All right, everyone, welcome back to our afternoon session of the first day of the Leerink Partners Global Healthcare Conference here in Miami. I'm Mani Foroohar, Senior Analyst at Leerink Partners, and I am very fortunate to be hosting Chris Anzalone from Arrowhead Pharmaceuticals, all the way from Lo s Angeles.
Thanks for having us. It's always great to be here and join this confe rence.
Yeah, the volume can surprise you sometimes.
It surprised me, but I think we're under control now.
No. Before we dive in, you guys have a broad pipeline, a lot of data this year. Let's do a quick review on when we're gonna see what over this year, 'cause it is dizzying in terms of when we're gonna see the next, obesity slash metabolic data from, ALK7, where we are on SHASTA-3, SHASTA-4.
Okay.
Separately, where we are on expansion of the pi peline beyond into other CTCA types, etc .
Okay. Okay, we have a lot to talk about.
Just set the table.
Okay. We have a number of things coming down this year. Most of which are in the third quarter. We expect our SHASTA-3 and 4, these are our phase III studies, of Plozasiran, in SHTG population. We expect those to read out in the third quarter. Last patient, last visit is in June, we'll top line in the third quarter. We also expect our first slug of data in our first dimer or bispecific. This is a single molecule, RNA molecule that is designed to reduce expression of both PCSK9 and APOC3 for the treatment of mixed hyperlipidemia. We are treating mixed hyperlipidemia patients in this phase 1/2 study. We'll have our first data in the third quarter.
To be honest, I really think that tells us whether or not we have a drug. We'll see LDL reductions, we'll see triglyceride reductions, etc . We'll have our 1st slug of data from ARO-MAPT. That's our 1st CNS target that we're addressing via our subQ platform. We'll have CSF tau data towards the end of the third quarter. That's an important value driver for us, not only to help to validate that target, but importantly to validate the whole platform. You know, if we see, you know, if we see well-tolerated, good knockdown of tau, it'll give us good confidence to go after a number of new targets as well in the CNS.
Then, sometime in the second half of the year, we will have updates for both ARO-ALK7 and ARO-INHBE. These are our first two, but not our last two obesity targets. We had the first little disclosure of data in January that was mostly inhibin E. We had a very small amount of ALK7. We're about two quarters behind with ALK7, and also that the MAD portion of that are two doses separated by three months rather than two doses separated by one month in inhibin E. Just takes us a bit longer to read that out. We'll have some more data from both those in the seco nd half of 2026.
That is a dizzying barrage.
That's just in 2026. You know, wait till you see 2027.
Let's start with how to interpret data. For ARO-ALK7, should we interpret this as its obesity assets, diabetes assets, combo, maintenance? I know we talked about this at JPMorgan.
Yep
...at the Analyst Day. Just how does your thinking evolve with this next data set? Which of those questions are we answering, and in what order?
Yeah, yeah. Look, we're just following the data on this. What we've seen so far with inhibin E, and let me just preface, it's very early and these are very small numbers and so, you know, we need to verify this as we build out these cohorts. What we've seen so far is a good redistribution of fat across all cohorts. That's interesting. Is that approvable in and of itself? I don't think so, at least not right now, but that's interesting, and potentially helpful. Second, we did see, you know, in the obese diabetic cohort, in combination with tirzepatide, we did see what appears to be interesting weight loss.
Let's see how that grows as we increase the size of that cohort and such, but at least early signals were interesting there. Also in that cohort, we saw really compelling, again, early, but really compelling liver fat reduction. In combination with tirzepatide, we saw, I think, a 76.7% reduction in liver fat after a short period of time. There may be a MASH play here as well in inhibin E. You know, 2026 will help to better define what populations we will be focusing on and what indications, frankly, we'll be focusing on in 2027 and beyond. With ALK7, we're even earlier. You know, we've seen what appears to be good knockdown, in fat biopsies.
there's not a circulating biomarker, at least that we know of, for ALK7, so the way we have to interrogate that is via or the way we have to assay that is via a biopsy. But it looks like we're getting good knockdown. The animal data were compelling. They were a bit more powerful in ALK7 versus INHBE in animal studies with the weight loss. We looked forward to see how that goes. Agai n, you know, 26 is gonna tell us a lot about how we wanna position that drug going forward.
You know, if we had this conversation a year ago, what I would've told you is that this is a bake off, and whichever looks better, Inhibin E or ALK7, we're gonna take into phase IIs. I'm not convinced that's the case right now. We are happy to bring both forward if, in fact, we can identify populations or indications that are unique to either.
Let's talk a little bit, a little deeper later stage pipeline. There's a lot of debate around the evolution of the FCS market, SHTG. We're gonna spend some time on SHTG. Let's start with FCS, where we are in terms of tempo of the launch, evolution of competitive position in terms of pricing, access, and we'll get to SHTG after this. Let's start with what we're actually approved right now.
Yeah. We've had a good rapid launch, a bit faster in fact than we expected in FCS. We've had good responses from payers, from physicians, from patients. We mentioned in our last conference call that we had received more than 100 prescriptions so far. We also have some switches from the Ionis drug, so far so good. That market, I think, is maybe a bit larger than people are thinking about. You know, what we studied was both genetic FCS, as well as clinically defined FCS.
Clinically defined, at least in our hands, FCS are patients with triglycerides above 880 and a history of either pancreatitis or abdominal pain. When you categorize that group in that sense, I think it, you know, this may be low tens of thousands of patients, and that's what we're kind of seeing out in the field right now as well.
Let's talk about how this evolves when we see SHASTA 3/4. Presumably we'll show a positive top line, meaningful triglyceride reduction, AP, etc . Talk to us about the transition to launching SHTG versus a competitor in the market at some price point, TBD. When does contracting conversations start? When do you start setting your price point? When do you start establishing contract position for that launch and that expanded indication, the supplemental filing?
Yeah. Well, I think we should have our top line readout in the third quarter of this year. We expect to file our sNDA in the fourth quarter of this year. You know, assuming that we are approved sometime in the fourth quarter of 2027, we'll start to have those discussions, you know, at that time. You know, we have talked rather obliquely, you know, with payers about SHTG, 'cause as you mentioned, we're only approved for FCS right now. We've started those discussions. We've started talking about, I think, the value of this drug in the broader population.
You know, we still think that the real core of this market, at least initially, are those high-risk individuals, you know, those people with triglycerides above 880, and those patients with triglycerides above 500 and history of pancreatitis. We think there's 750,000 to maybe 1 million of those, and we think that, you know, that is a population that needs this drug the most and can benefit most from this drug. You know, that's our core group, at least initially, and we expect to price to that core patient population.
I think one of the debates that is had is around exactly what the pancreatitis events, AP, reduction will be. Obviously hard and impossible to predict. Is that a little bit of a Wall Street debate? Like, does it matter if your number from a labeling commercial perspective, if your number is 83, 87, 85? Like, the, like, these are not really comparable patient populations necessarily. Like, how commercially relevant is that number despite the obsession of everyone who's listening to my voice right now about it?
Yeah. You know, I think in the United States it is... First, it's not necessary, you know, showing an improvement in AP is not necessary for regulatory approval. Simply lowering triglycerides, and we are grossly overpowered for that. We expect to see that. We are cautiously optimistic that we will see an improvement in AP risk in SHASTA-3 and SHASTA-4. We also have SHASTA-5 going, which is designed to show an improvement in AP. It's looking at a high-risk population. That's ongoing right now. That's an event-driven study. We'll see where that goes.
Look, if we see an improvement in AP risk in three and four, that's great, but I don't think that it's critical in the United States.
I think in Europe it's gonna be critical. We're gonna need to show that to have the right type of reimbursement. In the U.S., I don't think so. I hope we see it and, you know, I think we've got a good shot. You know, we have run the numbers and if we see, you know, the same. We have very similar baseline characteristics in our patients in SHASTA-3 and -4 compared to Ionis' core and core 2.
If we see the same drug effect and if we see the same event rate that they saw in their studies, ours are a bit smaller, we just need nine events to have an 80% power to show an improvement in AP and low teens to show a 90% power. It's not a huge number of events. Because of that we're cautiously optimistic. We mentioned in our last conference call that we are seeing events. We're hopeful that that's that that is gonna play out.
I think one of the debates that occurs is around the elevated hepatic fat fraction seen on, in Ionis' study, in their, in their pivotal study. We don't have your pivotal data yet, so we can't compare across trial, which has caveats regardless. There's a lot of debates about what is that? Is it on target? Is it off target? Is it something we should expect to see in SHASTA-3, SHASTA-4? Is it dose dependent? Talk about how you think about the logic of the possible causes for you guys to see or not see that same imaging finding. Separately, what does it mean?
I'll take that first. Well, I think that we are well-positioned here because if we do see an increase in liver fat, we're both in the same boat and we'll deal with that. I think most KOLs will trade an increase in liver fat, you're gonna watch it, but trade that for a decrease in AP risk. Having said that, I don't expect to see it. you know, we're dosing right now at 25 milligrams. We haven't seen it. We haven't seen it in the past.
I don't, you know, I don't wanna over-rotate on this possibility that it is a on-target effect, because, you know, you remember Ionis's old drug, vupanorsen, which was not approved in the United States because of thrombocytopenia, and showed better triglyceride reduction than Ionis's current drug, didn't show an increase in liver fat. They were knocking down APOC3. Also, Ionis had an ANGPTL3 program, partnered with Pfizer, and they saw an increase in liver fat. People asked us about that because we also have an ANGPTL3 program that we call Zodasiran right now, and not only do we not see an increase in liver fat, we see a decrease in liver fat.
There may be, you know, this may be molecule specific. In any event, we'll find out. We'll know this in the third quarter.
Let's talk about the commercial value of less frequent dosing. Like how meaningful from a patient perspective is every two months, every one month? Like how, and how different is the form factor going to be of your product versus their pen?
Yeah, it's a good question. For FCS, we are using prefilled syringes. For SHTG, we expect to use an auto-injector. In terms of convenience, I think the value of that is affected by the severity of the disease. You know, for those less symptomatic individuals, I think a once, you know, a 4 x a year administration at home is gonna be a, you know, a big benefit compared to 12 x at home, if, you know, as in a less severe population. In a more severe population, you know, like FCS, you know, that probably makes, you know, less of a difference. What we're hearing in the field is within FCS, people are switching because of two reasons.
We haven't heard anything about convenience, at least not yet, but we've heard about activity, and we've heard about safety. On the safety side, we know that Ionis has on their label thrombocytopenia, hypersensitivity, anti-drug antibodies, and we don't have any of those three, and I think physicians are taking a look at that. You know, those are all at least the hypersensitivity and the thrombocytopenia are low rates for that, but they're there, and I think people are taking a look at that. Also activity. You know, we had in our FCS phase III, we had 80% reduction from baseline. I think they had 30%-40% reduction from baseline.
You are right, it's difficult to compare cross-study, but, you know, these are the data. We didn't have any non-responders. I think they had 20% or so non-responders. I would expect that delta to decrease once we get into the broader population of SHTG where these TG levels are lower. At least in FCS, there has been a, you know, a relatively sizable delta in activity, and we've heard physicians talk about that as well.
Let's talk about how we think about the OUS opportunity for this for this indication. obviously, you talked about needing AP. There's not any AP in the U.S. for approval. Let's talk the commercial opportunity and how you think about your strategy to approach the OUS opportunity.
Yeah. Ex-U.S., as I mentioned, it is critical that we show an improvement in pancreatitis. Again, that's why we have SHASTA-5 as belt and suspenders. You know, this summer, once three and four read out, if we see an improvement in pancreatitis risk, then we'll ask ourselves, you know, is there added value in continuing with SHASTA-5? We'll see. We see big opportunity ex-U.S., you know, Europe and Japan certainly, for Plozasiran in SHTG and frankly in FCS. The opportunity is complicated though with Most-Favored-Nation right now. Again, if we were having this conversation a year ago, I'd say it would make sense for us to partner this ex-U.S., and just focus on U.S. markets.
With the uncertainty around Most-Favored-Nation, we feel like we need to have more control over pricing, ex-US. You know, we will do that ourselves. We are working. You know, we're trying to figure out if we do it ourselves entirely, or do we do it through a distributor or do we do some kind of hybrid approach? We've not settled on that yet. We are approved in Canada and in China. This is partnered with Sanofi in China. It's not yet approved in Europe. We're hopeful that it will be approved sometime in the next, you know, quarter or two in Europe.
I wanna talk a little about how you think about Most-Favored-Nation across your portfolio now you brought it up. Obviously, some of the assets in your hands are quite mass market, and others are quite orphan, with ALK7 TBD a little bit based on where you're gonna put them. As you think about the reality of Most-Favored-Nation, whatever that's gonna be, things can obviously change quickly in the current environment, does that change how you think about partnering assets and make you value retaining OUS control more than you would have previously?
Yes.
How do you think about... Is there a threshold for how large or how high priced, how orphan an indication has to be for that to matter? Or does it apply to mass market, orphan, everything?
The short answer is it probably applies to all, but I don't know. You know we really have to look at this on an indication by indication and drug by drug basis. At least right now, while there's a lot of uncertainty around Most-Favored-Nation, it feels like, at least right now that we either hold something, you know, entirely, or we license it entirely. This hybrid approach, which, you know, I've always liked the idea of is a bit problematic at this point.
I wanna talk a little bit about the value of these assets in a world where you license things entirely or sell them, partner, however.
'Cause obviously is demand, obviously RNAi is a markedly more de-risked approach than it was five, 10 years ago.
Sure.
Multiple products approved, blockbusters, TTR, etc , I think two ASHG assets, etc , the one that was an AASLD. To what extent do you see competitive risk from emerging companies in everywhere from Boston, San Diego, China, etc ?
Yeah.
Like to what extent do you see fast follower risk?
Yeah.
How do you position yourself to be less exposed?
Yeah. The answer to that is innovation. You know, we have spent a ton of time and resources starting back in probably, you know, before 2015, getting outside the liver. You know, we thought early on that the way to properly extract value from RNAi, is to, is to bring it to where disease is. Certainly there are, there are important diseases that we can address by getting into hepatocytes, but there's a ton of other ones. We can at this point, we can address seven different cell types, and we've got representatives of five of those in clinical studies as we speak. You know, we see that, as, the big growth opportunity for us going forward, and also dimers or bispecifics.
You know, right now we are the only ones who can do that. Right now we're the only ones who can bring RNAi to a variety of different tissues. There's no fast follower for that right now. There's a slow follower, you know. Look, we always thought that science is a great thing and people will catch up to what we're doing, but, you know, our thinking all along was to move very quickly in these new areas and get into well-validated targets. So fast or not so fast followers will have to ask themselves, "All right.
Do we wanna be, you know, five years behind a validated target or take more target risk and be more alone there? I think we're seeing that, you know, these smaller and newer companies, their pipelines look like Alnylam's and our liver pipeline. And that's okay, you know. I think the majority of the value that we're gonna be creating going forward outside of Plozasiran is gonna be outside the liver plus the use of dimers. And there's also, you know, there's something to be said about banging your head against the RNAi wall for almost 20 years now.
We've learned a heck of a lot over that time, and we've made hundreds and hundreds of thousands of RNAi molecules, and we've learned a lot about that. We've learned a lot about what makes, you know, some potent and some less potent. We've learned a lot about sequence. We've learned a lot about stabilization chemistries, etc . There's just no substitute for that time. You know, I don't care what sort of powerful AI engine some of these upstart companies have. If they don't have the data to feed into that engine, there's only so much they can do. We have an awful lot of data we can feed into, you know, to our rules and to our AI engines to help us to make the most potent RNAi molecules around.
We feel good about our position right now. I think there are two companies that have really driven RNAi innovation. That's Alnylam and us, and I think that these smaller companies are gonna take a while to catch up to what we've developed.
Let's talk a little bit about expanding into other tissue types, which has been a hotbed of debate for a lot of these companies. Obviously, the once upon a time assumption that, well, we're just gonna find a GalNAc for everything. About that, it turned out not to be so easy.
Yeah.
It's kind of like we're gonna find a PD-1 for everything.
Proved not to be. Biology's not that generous. Let's talk about what it takes to access new tissue types and on what tempo we should expect de-risking data, recognizing this is real pioneer science, so there's wide error bars.
Right. You know, there's not one thing, there's not one thing that you need to do well to get outside the liver. You know, we have a library of linker chemistries. That's important. You know, we do an awful lot of work in ligand-receptor pairs to find, you know, delivery ligands. You know, that takes an awful lot of time. We've done an awful lot of work on stabilization chemistries, and the like. That takes a lot of work. We've done an awful lot of work on optimizing various sequences that will be potent in vivo, and that's critical. You know, as you say, you know, the field talked about finding GalNAc in other tissues, but that just doesn't exist. GalNAc is really a unique thing, right?
It's a rapidly recycling receptor, and it's a good front door into these hepatocytes, and we haven't seen anything that is that efficient in any other cell type. That's okay. It's just a harder job. But it also means you've gotta squeeze all the potency you can out of these RNAi molecules 'cause you're gonna get a vanishingly small amount of that into these other cell types. We have had deep initiatives in all these areas for years now, and it's starting to pay off. As I mentioned, we can get into seven cell types. We've said publicly that we think we can get into a new cell type every 18 or 24 months. I think that will continue.
You know, we'll have, you know, you talk about de-risking. You know, RNAi is helpful in that, in that early data, if done right, can really tell you a lot about where this is gonna go, right? Because you know, once you validate your ability to deliver into a cell type, that cell type generally doesn't care what gene type you're knocking down, right? And so if you can get it in there and knock down a gene, you should be able to knock down other genes. I think that this summer we will, we'll see if we validate our CNS platform. Yeah, and just to remind you again, you know, we're getting in via simple subQ injection, this is not, you know, intrathecal injection.
This, you know, third quarter or so, we'll see how well we're knocking down tau in the CSF. If that's well-tolerated and we get good knockdown, we're off to the races, not just with ARO-MAPT, but with follow-on CNS targets. Same thing for the dimer. You know, our first dimer or bispecific, as I mentioned, is designed. It's one molecule designed to reduce expression of both PCSK9 and APOC3. That sounds simple, but it's not just, you know, sticking two RNAi molecules together. It's different chemistry. It has been complicated. It's taken us several years to get good at. Once we see good knockdown there, I think that we're off to the races there as well. You can imagine, and I mentioned Inhibin E, you know, showing, you know, good reduction in liver fat.
You know, what if we make a dimer with Inhibin E and some other, some other MASH target? That's an interesting idea. We mentioned ALK7 and you know, the non-clinical data were interesting in terms of weight loss as it was with Inhibin E. What if we have dimers with ALK7 and some other adipose target for weight loss? That's interesting. Pulmonary. You know, we haven't talked about pulmonary in quite some time. We've got, you know, a challenge study going on in Canada right now with ARO-RAGE to see if we can see a clinical benefit in that population. If we do, you know, we're happy to build out that franchise or partner it, but it also opens the door to dimers or bispecifics.
I wanna talk about dimers a little bit. We're coming down to just last few minutes. There are challenges to combining anything into a dimer dynamic because you're essentially producing the equivalent of a fixed-dose combination, as some of those characters. How do you decide when two constructs separately is better versus when there's a meaningful advantage to a single dimer? What are sort of the key elements of a patient population or indication where the dimer is better than two constructs developed separately where you have some more flexibility?
Right. Well, so two constructs separately is fine, you know, and let's assume you can, you know, the advantage of a single injection rather than two injections doesn't matter. You know, you still have the regulatory pathway of being regulated as a combination product, and that's expensive and complicated. It's much simpler with a single molecule, and we firmly expect that our dimer is gonna be regulated as a single entity. From a regulatory standpoint, it's advantageous. There may be some targets that are synergistic as well that knocking them down with a single molecule may be helpful.
Where not to use this, I think, is when you don't wanna get knockdown is when you don't wanna breach a certain level of knockdown. We frankly don't wanna stay out of those targets anyway, because I don't like having to dial in and out an RNAi. In the case of a dimer, it becomes even more complicated to really highly tune that so you're, for instance, you're no higher than 80% knockdown. That's harder to do. We look at APOC3 and PCSK9, and we think that's a great test case because from our perspective, you know, the more knockdown in each of those, the better. Let's see if we can max that out. I'll give you an example.
The APOC3 sequence is very potent. We had to kinda tune that down a little bit when we were designing the dimer, just so that didn't hog up all the, you know, all the knockdown. If you do see that, you know, not equal knockdown, you can potentially overcome that by brute force and just dose up. We saw that as a possibility with APOC3. We tried to dial that down a little bit.
Great. Well, we're gonna be looking forward to seeing that data as we think about the value of the dimer and how it's gonna expand. We're down to less than a minute. Thank you for this time. I do fully expect we're gonna be talking about all these targets all throughout this year. It's gonna be a eventful year for you guys.
Thanks so much.
A pleasure to have you.
Tha nk you.