some point, we'll involve an outcome study in the mixed hyperlipidemia patients. And 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.

Maury Raycroft, Analyst — Jefferies

okay so maybe we learn more about that next year i think so yeah okay we do plan to update later this year q3 as you mentioned with the dimer right okay so we're out of time but maybe in closing up um if you want to just comment on any potential bd activities uh key catalysts ahead and then

Christopher Anzalone, CEO

cash runway yeah uh no no uh no bd uh activities that we're planning so we're not you know planning I'll license anything or anything of that nature. Nothing to disclose. Catalyst, I think James touched upon all of them, so Shasta 3-4 readout. We'll get the data on the DIMER, some data on the MAP-T and the CSF. Sodasterin, we're hoping to get full enrollment for that program later this year. And the additional data on obesity. I don't know if James has anything to add to that as well.

Maury Raycroft, Analyst — Jefferies

I think that covers it.

Christopher Anzalone, CEO

Yeah, those are the main catalysts coming up.

Maury Raycroft, Analyst — Jefferies

Got it. Thanks so much for joining us today. Thanks for speaking. Thanks for having us.