All right, everybody. We're gonna get going here with our next company presenter at the BofA Annual Healthcare Conference. My name is Jason Gerberry. I cover pharma and biotech here, and I am joined by CEO Chris Anzalone of Arrowhead Pharmaceuticals. Christopher, thanks for joining us.
Thank you. It's great to be here.
Arrowhead's at a pretty interesting pivot point as a company. Historically, a lot of earlier stage R&D efforts establishing siRNA therapies for different tissue types and figuring out where your kinda next shot on goal would be. Now you're at a point where you're pivoting to commercial, but you still have a lot going on in the pipeline. Maybe we can just start there as, you know, how you're managing that transition as a company to now becoming a commercial organization and how that alters your focus as a CEO.
Sure. We're an "and" company, we're not an "or" company. Commercial is critical, obviously. You know, this is why we're all here. R&D is great, but unless you can bring these medicines to patients, then there's no point in that, right? It's been a big transition for us, you know, to build, to start to build out this commercial force. It's been successful so far. You know, in our core, we are an R&D company, and we needed to make sure that that drive, you know, didn't slow down, and it has not. In fact, it's even sped up. You know, we are now able to address, I think, seven different cell types. Five of those are in clinical studies as we speak.
You know, we are now on the cusp of blowing out our dimer or bispecific approach. You know, we've got an increasingly validated platform there, you know, there's a ton of good opportunities there to knock down multiple genes with the same single molecule. We'll have our first data coming out of the dimer platform later this year, I guess in the third quarter. That's our PCSK9 APOC3 dimer. We think we can address the 20 million or so, you know, person population in the U.S. that's mixed hyperlipidemia. Of course, our CNS platform now will have our first data to come out at the end of Q3, early Q4.
This is still an important part of our, of our growth, of course, and, an important part of the culture of this company, and we continue to be, I think, at the forefront of RNAi innovation.
Okay. Let's maybe start with REDEMPLO. Given, you know, you recently had your quarterly earnings call, that was a focus of the discussion as you know, That's your commercial intro, and then we can get into pipeline. You've launched REDEMPLO now for FCS, and you've got pivotal data in 3Q for the larger commercial market that will drive future revenue for REDEMPLO, which is severe hypertriglyceridemia. Maybe talk about the early FCS launch, what you've learned from that, how you'll be able to carry forward those learnings into the eventual launch into sHTG.
Sure. The launch has gone well so far. As we mentioned on our conference call last week, we've had more than 400 scripts, and that's, you know, just one full quarter of sales. Adoption has been a bit more rapid than we expected even. You know, this is an education market. Even FCS is an education market. Of course, the genetic FCS population, you know, many of those folks are diagnosed. That's, we think, you know, quite a small portion of the overall FCS population. As you'll recall, in our phase III study, we studied, you know, both clinical FCS as well as genetic FCS.
The clinical FCS are those patients that don't have the known genetic mutations associated with traditional FCS, but still have very high triglycerides, a substantially increased risk of pancreatitis. We, again, we view that as the, as the lion's share of that market. Many of those folks will be undiagnosed or misdiagnosed. It's incumbent on us to educate the community that those folks need to be treated and we've been pleased with our progress in finding those patients and helping those patients. Frankly, that bleeds into sHTG a little bit.
A lot of that, you know, a portion of the high-risk sHTG population, we think can be and frankly should be diagnosed as FCS. These are clinical FCS patients. You know, it is, I think we will be getting into what is the traditional sHTG market right now, because we think those folks have been misdiagnosed as having severe hypertriglyceridemia when, where they should be diagnosed with having FCS.
Okay. with FCS, my sense was, some of it was patient identification, and the other part was, as you alluded to, maybe educating the doctor. As we think about sHTG and the challenges, my sense is it's less about patient identification and perhaps more educating the healthcare provider on the importance of treating and preventing acute pancreatitis. Do I have that distinction correct?
I think that's right, although those are related, of course. You know, it is I think there's tons of patients walking around who should be treated, who should get their TGs in under control, and they have no idea that they're at risk, and frankly, their physicians may have no idea that they need to get them under control. You know, the sharp end of the spear there is, are those physicians. You know, this is a brand new market. You know, folks aren't used to thinking about triglycerides as bad actors. This is a bad analogy because it's ASCVD, but think of this almost as monitoring LDL decades ago before there were statins.
You know, people didn't know that they should be looking at their LDL, then statins came around and lo and behold, this is something that we should all be thinking about. We think that elevated triglycerides, you know, are similar in that they have, you know, people have not monitored their TGs. Even physicians haven't really monitored TGs. At least for the severe population above 500, they should be looking at that, and we think they should all get under control. This is a multi-step process, right? The first step I think has been to help the community understand the severity of FCS and get those patients treated, both genetic FCS and clinical FCS. The next step is sHTG more broadly.
These are the high-risk FCS patients. I'm sorry, high-risk sHTG patients. These are folks with triglycerides above 880, you know, with or without a history of pancreatitis. We think there's 750,000 or maybe 1 million of those folks in the United States There's increasing data, you know, from our competitor as well as from our own studies that those folks are at high risk of pancreatitis. We need to help the community understand that we absolutely need to get their TGs under control. I think the next step then is the less severe sHTG population. You know, these people with triglycerides at 700 mg or 600 mg per dL.
You know, we are really looking forward to seeing what our pancreatitis data look like in SHASTA-3 and SHASTA-4. Our competitor, you know, showed very good data, very promising data, and most of those acute pancreatitis events were in the very high-risk population. We're looking forward to seeing, you know, whether or not, you know, you see events in those, in those less traditional, you know, severe population. If that's the case, then that is the third step in this market where physicians start to understand, you know what? It's not just the high-risk folks who need to get under control. It's anybody who has trigs above 500 that we need to get under control.
Okay. As you mentioned, this is a two-player market in APOC3 modulating drugs with Ionis' TRYNGOLZA. It, you know, as we look ahead to the SHASTA-3 and SHASTA-4 study readouts, based on some of the phase II work that you've done, FCS work, what do you think, A, in terms of potential clinical differentiation for REDEMPLO in sHTG, and does it ultimately matter, or is this a big category, two players are gonna grow it, and two players can kinda enough to feed?
Yeah, look, this is a big category. There's a lot of patients that need treatment, and there's a lot of education to be had, and I just think that this is better served, frankly, by two players than one player. Ionis has a good drug, and that's helpful. I think that we will grow this market much more rapidly and much more completely with two of us rather than one of us. Again, there's plenty of room for both of us to be successful there. Now, with regard to what we're gonna see, who knows? You know, this will read out in the third quarter. Last patient, last visit, in SHASTA-3 and SHASTA-4 is towards the end of June.
Once we lock the database and analyze data and such, we can at least top-line this. We expect a good safety profile. We have seen that now in many patients. We expect that to continue. We, you know, we don't see hypersensitivity. We don't see thrombocytopenia. The question here is, I guess, you know, do we see an increase in liver fat? We don't expect to see that, but our competitor has seen that, we'll see if, you know, if that is another differentiator for us. I just don't know at this point.
Yep.
With triglycerides, you know, that is the approval endpoint, you know, lowering triglycerides. We've seen that in spades. You know, this essentially works in 100% of people. We had no non-responders in our FCS phase III study. Our competitor had about 20% non-responders. We expect that to continue. You know, this is not one of those, you know, I don't think, you know, scary binary phase III readouts where a drug is either worth a lot or worth zero, depending upon what the data show. You know, the drug appears to work well and consistently, and so I think it's going to, it's gonna work, and we'll see very good My expectation is we'll see very good reductions of triglycerides. Now, will we see an improvement in pancreatitis? We will see.
You know, we were really pleased to see that Ionis showed that. You know, those data were good. Historically, you know, we've seen frankly better, you know, TG reduction than Ionis, and so we would expect that if they saw it, that we've got a good chance. You know, these are still small-ish numbers, and funny things can happen with small numbers, and so you never know until you know. We are cautiously optimistic that we will see an improvement in pancreatitis once we have the full data sets.
Yep. Okay. You guys have been vocal about that this is a category and a value proposition of drug that's worth a price premium. I think you've talked a lot about in the past about MASH drugs. You've priced at a slight premium to TRYNGOLZA, presumably on the quarterly convenience dynamic, I would assume.
I know you don't wanna specifically comment on gross to net, but from everything I hear from you guys, it sounds like you don't think this is a category where you need to offer huge concessions in terms of rebates and discounts, mindful that there are some things that perhaps are a little bit out of your control probably, and that's what limits your ability to guide to it today because you have a competitor that still has to go through those negotiations and that kind of impacts how you kinda have to respond. Is that a fair summary of kinda the pricing dynamics? 'Cause it is a very topical aspect of the story right now with investors.
Yeah, I think that's fair. I don't know what the, what the gross to net's gonna be, but qualitatively, we don't expect to aggressively discount this. You know, think of, you know The way I think about this is not as necessarily a triglyceride-lowering drug. I think about this as a pancreatitis drug. You know, our goal here is to lower, substantially hopefully, lower the risk of pancreatitis in patients with severe hypertriglyceridemia. As you point out, you know, that feels to me more analogous to a MASH market. This to me feels like it should be a premium-priced product.
As it relates to our competitor, you know, we're comfortable with a list price that is a slight premium to theirs because we think that the data support that, right? You know, it's more convenient dosing once a quarter rather than once a month. The safety profile is substantially cleaner and at least historically, our TG reduction has been better. Again, you know, not to wipe my feet on TRYNGOLZA. I think that's a good drug. I think that their data have been impressive and have been really helpful for a lot of patients. I just think that we can, that we should, you know, price that slight premium to that given these other benefits.
Yep. Okay. The sHTG pivotal, the primary endpoint of triglyceride lowering, that seems like a very highly de-risked endpoint, thus the focus is on the key secondary endpoint, which is acute pancreatitis benefit, which is important, I think, across all geographies. Our general sense is you know, if your event rate was similar to CORE, you've got a very good chance of showing stats as long as nothing in the statistical hierarchy gets in the way. If it's kinda mid-teens number of events in absolute numbers, then you just need to show a really high absolute reduction, but could still hit stats. Is that sort of a general sense?
Ultimately, I do wonder how much of this matters if your benefit on trigs and APOC3 is as good or better, and it's just a function of trial design where maybe there are some differences in either percentage of AP reduction or the statistical parameters.
Yeah, I think that's all fair. We do have belt and suspenders here. You know, we designed SHASTA-5, you know, a while ago, that is powered to show an improvement in pancreatitis. It's ongoing, and it's an event-driven study. That will, you know, assuming that we continue with that study, and, you know, we'll see when SHASTA-3 and SHASTA-4 read out if we hit, if we hit on acute pancreatitis. It could be that we decide to shutter that study. You know, it's ongoing. One way or the other, I think we will have this on the label. I think our lives are easier if we can show it with SHASTA-3 and SHASTA-4.
Ultimately, to your point, you know, these are still smallish numbers, and funny things can happen with small numbers. If that's the case, then fine. You know, our commercial team's gonna have to work a bit harder. As long as we're seeing very good, you know, TG reduction and good APOC3 reduction, you know, this, you know, we still would expect to see good adoption. Excuse me.
What's the timeline for SHASTA-5 in a scenario where you do have to roll that out to completion and get those data from the outcomes trial versus, say, your pooled SHASTA-3, SHASTA-4?
It's a bit hard to say, because it's an event-driven study, as I said. You know, it's accruing patients now. You know, we've seen events, and so it's ongoing. I can't give you a good idea about when that could read out. I just don't know right now.
Okay. To your point, in a scenario where, you know, if you didn't have it from the initial pooled analysis just makes life a little bit harder, is that more commercially with doctors in those discussions, with payers, or is it all about OUS and the pathway there?
Yeah. It's a good question. I think it's not about payers in the United States. You know, I don't think that showing AP is gating for payers in the United States. We feel good about that. It will, you know, it will require our commercial team to, you know, talk a bit more, you know, with providers potentially, you know, about the drug and show our data and, you know, what our commercial team likes to say that if, you know, if you're explaining, you're losing. It'll take an extra step or two for them.
Look, we have a drug that works, and so I think that we can get around that. I think your point is a good one about ex-US. I think that in some geographies, we're going to truly need to have AP on the label in order to get reimbursed. Again, hopefully we see it in SHASTA-3 and SHASTA-4, but if not, we have SHASTA-5 where we're quite confident that we would see it.
Yeah. I hate to belabor the point, but I just wanted to make sure. If you think about SHASTA-3, SHASTA-4, the main differences or just uncertainties as you think about kinda projecting the number of events, is it that it's 25% smaller study? Is it that we just don't have a lot of data around AP events and we're talking small numbers, perhaps that's a little bit tricky? Or maybe any slight differences in baseline characteristics, say versus the CORE study? How would you kinda rank order those uncertainties?
Yeah. I think it's one, two, not three. Our baseline characteristics are quite similar to CORE and CORE2, so I feel good about that. It's, you know, I think I'm gonna get these numbers wrong, we have around 750 people, that's not a huge number. You know, small numbers can have funny effects. It's really just that. It's only a one-year study, right? You know, if we were carrying this out for more than a year, for two years or three years for sure, we'd be quite confident. Let me take a step back.
When we first designed SHASTA-3 and SHASTA-4, it was not powered to show AP. That's why we decided to design SHASTA-5. We didn't have any expectation at all of showing any improvement in AP in SHASTA-3 and SHASTA-4. When people would ask us about the Ionis studies, CORE, CORE2, you know, they would ask us if we thought they would show AP in those, and we said absolutely not. You know, this pancreatitis event is severe, but it doesn't happen every day, we didn't think they were gonna show it. Well, they did show it a nd we are seeing events in SHASTA-3 and SHASTA-4.
What we learned, and the field has learned, is that pancreatitis, TG-related pancreatitis is a lot more common than we all used to think it was. It just underlines the fact that these patients really do need to be treated, not just, you know, those severe patients, you know, above 880 with history of pancreatitis, but really any, you know, anybody with substantially elevated triglycerides. We are now, again, cautiously optimistic that three and four will show it. We are also much more confident that these are important drugs that need to get to patients.
Okay. Last question, just is, do you think this is a category that ramps and launches fast, given, you know, some of the patients who are high risk, who've had past AP events that, you know, I presume that they would be highly motivated to treat, and I think Ionis has guided to, like, a $3 billion peak. Is that, is that a rough proxy of how you see REDEMPLO peak in the U.S.?
Yeah. I'll be a bit more aggressive on that. You know, I think the peak for us is $3 billion-$4 billion. That peak's not gonna happen in the first six months. This is an education market. So I do expect, you know, a bit of a, w ell, slow is a strong word. I wouldn't use the word slow, but a, you know, but a I'll use the word slow. I expect a bit of a slow adoption curve because this really is an education play.
You know, I'm glad that there are two good drugs out there, and there are two companies that are bringing the story to providers and to payers, but that'll take a bit of time.
Yep. Okay. Now maybe shifting gears to obesity, in the last 10- minutes, got a couple pipeline topics to hit. INHBE, plus tirzepatide, more data this year. I think the goal is to improve the weight reduction, maybe 5% versus tirzepatide alone. You know, maybe the additional data you expect to generate here, you know, your how that will inform your confidence level on a go-forward strategy, I imagine in Type 2 obese patients would be the play for INHBE. Is that right?
Yeah. Yeah. Yes. We've thought all along, even before we started clinical studies for ARO- INHBE, we always thought that the play here, if there's a play, you know, if this translates from animals to humans, the play is in combination with the GLPs. That's a good class of drugs. There's no reason to try to make this a monotherapy, and frankly, I think the biology doesn't support that. You know, we always thought that this could be a powerful addition to GLPs to increase weight loss potentially, and more importantly, or equally importantly, to make that high-quality weight loss. We saw that, you know, in the early data. We really saw that in this, you know, in this obese diabetic population.
We saw a doubling of fat reduction and a tripling of liver fat reduction. You know, that was really eye-opening to us. Wasn't entirely shocking to us, but it was eye-opening and important. We are designing phase II studies as we speak. I expect to start those, you know, this year, where we'll be looking, you know, at that population, and we'll be looking at INHBE to contribute to, you know, as a MASH therapy as well as potentially an obesity therapy.
Okay.
Sorry, one more thing on that. There are additional good targets in the liver against obesity. You know, we talked about, or I mentioned earlier, you know, this burgeoning platform we have in dimers, and we have an awful lot of interesting ideas about what we can combine, you know, in a dimer or bispecific with INHBE to make it an even more complete and powerful drug class. I think you'll hear more about that, you know, into 2027 and beyond.
Yep. If we're to think ahead, the 5% seems very relevant to the regulatory bar. What else, you know, in terms of composition or blood sugar do you feel like, is table stakes to having a differentiated product that can compete given just how competitively intense obesity is? We know that Lilly's retatrutide can push the boundary even further for weight loss reduction. I imagine, you know, how are you thinking about some of those other aspects of the profile?
Yeah. We'll see. You know, you know, I don't know, I don't know if INHBE is a, is, you know, will be helpful with blood sugar. I just don't know. You know, it's too early to tell with our data now. You know, what it appears to be good at is moving fat around in a healthier fashion. You know, getting fat out of, d creasing liver fat, decreasing visceral fat and liver fat. I think that's important and retaining lean muscle mass.
Look, you know, if we have something that could enable patients to use a relatively low dose of a GLP, tirzepatide or a standard GLP-1, and get better weight loss with a lower dose of those and have that a higher quality weight loss and potentially treat, you know, a fatty liver, I think that's a really compelling set of possibilities.
Yeah. What would you be looking for for ALK-7? Is it, maybe proof of principle on adipose targeting, and that opens up the door for a lot of other things that could be interesting? Or, hey, we don't know, we just wanna see what the data is, and then we'll kind of inform you, on maybe the strategy on how to utilize this tool and what it may be beneficial for.
Right. Yeah. We think this Activin E, ALK-7 axis is really interesting biology. Interrogating ALK-7 is really essentially a different way of interrogating this axis, and we think it's interesting. I look forward to seeing what that looks like. You're right, you know, the value here is at least, well, I guess threefold. You know, one, let's see what ALK-7 does in terms of weight loss. We are, what, two quarters behind INHBE with ALK-7, but also the MAD portion of that study, the doses are separated by three months rather than one month, so it just takes us a bit more time to generate those data.
You'll see more data, you know, second half of this year. Let's see what that looks like. You know, we're excited to see what that looks like. That's value, potential value, number one. Potential value number two is, as you mentioned, this opens the door to our ability to deliver, you know, to adipose. We've seen really good data in animal studies. Let's see if it translates into humans. If it does, there's a number of good targets that we can go after. I think that is a value creation event. The third is, as with Activin E, this is a potential component of a dimer approach. You know, what if you can knock down ALK-7 and something else?
There's several good targets that we like in adipose that we can think of pushing into the clinic sometime in 2027 maybe and beyond. We look forward to seeing these data and we look forward to this being potentially a franchise of its own.
Okay. I imagine between the work you're doing on your PCSK9, APOC3 dimer, if that looks good, if the obesity assets look interesting, companies in your space eventually do need to consider partnering at a time, just given constraint of resources and the ability to sort of maximize what you're working on. I think you moved off of obesity as a partnership candidate. Could that be revisited? I'm just curious. I imagine anything can be revisited.
Anything could be revisited. You know, we reported on our last conference call or on our Q last week about $1.8 billion of cash. We're well capitalized. You know, we are positioned to take all of these forward ourselves, and that's our posture right now. I think there's a ton of value there. You know, that may change at some point in the future, but right now at least, you know, we really like blowing out obesity, you know, ourselves. Not just INHBE and ALK-7, not just the dimers that could be made with those two candidates, but other ones. You know, I mentioned CNS. You know, there are really interesting obesity candidates, you know, in the brain.
We'll have data from ARO-MAPT, our, you know, our first, you know, subQ administered CNS drug. We'll have data, you know, later this year. If that's positive, that opens up a whole new area for obesity. We're talking about obesity.
Yeah.
We wanna hold onto that cardiometabolic between plozasiran and zodasiran. zodasiran is our ANGPTL3 program, where we're treating HoFH patients. We have no interest in partnering either of those. We're gonna bring those forward ourselves. The dimer, as you say, PCSK9, APOC3, that is a big opportunity to treat the 20 million or so people with mixed hyperlipidemia. We wanna hold on to that ourselves. Let's see what, you know, where we sit with the broader CNS platform.
Yep. Okay, we only have, like, two minutes, so I'm gonna lump these two assets together in one question, which is your MAPT and your ALK-7 data updates this year. Think about these as primarily safety, and you just wanna see deep target knockdown, and that's going to be the key learning that will inform, "Hey, we got something here. Let's keep going.
Yeah, I think that's fair, particularly for MAPT. You know, the data we'll have this year is just in healthy volunteers. I think that's important. You know, let's see if this translates from NHPs to humans. Let's see if we get good knockdown of tau. Let's see if this is well-tolerated. If those are the case, you know, it opens up a lot of opportunities for us in CNS and beyond, and we're preparing for that. You know, we've got a number of CNS programs behind that, you know, should this initial readout be positive, we're gonna push as quickly as we can.
I think you'll see a number of new CNS candidates in clinical studies in 2027, and you might see the first one at the end of 2026.
Yeah.
Certainly for MAPT. For ALK- 7, same thing. You know, we are really interested in safety. We're really interested in knockdown. Look, you know, let's, we're also interested to see if this Activin E ALK- 7 axis translates from animals to humans, that we do see, you know, some effects in terms of maybe weight loss, but also in terms of fat distribution.
Okay. If you think about MAPT, and if you do validate systemic delivery, some of the opportunities that that may open up, or should we be thinking about that as some of the areas where maybe intrathecal ASOs have been studied, but like Huntington's that, or even ALS or different Alzheimer's settings, like, or targets, I should say, like what is the, what does the menu of options start to look like?
It's a large menu. Certainly all those things. But there are other conditions. I don't want to pick on obesity and that's, you know, that's not, you know, our sole focus obviously, let's talk about obesity. You know, it's inconceivable to me that an obesity therapy could be administered via intrathecal injection. It is certainly conceivable that an obesity therapy could be a simple subQ injection at home, you know, once every two or three months. So it opens up less severe, if you will, diseases, if we really can translate the systemic delivery from animals to humans.
It runs the gamut, you know, from grindingly, you know, awful neurodegenerative conditions, you know, to, you know, to things like obesity that, you know, are less severe.
Okay. Well, we're out of time. There's a lot we didn't get to cover. Appreciate your time and the insights as always.
Of course. Thank you. Good to be here.