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.
Thanks, a pleasure to be here.
And maybe for those who are new to this story, if you guys can provide a one-minute intro to your programs at Arrowhead.
Yeah, sure. Happy to take that. And just for folks new to the story, high level, I think most people know we're an sRNA therapeutics company. 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 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 Olpacaran, which is partnered with Amgen, Fizir 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 holy-owned 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 Odaciran for homozygous familial hypercholesterolemia. Some of the earlier holy-owned programs include Aero-ALC7 and Aero-Inhibony, both for obesity. maybe there's a mash indication there also and then a little earlier is arrow map T which targets the map T 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 great yeah it's a good
overview of the company and a lot of interest in plozasterin in 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 yes so so far so good
everything's on track there should have the 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 of guidance i think it's just it's 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 to narrow that down to a specific month so everything's on track now i think and we're planning on on q3 for uh for data got it okay and there's also a lot of interest in ap uh the acute
pancreatitis, and I think people want to know if you can achieve stat sig on the AP endpoint. The trial is blinded, 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 minimum threshold of having greater than or equal to nine total events needed? Yep, yeah, what we've said all
All along 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 core two studies show, we should have around 80 percent power and of course anything, any more events than that just increases our power. So we feel pretty good, but, you know, we're still blinded, so we'll see in Q3 where things land.
And I guess can you say if the events are tracking any more specifics around that?
Yeah, I think we can't give any more specific guidance other than, you know,
we haven't seen anything sort of wildly out of our range of expectations. And are you contemplating any stats plans, changes to potentially include crossover data and AP analysis if needed?
No plans 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, you know, no change in that regard. So, yeah, I don't anticipate any changes going forward.
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 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 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 etc 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 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 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, that's not one of them.
Got it. Okay. And IONIS, their Olazarsin 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 mean, 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 mean, I thought the core and core two data looked really good and really convincing, particularly the AP data.
Yeah. yeah okay and um uh on safety you've highlighted uh you 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 plizasterin's rnai modality versus ionis's aso and are you collecting liver fat uh data and shots to three and four 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 olizarcin same with 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 2 phase 2 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 two to four percent 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 Vupenorsin, 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 that we don't see an increase in liver fat that being said if we did 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
got it yeah that makes sense yeah what do you hear from your doctors on the liver fat increase and and just whether they're concerned about that.
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.
And when you report your SHTG data, will you have some sort of an update on liver fat as well? Yes, we should. 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?
Yeah, so I'll take that. So it's true. We are, you know, if you look at the first full commercial quarter sales, we are trending better. that's when you normalize for price and look at that sort of a unit basis but I wouldn't over index on that these are you know ultra rare indication small numbers but it is true and you know 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 uptick uptick in demand perhaps with a little bit of an acceleration in the last uh last month or so got it okay um and so you're not providing
more specifics on like patient numbers at this point uh nope yeah okay and uh and what are your expectations and how patients naive to the apoc3 class and patients switching from tringles uh will evolve this year what type of feedback are you getting from prescribers and how will they choose between Redumplo and Tringosa?
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, Tringosa's a good product, obviously, and so, but they did have a subset of non-responders, around 20% of their balance trial, and then there are always gonna be people that don't tolerate it well, or have some sort of frustration. So 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. So more potent, convenient dosing with the three-month schedule versus every single month. And importantly, sort of no warnings, no precautions or no contraindications. So we'll let that sort of 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 the feedback's been very positive, I think, you know, Tringosa came out at $600,000, we came out at $60,000, they very much welcomed that. When Tringosa went down to $40,000, I think us moving down to $45,000 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 they had in terms that the pairs had in terms of how how do we have to react to to get them to view it as cost comparable our research indicates if we're within 15 or 20 percent we're viewed 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 has it Sorry, has it meaningfully accelerated formulary decision-making? I would say it's been, certainly it's 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 in things like diagnostic scoring tools and whatnot. So very happy with those discussions and they're proceeding very well.
Got it. 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 half of this year across your inhibiting and L7 cohorts for both monotherapy and the glute combo cohorts yeah I can take that
one so at easel we focused on inhibiting and that presentation was really more focused on the liver fat as a monotherapy with arrow inhibiting we're 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 aeroinhibony 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 ELK7, and we'll have more data by end of the year with regards to changes in body composition.
That's all full. And 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? And can you talk about just new dosing regimens, maintenance schedules, or GLP-1 dose combinations that are being explored beyond the initial terzepatide combo data?
Yeah, so both of those studies 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 in Hiboney plus five milligrams of terzepatide. Those both go for a full year. So we should get 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 a high dose. And then we added a high-dose terzepatide cohort. So we'll do 400 milligrams aero-inhibony with 15 milligrams of terzepatide. And we'll see how many patients can get up to 15 milligrams, but the idea is to see if we still see an additive effect in the diabetics with a higher dose of trisepatide using the combination regimen.
For any of these cohorts, do you have options to do maintenance assessment where you basically stop the CLIP1?
We could. It's not built in right now, 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 the glip, remove the glip.
Right. Okay. And, yeah, I guess when would you make that decision? Could that be something that happens this year? Probably next year.
I mean, like I said, we're going to follow those for a year. And so probably mid to late 27.
and so there's a lot of 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 greater than 25 for combo is that those correct or yeah i mean
for monotherapy, we're still just following the guidelines of a 5% change, 5% decline in overall body weight over a 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 GOP-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. But I think those are all still things we have to sort out 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 GOP-1 combination therapies that kind of need to sort out 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 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 glip ones yeah potentially i mean i think we're still of the mind that we're likely going to combine and not compete with glip ones 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 percent 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 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 um 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% or 0.25% reduction, that'd be helpful. But I don't
think it's required to get 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 sufficient? Yeah, on the latter question,
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 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 you add with 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, 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 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 seeing the knockdown there with the sub-Q injection, does that help de-risk these potential obesity targets?
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 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 the IND or the CTA and I think you know the world will learn what the targets are and sorry what was your the
second part of the question for the MAPT data later this year with the sub Q injection to get a cns target does that help de-risk the obesity uh yeah i don't i don't know
that it helps um d the map t program it's so that's a different platform the uh arrow map t uses a transfer and targeted fab whereas the the obesity platform uses a small molecule lipid that targets the adipocyte i do think the the map t platform will be significantly de-risk 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
CNS platform. Okay. Okay. And then, 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 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. 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?
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.
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 this how this de-risked the platform I guess what could next steps be after you did this update later this year
yeah the update later this year will be healthy volunteer data primarily looking at safety of course and then knockdown in the healthies the the ionis knockdown data that's been shown was in patients in Alzheimer's patients and they were seeing about 50 to 60 percent total tau knockdown in the CSF. We're in healthy volunteers, but I think we should be able to reach something equivalent, 50, 60 percent. That'd be the hurdle we'd like to get over. We are also enrolling patients in this study that 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 got it okay
that's helpful and um you've got a unique dimer for apoc3 pcsk9 they're going to report data on third quarter of this year um what could initial success look like for this program and how quickly
could you move this into a pivotal yeah for the dimer i mean that 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 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 will involve an outcome study in the mixed hyperlipidemia patients. And of course, we want to sort out long-term safety and figure out right dose before we get to that outcome study but we want to get there as fast as possible
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 cash
runway. Yeah, no BD activities that we're planning, so we're not planning to out-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, if you have anything to add to that as well.
I think that covers it.
Yeah, those are the main catalysts coming up.
Got it. Thanks so much for joining us today. Thanks for having us. Thank you.