... Good. All right, welcome everyone. Day two of Cantor's Global Healthcare Conference. My name is Prakhar Agrawal, biotech analyst at Cantor. For the next session, we have the team of Arrowhead, and representing Arrowhead, we have Christopher Anzalone, President, Chairman, and CEO of the company. Christopher, appreciate your time.
Thank you for having us. It's great to be here.
I'm sure we have a lot to talk about in terms of some of the updates from this week, but maybe just level set expectations in terms of what you see as the key priorities for the company right now.
Sure, we have a really busy six to nine months ahead of us. You know, in essentially chronological order, I think what you're gonna see is we will bring MAPT to the clinic. That's gonna be our first CNS drug that is administered via a subq injection. After that, I think we'll bring our first dimer into the clinic. That's PCSK9 ApoC3 dimer that we think is a really potentially powerful tool against ASCVD. In November, we've got our PDUFA date for plozasiran. That's a huge event for us to transition from an R&D only to an R&D plus commercial company. We'll have some Inhibin E and ALK7 data in obesity.
I think by the end of the year, we'll have a bit more ALK7 data in the first half of 2026. That's about six months behind Inhibin E in dosing. And then I think we'll start to see some MAPT and dimer data around the middle of the year, which I think will be important. I think for the dimer, that will tell us if we have... if we have a drug, you know, we'll see how much we can reduce LDL cholesterol. We'll see how much we can reduce triglycerides. And with MAPT, I think that could be a transformational event in that, it will give us some proof of concept about our blood-brain barrier platform broadly, and of course, MAPT in particular.
Got it. Maybe start with plozasiran. I'm sure we'll have a lot of questions around SHTG, but FCS, I did want to get a few questions. You have the PDUFA in November. Anything that you comment on the latest regulatory interactions there?
So everything's going smoothly. You know, it's. People have asked us whether or not things have slowed down with whatever's going on in the government, and the answer is, we haven't seen any slowdown. You know, it's been. We've had productive and timely discussions, and our expectation is that we are on track there.
Okay, and Olezarsen from Ionis has actually had a pretty strong launch in FCS. I think they've guided to $75 million-$80 million for this year. What are you doing as it relates to some of the commercial preparations in FCS and the uptake of their-
Sure. Yeah, we're ready. You know, we've been building out our commercial team for now a couple of years. Boy, as of last week, I think, everyone's installed, all the reps are installed. You know, they're in training as we speak, and so we are prepared to hit the ground running in November.
Got it, and on SHTG, obviously, we saw the news this week, from your competitor. Maybe just outline your perspectives on the data.
So look, you know, it's just top-line data, you know, just a press release, and so we know we have not been able to dig into anything. Nobody's been able to dig into the data yet, but the top line looks good. You know, good for them, good for patients, good for the field. You know, ultimately, the SHTG market is an education market, and so we've always thought that it's better for patients, it's better for the field to have two companies, you know, banging that drum and bringing that education than one, and so that's helpful. On the AP side, you know, they said that they showed stats for acute pancreatitis. You know, we'll see if that's for the broader studies or just for a small nested population.
It almost doesn't matter from my perspective because it's a really important step forward for the field. And also, I think it helps to crystallize where I think this drug should be in terms of pricing. You know, there is this funny dogma out there that a cardiovascular drug should be priced in the $10,000-$12,000 per year range, and that's it. And that may be true, but this is not a cardiovascular drug. Plozasiran has always been, at least in these markets, a pancreatitis drug, and so I think the better analogy there is a MASH drug. And so to the extent that we are now seeing, you know, effects on pancreatitis in this population, I think will help the field and physicians, and payers to view this in that way, and I think that's the right way to see it.
Right, and so the MASH drug is actually $50,000 per year. So is that some of the... I know you'll not comment on the pricing yet, but is that some of the benchmarks that you're-
Yeah
... sort of flagging now?
Yeah, yeah. We are still in that process of trying to figure out what the right price is here. But you know, so not to get too granular, I think that it is not, you know. If the goal here and if you're able to substantially reduce the risk of pancreatitis, that doesn't feel like a you know, broad market, $10,000-$12,000 a year drug. That feels substantially higher than that.
Got it, and so given the data you have seen with Ionis, you have a little bit of a different trial strategy, right, with two trials focused on. There's a specific trial that's focused on acute pancreatitis. Now, what's your confidence level on replicating the data on acute pancreatitis in SHASTA three and four?
Yeah, we'll see. You know, we knew the approval endpoint there simply is lowering triglycerides, and so they're powered to do that. They're way overpowered, frankly, and so my expectation is that we will see, you know, drastic lowering of triglycerides, and that will be enough to see approval. You know, we are looking for pancreatitis events, and so we will, of course, you know, collect those data. But, you know, those studies were not designed to show that. That's what SHASTA five is for, as you know. SHASTA five is powered to show effects in pancreatitis in a high-risk population, and so look, from my perspective, this is belt and suspenders.
You know, if we are lucky enough to show it in a combination of three and four, that's great, but if not, that's okay. You know, that's what SHASTA five is for. Ultimately, SHASTA five was designed to help payers in the United States, and I think that will be marginally helpful there, but its real benefit is in the rest of the world, is in Europe, you know, to show those hard outcomes.
And do you think the physicians might read across the data from, let's say, in a scenario that it's not stat sig?
Yeah
on acute pancreatitis, because we've seen somewhat similar trend for the, let's say, GLP-1 class, where if one drug shows benefit on outcomes, everybody assumes that all drugs will do the same. Like, is that something that you could foresee with-
Yeah, I think that's a really good point. I think that's probably right. You know, the biology here is quite clear, that in this population, you know, the severely elevated levels of triglycerides can cause acute pancreatitis, and so I don't think that's controversial. And so, yes, you know, I think that's probably right.
Yeah, and on acute pancreatitis, because we get some questions like, around the unmet need there is, like, about 30,000 hospitalizations due to hypertriglyceride-induced pancreatitis event. So can we just talk about, like, why is this such a big deal?
Look, it... You know, it's two things. You know, one, I think there may be more events than that. But second, you know, this is not a binary event in that it's not as though these patients feel great, you know, or they have pancreatitis, and there's nothing in between. You know, there's a spectrum here. You know, these folks suffer from acute and severe abdominal pain. There can be brain fog, and there can be other sequelae. And so it's, you know, even upstream of acute pancreatitis events, you know, there's discomfort, and there are symptoms that can be treated.
Okay. And so how do you think about the addressable market here for?
The which market?
Addressable market-
Mm-hmm
... for SHTG, is like high tr- You know, I think Ionis has also commented on some of the initial launch focus, going after 880 and above triglycerides or patients who have a history that's part of million population as well. Like, what's, what's your sort of launch strategy going to be?
Yeah, I think that's very smart. You know, I would agree with them on that, that this is not a homogeneous market, you know. You know, so we know that there is this, you know, this rather linear relationship between elevated triglycerides and risk of acute pancreatitis. That slope increases around 500, and then it increases substantially at around 880. And so the low-hanging fruit from my perspective, you know, are those patients. There's about a million of them in the United States with triglycerides above 800. You know, a substantial potentially proportion of those folks will have had pancreatitis at some point in their lives. But even those who have not, you know, are sitting on a ticking time bomb.
You know, that's a very dangerous condition. And so they are the easiest, you know, to address, and their physicians, you know, should understand the risk factors here. I think, you know, again, to come back to an earlier point, this is an education market, and we need to help physicians and patients understand that that is, you know, that is supremely unhealthy to have triglycerides above 800. So clearly, you know, clearly they will be a focus. But look, you know, I think, you know, those patients with triglycerides between 500 and 800 are also at substantial risk, and so should be treated.
Right. And so what could be the commercial level of investment to sort of build this market in terms of the sales force, marketing efforts, to launch plozasiran and SHTG?
Right. We'll see about that. We have not given guidance on that, but here's what is attractive about plozasiran to us, in no particular order. First, you know, it is a supremely well-tolerated drug. You know, that is helpful. Two, it is extremely active. You know, our data in our phase 3 study in FCS showed triglyceride lowering of around 80%. That's a uniquely helpful thing, right?
Third, from just a business standpoint, you know, we are an R&D company, and any company that makes the transition to commercial is gonna have some growing pains as it builds out a commercial team and figures out how to add that component to its culture. We get to do that in a stepwise fashion. FCS is a relatively small market. You know, we can address that with a couple of dozen commercial folks, I think. And so it allows us to figure out organizationally how to be a commercial company in a fairly small stage. And then it prepares us, you know, to expand into SHTG, which would be, of course, quite a bit larger.
Right. And so on the differentiation versus Ionis's drug, now that we have seen the efficacy and some high-level safety data, what's your view on how will you differentiate in the market?
Yeah. So look, I can't speak to potentially how we would differentiate in an SHTG market because I haven't seen their data yet. We don't even have, you know, SHTG data yet other than phase II data. So we'll leave that aside. You know, if we talk about FCS only, I think the differentiation is fairly clear. Now it's difficult, of course, to compare two different drugs across two different studies, but you can just look at the numbers. You know, in their study, they showed about 40% reduction of triglycerides from baseline. We showed about an 80% reduction in triglycerides from baseline. You know, I will stand by our safety profile. I think that it is potentially superior.
And then we dose once a quarter, and they dose once a month, and so this feels like a compelling. We can make a compelling argument as to why this may be more appropriate, you know, for some patients. And also, look, you know, what we hear from physicians is: how many patients can we get to goal, right? Now, it depends on what your goal is. You know, goal could be 880, goal could be 500. And if you look at our FCS data, I think we had around 75% get below 880. That's substantial, and I think around 50% get below 500. And remember, you know, these patients, you know, have triglycerides in the thousands, and so that, that's doing something. And I... I think that olezarsen didn't have anybody get below 500, and I think, you know, in the teens or so, 15%-16%, maybe a couple below 880. I could be wrong about that, but something around that range.
Yeah. And so maybe on the FCS, given that you have a little bit better data and maybe possibly better safety and convenience, like, do you expect some switching from Amgen's drugs?
Yeah, we'll see. Look, you know, we have a strategy for that. We have a strategy for pushing the switch, but also for you know, for de novo users. You know, what I think that physicians should do is just monitor their patients. You know, if they are on olezarsen and they're meeting goal, you know, they may be happy with that drug. But let's see if they're meeting goal, and if they're not, then you might wanna consider switching.
Okay, and maybe on Europe, for plozasiran and SHTG specifically, like, what's the strategy there in terms of launching yourself or is it looking for a partner?
Yeah, so we are gearing up to do that ourselves, with, you know, with the understanding that we would certainly be open to some kind of ex U.S. deal, and so I can't rely on that because I don't know if it's gonna happen, and I don't know if it's, you know, if there is an attractive deal to be done there, so we have to, you know, to prepare ourselves, but we'll see where that goes.
Okay. And your strategy in the broader mixed dyslipidemia market, I think obviously a much larger market, but requires a cardio outcomes trial as well. So what's the latest thinking there?
Sure. So, you know, we have. As you know, there was a time when we were thinking about plozasiran for that market as well. You know, right now it's a two-step drug for us. Step one is FCS, step two is SHTG. There was a time when we were thinking about a third step, and then you know, stepping into this mixed hyperlipidemia market. That does not make too much sense to us at this point. I think we keep plozasiran as a pure play pancreatitis drug, full stop. We are developing the dimer for addressing the mixed hyperlipidemia market. We're really excited about that. You know, we think there could be 20 million or so people in the United States that would fall into that category, who have never been prospectively studied.
The concept is, you know, stunning, right? That if we can knock down both PCSK9 and APOC3, as we've shown in NHP studies, we'll see if it translates into humans. We've had good luck with translation in the past, but let's see how that goes. But if we can reduce LDL-C and triglycerides in these same patients who have elevated triglycerides and elevated LDL, we think it's a very powerful tool for these patients.
Does anyone else have a dimer? I mean, it seems a very interesting concept.
It's an interesting concept. I believe that we will be the first ones with a dimer in the clinic, and I expect that to be this year. It's not... You know, this has taken us some innovation, right? You know, it's not as simple as clipping two RNAi molecules together. There is different chemistry. There's a lot that has gone into this. And so we're really looking forward to seeing how this looks. As I mentioned, you know, we will have LDL and triglyceride data in 2026, and I think that's gonna tell us, you know, is the stoichiometry working for us? Are we getting enough knockdown of both PCSK9 and APOC3, you know, to have something? But I think we'll know that next year.
Okay.
And then I think, I think we can move relatively quickly into a cardiovascular outcomes trial.
Right. But, I mean, your translation from NHP to humans has historically been very good, so-
It's been very good. Yes.
You saw the same signal for the dimer as well?
We did, yes. Yes.
Okay. Got it. Maybe moving on to the obesity portfolio, you have two assets in the clinic, so maybe just walk us through why two targets?
Sure
... and the rationale there.
Sure. So these two targets, Inhibin E and ELK seven, are opposite ends of the same pathway, right? This activin pathway. ELK seven targets adipose tissue. This is our first time in the clinic, I think the first time anybody in the clinic, frankly, to bring an RNAi drug directed at adipose. And we've seen good data, you know, in animal studies with ELK seven. In fact, we've seen good weight loss. We've seen good, high-quality weight loss. And so we're excited about that, and it's a very durable drug, you know, that could be dosed, you know, potentially once every six months or less frequently. So we're excited about that.
Inhibin E is again the proximal side of that pathway. And we are interested in that, and the data also, the animal data were quite good there as well, and that's a hepatocyte-directed construct. We know we're good at knocking down hepatocyte gene targets. So for us, it was belt and suspenders. You know, ELK seven in animals was more potent. I don't know if that's gonna translate to humans, but in animals it was. And so it made sense to bring both into phase one, and let's do a bake off. Presumably, you know, one will come out, one will look better, and we will take one of those into phase two and beyond. But I suppose it's possible that they both look good for different reasons, and we may develop both. My expectation is that we will, you know, we will collect these data this year, and then in 2026, we'll be doing phase two studies in just one of those.
Okay. Got it. And so maybe, like, where will these targets fit in relative to the semaglutide, tirzepatide? It could be a monotherapy option as well, or do you see it as more like a combination play?
Yeah, it's. You know, look, there's a lot of white space in this field. You know, obesity is obviously a very large market, and it's a bit diverse, and so, you know, let's see what these data look like. In the animal studies, what we saw was good weight loss as a monotherapy, but more importantly, high-quality weight loss. You know, we saw a sparing of muscle, we saw a loss of visceral fat, and this wasn't due to caloric restriction. These animals were eating the same amount of food as control animals, but were still losing weight. They were metabolizing fat. That's a very attractive profile. So, it is possible this could be used as a monotherapy, but I'm frankly a bit more-... Excited about potentially using it in combination with one of the GLP-1s. Either, you know, for instance, using it, you know, in combination with a subtherapeutic dose of tirzepatide-
Mm-hmm
To maybe, you know, lower or eliminate the sarcopenia issues and the GI issues, but still see good weight loss. Also I like the idea of using this for maintenance therapy. We know that that's a real opportunity, and so it could be that the patients lose a lot of weight with existing therapies, go off those, and then go on either Inhibin E or ALK7 as maintenance therapy. We'll see where that goes. You know, our phase 1 studies will tell us a lot.
Okay.
I think we'll... You know, this time next year we'll know a lot better about how these could fit in.
Right, and so the update that you'll have on the clinical trial, Inhibin E, will come later this year?
Yes. Yeah, we'll have an incomplete data set for Inhibin E by the end of this year. We will have an even more incomplete data set, you know, with ALK7 by the end of the year. But my hope is that we have data that is interpretable, and so we can have some idea how these are working and if they're working. And then probably in the first half of 2026, we'll have a bit more ALK7 data because, as I said, that's about six months behind Inhibin E.
Six months behind. Okay. And so one of your competitors, Wave, also has an Inhibin E readout. Anything that you would hope to see there as it relates to your approach?
No, you know, we're really focused on how our data look. You know, we pay attention to other modalities and drugs as well, but we're really. You know, it's hard for me to imagine being overly influenced by whatever data they have.
Okay. And longer term for these obesity assets, because these are, like, large markets, more big pharma play, so... And, you know, you've historically done partnerships across multiple assets for your pipeline as well. So what's the longer term strategy here in obesity? Is partnership something that you could explore early on, or you wanna explore this in, like, a phase 2 trial and maybe take it a little bit further along?
Yeah, so let's be clear, you know, our model has always been a combination of partnering and wholly owned assets. You know, in order to create real value, long-term value, we need to have wholly owned assets that we are commercializing ourselves. Plozasiran will be the first one, and that will continue to be the case. But we also have this extraordinarily productive discovery engine that is capable of spitting out, you know, more drugs than we could ever commercialize. You know, I continue to be confident that going forward we will bring three to four new drug candidates in the clinic every single year, and so there will always be partnering here. Now, with obesity, let's just see how that plays out.
You know, it's easy to say that a company our size is not really able to do these large and expensive obesity studies. But right now, you know, these are fairly cheap studies, and so, you know, let's see what kind of company we look like, you know, two years from now, you know, when those studies could be expensive and broad. You know, we could be a different-looking company with different access to capital, and you know, Plozasiran will be launched by then with different revenue than we have now. And so let's see what that looks like. We are in no hurry to partner these. In fact, you know, they have been... You know, to date at least, these have been off limits for partnering, just because we think there's too much near to midterm value to part with them at this point. Let's see what the data look like, and then we can make decisions going forward.
Right. And, on BD, you announced a pretty good deal with Novartis on SNCA, $200 million upfront for a preclinical asset. Strong, really strong upfront. So, like, what was attractive about that asset in specifically?
Yeah, it was a great deal. We look forward to working with Novartis. They are the right company to partner alpha-synuclein. We are convinced of that. They're excited about it, and we are excited to work with them. Look, we may have something that is breathtaking in CNS. You know, we have this platform that enables us to administer via subQ injection that gets into the brain and importantly, into deep brain regions. Let's see if that translates from animals to humans. You know, should it do that, then this is a disruptive technology. Absolutely. And so I... You know, I don't want to speak for Novartis, but I think what they saw was that potential. There's an awful lot... As they say in billiards, there's an awful lot of green between the ball and the pocket here, and so let's see if this translates. We haven't been in humans with this platform at all yet. But should it translate, it's a potentially very powerful tool, I think.
Right. And so maybe just talk about your broader CNS portfolio as well. MAPT is moving into the clinic. Where will that be tested, and is it, like, something similar in terms of the technology that you have with,
Yep
... SNCA?
Yeah, I appreciate that. Yes, it, it's the same delivery technology. It's the same delivery, platform. We call it, you know, the BBB platform, the blood-brain barrier platform. So MAPT will be the first against the. The target is tau for Alzheimer's, as well as other tauopathies. I expect us to file a CTA for that over the next month or so. And so that will be the first one in the clinic, and that will be the first one where we will have some knockdown data, I think, in 2026. The next one will be ARO-HTT, that's against Huntington's. That will be by the end of this year we'll file a CTA. That's partnering with Sarepta. And then the alpha-synuclein drug candidate, we should be filing a CTA in the Q1 of 2026 for, you know, with Novartis. And then we have a whole host of potential drug candidates underneath that, and so I would stay tuned. I would expect additional neuro assets in the clinic in 2026.
Okay. And on the cadence of partnership, obviously we saw this deal this week, but going forward, what could be the trend there?
Yeah, look, this is a big part of our model, as I mentioned. And so we will continue to partner. You know, should you expect to see any new partnerships in the very near term? Probably not. You know, particularly discovery based partnerships. You know, we need to make sure. You know, we probably wanna take a bit of a breath on discovery partnerships, just to make sure that we can serve Novartis, we can serve Sarepta, and we can serve ourselves. But, you know, maybe in 2026, we could think about additional discovery partnerships. Now, you know, there's other deals we can do in the meantime, just not discovery. You know, as I mentioned, you know, we could consider some type of ex-US partnership for plozasiran. We could consider some type of ex-US partnership with other assets, and so, you know, that's certainly on the table.
Right. And, I mean, you have a lot of clinical stage assets that we haven't talked about. Obviously, pulmonary used to be very important as well. I think you're looking for a partnership there as well, PNPLA3 and NASH, and some other host of other assets. So, like, any specific categories where you feel that there is more opportunity to partner out?
So, I would view it the other way. So, you know, we like the idea of building out our development infrastructure and commercial infrastructure in the cardiometabolic space broadly.
Okay.
And so that would include obesity, that would include, you know, cardiovascular, that would, that would include plozasiran, zodasiran, the dimer, et cetera. You know, I like the idea of continuing to hold on to assets in that area. And then, you know, there will be these non-core assets. We'll see where pulmonary goes. You know, I still like the idea of building out pulmonary expertise at some point, and so we'll see where that goes, you know, with the current assets and additional ones.
Right. And maybe anything else on the early-stage pipeline that we haven't talked about that you guys are super excited internally?
I think we did it. You know, we're really excited to see what MAPT looks like. You know, that, like obesity, has been off limits from partnering. We just wanna see how that. We wanna turn that card over. We wanna see how that, how the platform works. We wanna see how that, how that asset works. It's a well-validated target. There should be some data from competitors out next year on that target that's administered via a intrathecal injection. You know, what's important about this, the BBB platform is certainly helpful from a convenience standpoint. You know, rather than having a lumbar puncture, it could be a subq injection.
But more importantly, what we have seen is that we can get into deep brain regions and things like alpha-synuclein and Huntington's and MAPT for Alzheimer's. It really requires that deep brain region access, and so, you know, we'll see what some of these data look like later in 2026 with respect to the intrathecal injection for MAPT.
Okay.
But I think that could be a good harbinger for, you know, for that asset for us.
Right. And lastly, with the cash in hand, where does it take you in terms of the runway?
Sure. So we said publicly that before the Novartis deal we've got enough cash to get us into 2028. And that's assuming current cash as well as expected inflows from existing deals, you know, existing milestone payments. So we feel good about where we are there. My strong expectation is that there will be more business development between now and 2028 to continue.
Right
... to move this forward.
Okay, great. That's all the time we have today. Thank you, Christopher , for joining us.
Thank you.
Thank you to the audience for listening in.
It's a pleasure. Thank you.