All right, good afternoon, everyone. Thanks for joining us at the Morgan Stanley Global Healthcare Conference. I'm Mike Gold, one of the biotech analysts here, and it's my pleasure to introduce the team from Arrowhead Pharmaceuticals. To my immediate left, Chris Anzalone, CEO, and to my far left, James Hamilton, CMO and Head of R&D. Before we get started, I just need to read a quick disclosure. For important disclosures, please see the Morgan Stanley Research Disclosure website at www.morganstanley.com/researchdisclosures. If you have any questions, please reach out to your Morgan Stanley sales representative. With that, Chris and James, thanks for sharing your time with us today. We really appreciate it. Maybe to kick things off, I'll just hand it over to you, Chris, to make some introductory comments, and then we can hop in the Q&A.
Sure. Thanks very much for having us. It's really a pleasure to be here. It's a really exciting time for us right now. We have so much going on. We always have so much going on on the R&D side, but we are also about to make our transition into being a commercial company. We've got a November 18th PDUFA date for Plozasiran. We're excited about the data, have been quite good, and we look forward to making that transition. Even with that, you know our R&D organization continues to operate extraordinarily efficiently. We've got a ton to talk about.
Yeah, great. I thought that's where we could start. Maybe Plozasiran, FCS, as you mentioned, you have a PDUFA date coming up, so maybe talk about sort of launch prep and strategy there.
Sure. Plozasiran is our, you know, will be our first commercial product. It's designed to reduce the expression of ApoC3, and it lowers triglycerides, and it does that in FCS. Our FCS phase 3 study was very compelling. We were lowering triglycerides by around 80% from baseline. We saw a statistically significant improvement in risk of acute pancreatitis. We are guns a-blazing trying to develop this commercial organization. Everyone's in place, down to our reps. Everyone is hired and in training, and we're ready to go. We expect to have drug and channel in a timely fashion. I think we are ready to launch. We are just about to begin label negotiations with the FDA. So far, interactions have been productive and timely, so we look forward to it.
Yeah, very exciting launching your first drug, so congratulations. Maybe you can just talk about the market opportunity in FCS and how you think about that.
Sure. FCS is a very narrow market. It's an ultra-orphan disease. It's thought that there are about 1,000 people in the U.S. with familial chylomicronemia syndrome, at least genetically defined FCS. These are patients with the known genetic mutations associated with this. They've got very high triglycerides in the thousands. They are on extraordinarily restrictive diets. They can have recurrent bouts of pancreatitis, and it's been untreatable. There's just simply been no way to lower triglycerides enough to decrease the risk of pancreatitis. We think that's changing now. The market may be a little bit broader than that. We also study the population that we call clinically defined FCS. These are patients who have really similar phenotypes as genetic FCS patients. They've got, again, triglycerides in the thousands. They can have recurrent bouts of pancreatitis. They just don't have the known genetic mutations associated with FCS.
It was our thought, and frankly, the FDA's thought, that there's no reason to treat one and not the other. In our phase 3, we treated both, and both populations responded similarly to the drug. We'll see what our label says. We are hopeful that it stipulates both because both populations truly need this kind of therapy. It's hard to size those clinically defined FCS patients, but we think it is more than 1,000 or so genetic FCS patients. As I said, we are prepared to treat both, and we will see what the FDA says in our label, and we'll see how cooperative the payers are going to be in getting this, I think, important medicine to these patients who need them.
Yeah. You're also looking at SHTG for Plozasiran as well. Maybe talk a little bit about just the market opportunity there and how it compares to FCS.
We are. Yeah, that's a substantially larger market. The concept is the same, right? You know, in many people with elevated triglycerides, they have a heightened risk of pancreatitis. Pancreatitis is certainly painful, requires hospitalization, and can be fatal. This is a real thing. This SHTG population, or severe hypertriglyceridemia, will define as people with triglycerides above 500. 150 and below is normal. These are very, very elevated patients. Again, as with the FCS patients, the higher their triglycerides, the greater the chance is that they will have pancreatitis. Importantly, we want to get people treated even before they have their first bout of pancreatitis because once you have one bout of pancreatitis, you've got an enhanced risk of having it again and again and again. We have several phase 3 studies ongoing. I'll let James describe these. We are fully enrolled in three of these studies. Go ahead.
Sure. So just an overview of the phase 3 programs. The Shasta-3 and Shasta-4 programs are largely, well, they're the same population, but FDA wanted to see two studies with the same endpoint being triglycerides as the primary. Those each enroll several hundred patients. Fully enrolled, should have data probably second half of next year for Shasta-3 and Shasta-4. There is Shasta-5 that is focused on the highest risk population. That is a time-to-event study where we're enrolling patients with extremely high triglycerides, greater than 1,000, and a history of pancreatitis. They'll get drug, and we'll monitor them until they have events, essentially. We're looking at event rate and active versus placebo in Shasta-5. There is the NEER-3 study, which is in the hypertriglyceridemia population. This is the population with triglycerides 150 to 499, not as severe.
It's largely a study to build a safety database that was required by FDA. That's the largest of the study.
The take-home message here is that we're just, you know, we're looking for low-end triglycerides in these patients. The biology here is clear. Again, the higher the level of circulating triglycerides, the higher the risk of pancreatitis. In the familial chylomicronemia syndrome (FCS) phase 3 study, we saw, as I mentioned, a decrease of around 80% from baseline of triglycerides. Our goal here is to get as many patients at goal as we can. That first goal would be getting them below 880 milligrams per deciliter. The second goal then would be to get them below 500 because we know these are two important milestones for pancreatitis risk.
Yeah, makes sense. Can you talk a little bit about in terms of the phase 3 strategy? You kind of walked us through it, but it's including a little bit of an extra study to maybe look at acute pancreatitis relative to what your competitor has done, just the rationale there.
Right. We are looking at event rates in Shasta-3 and Shasta-4, and there is a secondary endpoint looking at pancreatitis in that. We'll be able to aggregate data from those studies and look at event rates. I think Shasta-5 is sort of a belt and suspenders approach that's specifically looking at acute pancreatitis event rates. In the event that we didn't have enough events in the Shasta-3 and Shasta-4 program, we'd have Shasta-5. To be clear, it's not that we don't think that the patients in Shasta-3 and Shasta-4 are at risk for pancreatitis. They absolutely are, but it's a short study. It's a year long, and we wanted to better ensure that we do show the improvement in acute pancreatitis risk that we expect. We did Shasta-5.
Yeah, makes sense. You know your competitor recently read out their two studies, and maybe just share what you've learned from that or anything you can apply to maybe your studies in any way.
Yeah. Those were compelling top-line data. We look forward to seeing the full data set whenever they're available. They had mentioned that they saw an improvement in acute pancreatitis risk. That's a very good thing for these patients. It's a very good thing for the field. This is an education field. It has been an untreated field forever because there's never been a way of lowering triglycerides substantially enough to move the needle on the risk of pancreatitis. There are lipidologists, there are cardiologists, there are endocrinologists who don't fully appreciate that triglycerides at these levels are really bad actors. To the extent that anybody shows this relationship between lowering triglycerides and therefore lowering the risk of acute pancreatitis, it's a very good thing and will help us to educate payers and providers and patients as to the need, the necessity of these therapies.
We think it's a good thing that there are two companies capable of treating this disease. It's a good thing for patients. It's a good thing for the field because two companies are better at educating the field than one company. We're happy to compete with them in the marketplace. Ultimately, we will be working together and helping the world understand the need for these.
Yeah, makes sense. Maybe just remind us again when those three studies read out.
Yeah. The Shasta-3 and Shasta-4 are fully enrolled as the NEER-3 study, and patients are on drug for years. We'll have readouts probably in Q3 next year.
Can you talk about the enrollment criteria you use versus maybe the competitor? Is it sort of similar? Do you expect similar sort of patient populations or could it be more severe or less severe?
I think they're pretty similar. I think we have not published our baseline characteristics yet. We will do so. From what Ionis Pharmaceuticals has shared, I think their core studies enrolled a very similar population to our Shasta studies, and likewise for our NEER-3 study versus their ESSENCE study.
Can you talk about the analysis of acute pancreatitis events in Shasta-2 and Shasta-3? Is that something you're going to combine across the studies, or what's the plan there?
Yeah, sure. We will be able to combine. That is the plan. That is built into the statistical analysis plan to pool events from those studies.
Three and four, not two and three.
Yeah, sorry. Too many studies, right?
All right. Great. Maybe just last question before we move on, just differentiation versus the competitor, you know as we stand now.
Sure. Historically, you know, look, it's hard to compare two different agents across various studies. Historically, what we've seen is Plozasiran has shown a greater decrease in triglycerides. That's not too much of a surprise, you know, given the modalities. You know, RNAi is generally a more potent way of silencing the target gene than the antisense methodology. Again, that's been borne out in the prior studies. For instance, in the familial chylomicronemia syndrome phase 3s, we showed, as I mentioned, around an 80% reduction from baseline. I think they showed around a 40% reduction from baseline. Their drug is also clearly active. We expect they've had a good launch for familial chylomicronemia syndrome so far, and we expect them to be in severe hypertriglyceridemia. Again, that's a good thing for all these patients. Our dosing also is a little bit different. We'll be dosing quarterly subcu.
They dose monthly subcu. We like how our drug stacks up against theirs. Ultimately, the world is a better place with these two drugs rather than one of them.
No, definitely makes sense. Maybe we can move on to just Zodasiran and maybe give us a little bit of background there and remind us where you are in development with that program.
Sure. James, do you want to talk about the pathway and the target?
Yep. Yep. For Zodasiran, right now, we're pretty focused on the HoFH population. We showed data a while ago at EAS, a couple of years ago from our Gateway study that was a small open-label phase 2 study in the HoFH population where after two doses, we were seeing a 40+% reduction in LDL cholesterol in that population. That has inspired us to launch the Yosemite phase 3 study that's also in the HoFH population. We'll enroll about 60 HoFH patients to receive 200 milligrams of the drug, and then LDL, of course, is the primary there.
Yeah. This felt like a layup to us. We have high confidence that this drug is going to work. It has been highly active in all the prior studies. It's been well tolerated. There is a clear need to lower LDL in these HoFH patients. There are antibodies out there that are doing that right now. We think that we should stack up well against them. We think that we should have very similar LDL-C reductions as them. We would expect a once-a-quarter subcu injection rather than a once-a-month IV infusion. We like where that sits. The incremental commercial costs for Zodasiran would be minimal. We will have sales folks out selling Plozasiran anyway, and we will just add this to the bag. We think that there's some revenue to be found there. It's a very small market.
This is not going to make or break the company, but we think incrementally, it's a positive thing for us.
Got it. Maybe we can keep moving on. There's a lot to talk about. Maybe move to obesity program. You have two assets there. Maybe give us a little bit of background. I think you're going to have some data later this year. Maybe highlight what you expect.
Sure. Again, James, do you want to talk about the pathway, the INHBE pathway?
Yeah. These are really interesting programs. This is another way, a non-GLP-1-mediated pathway to potentially address obesity. INHBE and ALK7 are part of the same axis that is essentially a way of sending messages in the setting of increased circulating nutrients, telling a message from the liver to the adipocyte, instructing the adipocyte to store fat. The idea here is that we could either knock down the protein that's being expressed by the hepatocyte that's active in E, the gene is INHBE. We can intercept that message, or we can knock down the receptor, which is ALK7, at the adipocyte cells. Both of those programs are in the clinic now. INHBE is probably about three months ahead of ALK7. As Chris mentioned, we should have data end of the year with both of those programs, probably a full set of SAD/MAD data in obese, otherwise healthy volunteers from INHBE.
We're also looking at combination cohorts of INHBE plus tirzepatide in that study. With ALK7, the study is a little bit behind INHBE. We'll have data from the SAD, some of the MAD data as well, same patient population, obese, otherwise healthy volunteers. We'll start to get some of the combo cohort data from ALK7, probably more of that into 2026.
Yeah, we're really excited about these programs. The animal data were very compelling. Not only did we see weight loss, but importantly, it was high-quality weight loss. We saw the loss of visceral fat. We saw muscle sparing. There's a lot of, we think there's a lot of places where that can fit in with existing obesity therapies should that translate into humans. We're doing full-body MRIs in these studies, and we will see the quality of weight loss in both of these. ALK7 is important not only because of these things, but also this is the first time that we have actually, frankly, anybody has been in the clinic delivering an RNAi molecule into adipocytes. It's important for us for two reasons. One, we're excited about the drug candidate, but two, we're excited about the platform.
Should we have proof of concept that we can knock down ALK7 in fat, there's a ton of additional targets that we'll be going after. As the largest endocrine organ in the body, there will be a number of good metabolic targets in adipocytes. Be prepared for several additional targets in the near term coming out of that platform. In addition, we have this ability to do dimers. We can talk about that in a few minutes if you have time. Our first dimer, or bispecific if you will, is a PCSK9 ApoC3 dimer that is directed towards hepatocytes. We also like the idea of bringing the dimer technology to adipocytes and maybe combining ALK7 with something else or maybe combining other targets that we've not talked about yet.
Yeah. When you share the obesity data later this year, you said, you know, proof of concept. What does proof of concept look like to you? Like sort of a specific threshold you're looking for on key endpoints or something like that?
Yeah. I don't, you know, we're truth seekers here, right? I don't know what we're going to see there. We are hoping that we see signs that these are translating from animals to humans. If we do see that, then we will design phase twos to really understand how these could fit into therapeutic paradigms. As the first studies, we're looking forward to seeing, you know, do we have some signals here? Do we see higher quality weight loss? Do we see weight loss at all? The animal studies were quite compelling. We saw weight loss that was not dependent on caloric restriction. That's interesting. We saw high-quality weight loss. That's also interesting.
Assuming you see what you want to see and you kind of keep moving it forward, just broadly, what's the strategy in obesity? Is it monotherapy? Is it combination of these things you might take forward yourself to commercialize, or how are you thinking about that?
Yeah. Let's see what the data look like. You know, our job, I can tell you one thing that we're not focused on. We're not focused on putting the GLPs out of business. Those are good drugs, and they certainly have a place within the broad paradigm of obesity treatment. There's a lot of white space there. Maybe these could be used as monotherapy, but also they could be used in combination with some of these existing therapies. They could be used as maintenance therapy. They could be maybe used in combination with lower dose of GLP. There's a lot of ways that we can play this in thinking. We look forward to seeing what the data look like. Broadly speaking, you know, we don't see these as our last two obesity candidates.
I think we'll see additional ones next year, either through adipocyte targeting or liver targeting or even potentially CNS targeting. We've got this burgeoning blood-brain barrier platform. We just announced back this morning that we filed a CTA for our first drug candidate, MAPT, against tau for Alzheimer's as well as other tauopathies. We can use that platform as well for other central targets relating to obesity. We see this as a burgeoning franchise for us. It really nests into a growing focus of ours in cardiometabolic.
Makes sense. You did mention the bispecific PCSK9/ApoC3 dimer, so maybe you wanted to talk a little bit more about that.
Sure. We're very excited about the dimer or bispecific, depending upon how you want to call it. James, do you want to talk about the two targets?
Right. The dimer targets simultaneously PCSK9, of course, with the intent of lowering LDL cholesterol, and then ApoC3 to lower triglycerides and remnant cholesterol. These are not co-formulated. These are linked as RNA, so it's a single molecule that can simultaneously target both of those genes. This should be entering the clinic by end of the year. The intent right out of the gate is to enroll mixed hyperlipidemia patients, patients with high triglycerides and high LDL cholesterol at baseline. We'll dose escalate, but we should know pretty quickly if the drug is working, if it's effectively hitting those targets, getting appropriate knockdown, the knockdown that we expect, and the commensurate effect on lipids.
Yeah, we're really excited about that. The world knows that lowering LDL cholesterol in patients with elevated LDL is an important tool to decrease the risk of major cardiovascular events. There's a ton of new and not-so-new data to suggest that remnant cholesterol is also a substantial risk factor. There's just been no way of lowering that to a large extent. APOC3 is a way of doing that. We are not going to address that with Plozasiran. That stays as a pure-play pancreatitis drug. We see a big opportunity here to combine the known benefits of lowering LDL with the potential benefits of lowering triglycerides and remnant cholesterol. Again, as James said, I think we know if we have a drug sometime in the middle of the third quarter or so of next year.
Okay. Great. Maybe we can move on to just CNS. You have a pretty powerful platform there. Maybe just give us a little bit of background and kind of where you're at with your program.
Sure. It is a potentially disruptive platform. I say potentially because we still have not yet been in humans. The animal data have been very compelling. We've shown that we can deliver RNAi molecules to deep brain regions. In fact, we have broad distribution within the brain. This is after a simple subcutaneous injection. This systemic delivery for treating CNS diseases has been a holy grail in this space for years and years. You know, once again, the animal data are compelling. We are looking forward to seeing if that translates into humans. We have three initial or near-term clinical programs. The first one is MAPT against tau. As I mentioned, we just filed a CTA for that, and we expect to begin dosing patients and healthy volunteers by the end of the year. The next one will be ARO-HTT against Huntington's disease. That has been licensed to Sarepta Therapeutics.
We expect to file a CTA for that one also by the end of the year. The third will be alpha-synuclein. We have just partnered with Novartis on that. We expect that to be CTA-ready sometime towards the end of the first quarter of next year. We have a number of additional targets that we are developing internally as well to follow those up. My hope is that sometime next year, we will have MAPT knockdown data in the CSF in humans to know, A, you know, is that drug candidate, ARO-MAPT, active? B, you know, is this broader platform working? I think that's a really important potential value driver for us. We are excited to see that.
Yeah. You mentioned the recent Novartis deal for alpha-synuclein. Maybe just talk a little bit about sort of the rationale there and maybe a little bit of detail to the transaction.
Sure. Our model is based on partnering. We have an extraordinarily productive discovery engine. We can do one of two things with that. We can either tap the brakes because we can't, and frankly, no company, I don't think, is capable of commercializing all the drugs that we are able to develop. We will routinely, every year, we think, push three to four new drug candidates into the clinic every single year. Either you slow that development down, which doesn't make any sense to us at all because it is value creating and we are creating things that are good for patients, or you have a model that's based on a mix of holding on to some candidates to develop and eventually commercialize ourselves. We find partners for other ones. This Novartis deal is just the latest in that model.
It included ARO-alpha-synuclein for treating Parkinson's, as well as three additional CNS targets that they've already given us. Importantly, those additional targets do not come from our pipeline. This truly has found value, and we'll begin working with them as soon as that deal closes. Alpha-synuclein is a great target. We look forward to seeing those data. It was important to us from the very beginning that MAPT was off-limits. We were not going to entertain partnering discussions with that. We wanted to turn those cards over ourselves, and we wanted to hold on to that at least for now for ourselves. Alpha-synuclein made sense for us to partner.
Okay. Got it. Anything else in the pipeline that we haven't talked about yet that you want to highlight?
Look.
Too much to pick from.
We have a lot going on. We have the ability to address five different cell types with RNAi. We are the clear leaders there. We're moving as quickly as we can to build out this pipeline, both for ourselves as well as for partners. We talked about MAPT. We talked about the bispecific PCSK9/ApoC3 dimer that will be in the clinic also this year. As part of our partnership with Sarepta Therapeutics, we are developing a drug, ARO-DUX4, against FSHD, and a drug, ARO-DM1, against DM1. I think that we will have some data with them by the end of this year. We're excited about those programs. There are competitors there, but we think there's substantial unmet medical need. Our animal data were compelling, and we look forward to seeing if that translates.
Yeah. Gotcha. Maybe you can talk a little bit about the Sarepta Therapeutics partnership. You know, there's been perceived challenges there this year a little bit that's weighed on the stock, but just, you know, talk about how that's going.
Sure. If you look at our stock chart, you can see when Sarepta Therapeutics ran into their challenges. I actually don't think that those read on us. My expectation is that Sarepta Therapeutics will continue to perform. They have indicated as such. We have already hit one of the near-term milestones, a $100 million milestone related to one dosing, I guess, about a month ago. We expect to hit the next milestone there to trigger $200 million by the end of the year. We have the first of five $50 million annuities that will be triggered, I think, in February of next year. We expect Sarepta Therapeutics to perform on all of those. It sounds as though these assets that they have partnered with us are important to their long-term strategy. I expect them to continue to perform. It's been a good partnership for us.
We've been paid almost $1 billion this year from that partnership. I think the all-in biobanks is somewhere around $11 billion. I think there'll be strong partners in the development and as well as commercialization for these assets. I think they are a good home for some of these assets. Again, we expect them to continue to perform.
Yeah. You mentioned, you know, sort of $50 million milestone next year as well. Over five years, you get $50 million, I think, each year. Are there other bigger milestones associated with some sort of development sort of progress next year as well, or, you know.
I don't expect other ones for next year. As I mentioned, we do expect to trigger a $200 million milestone by the end of this calendar year. Next year, my expectation is only that $50 million from that partnership. As you know, though, we've got partnerships with GSK on both HSD for MASH, as well as HBV. We have a partnership with Amgen on Olpasiran, our drug against LP(a). We've got a partnership with Takeda with Fazirsiran. That's our drug against AAT liver disease. They're in a phase 3 study there. We have 50/50 Plozasiran, for instance, in the U.S. and 20% to 25% low FEVX U.S. Of course, we've got the Sarepta Therapeutics deal, and we've got this new Novartis partnership. We've got a number of partnerships that are important for us. I think that there's a lot of value that they will create over time.
Importantly, you know, will enable a number of, we think, high-quality drugs to reach patients without having to commit capital to them.
Maybe you could talk about your current cash position and just how far that gets you and what that covers in terms of your pipeline plans.
Sure. We have said publicly that our current cash, as well as our existing partnerships that will bring in expected milestones, get us into 2028. Our last guidance was before the Novartis deal, and we have an additional $200 million on top of that. We feel like we are in a very good position financially. We are able to continue to move these programs forward. We do expect that we will be in position to do additional business development between now and 2028. We do not have enough cash to get us to break even, but we kind of see when that is, and it feels to us that we could piece together business development to get us there. We are at an interesting inflection point with this company. A, we are about to become commercial. That cannot be overstated.
That is an important transition for us, and it is not at the expense of a productive R&D organization. We will always continue to be a productive R&D organization. That is one transition. Second, we have the capital to move these important programs forward. Third, we have line of sight on when we could be independent of the capital markets. As the biotech markets ebb and flow, we can be masters of our own domain, if you will, and not be dependent upon any current bestsenders.
Great. Maybe in the last year and a half here, you hit on a lot of these things, but maybe you could just walk us through over the next year and a half or so, like what the catalyst path is and what we should be focused on.
We've got a ton just over the next 12 months. We just filed a CTA for MAPT. We expect to do that for the dimer also by the end of the year. We have a PDUFA update for Plozasiran on November 18th. We expect to have our first slug of obesity data by the end of the year. I expect that we'll have some DM1 and DUX4 data with Sarepta Therapeutics by the end of the year. I expect to have additional obesity data sometime in the first half of 2026. Toward the middle to late part of 2026, we'll start to have MAPT knockdown data from CSF in human subjects and patients with healthy volunteers. We'll have dimer data to know how well we're reducing LDL cholesterol and remnant cholesterol or triglycerides with the dimer. I think that's a substantial value creation moment.
In the second half of the year, our phase 3s against severe hypertriglyceridemia with Plozasiran are going to read out. Shasta-3, Shasta-4, NEER-3 will read out. Ultimately, towards the fourth quarter of next year, I think we'll file our sNDA to expand our Plozasiran label to include severe hypertriglyceridemia. I think we are in a great spot right now. Honestly, 12 months from now, I think we look like a vastly different company. I think we look like a good company right now.
Yeah. No, great. Lots to look forward to. It looks like we're out of time. Thanks so much, Chris and James. Appreciate your time.
Thank you. Pleasure.