Hi everyone, my name is Maury Raycroft, and I'm one of the biotech analysts at Jefferies. It's with great pleasure that I'd like to welcome Chris Anzalone, the CEO of Arrowhead. Thanks so much for joining us today, Chris.
Thank you, it's great to be here.
And we're going to do fireside chat format. So maybe to start off, for those who are new to the story, if you can provide a one-minute intro to Arrowhead. I know that's tough for a minute, but.
It is tough. Sure, so we are an RNAi company. We have been all in for 19 years, banging our head against the RNAi wall until it broke through. I think that we are leaders in bringing RNAi outside the liver. You know, we've got something around 16 clinical programs, some of which are outside the liver. Our primary focus going forward is really in the cardiometabolic space, but we've got programs in pulmonary and cardiometabolic, of course, in a variety of areas.
Got it. Yeah, that's a great intro. And you mentioned cardiometabolic programs, which you've got a clear focus there with these programs, with the lead one for APOC3, Plozasiran. And you recently noted plans to file the NDA by this month. You filed the NDA, congrats on that.
Thank you.
Can you talk about the feedback you've received from FDA on the filing package?
Sure. We're really excited about that. As you mentioned, we filed the NDA, I believe, yesterday now. That is for the narrow indication of familial chylomicronemia syndrome. However, the population that we studied was not only genetic FCS, but also what we call clinically validated FCS, or those patients who have triglycerides at 880 or above and a history of pancreatitis. We think that's actually an important distinction because we think it broadens out in the market a bit. From our perspective, it doesn't really matter what the genetic makeup is in a patient. What we care about is helping these clinical symptoms. What we found in our phase III was that both populations responded about the same to the drug. We saw reductions in triglycerides, reductions in APOC3. We saw a statistically significant improvement in pancreatitis events. We checked all the boxes.
And so we have breakthrough therapy designation with the FDA. We are looking forward to them reading the package and going forward.
Got it. And you've got a competitor out there, Ionis with Olezarsen, and they've got a PDUFA for FCS scheduled for December 19th. How do you expect their label to look as it relates to patient population? You mentioned you could have a broader population. So maybe talk a little bit about that and whether you think they could get acute pancreatitis events in their label and what's going to be the read-through to Arrowhead?
Sure. So the first lesson I learned in this business is not to try to predict what the FDA is going to do. So I'm not going to do that. I will say, though, that they studied genetically defined FCS. And so you generally get on your label what you study. And so we would expect that we would have both genetic and clinically validated FCS in our label. And we'll see what the FDA decides to give to Ionis. Look, we feel great about how Plozasiran stacks up. Generally, if you've got two competitors in the market, you find some areas where you are superior and you focus on those areas. We are superior just at every turn. We are lowering triglycerides by around 80%. They were lowering by around 40%. They had around a quarter of patients that were non-responders. We had 0% non-responders.
We had something like 75% or so of our patients get below 8 80 in triglycerides. I think they had around 10% or 14%, something like that. We are dosed once a quarter. They are dosed once a month. We are well tolerated. We will be second to market. We will see how fast we will see when our PDUFA date is. But my expectation is that our launch will be somewhere around six months behind them. We have med affairs out and about now trying to educate the market. Look, FCS is an important market for us, not only because there are patients there that require this treatment, but also it allows us to get into market and start talking about the much broader market of severe hypertriglyceridemia, which is a much more economically meaningful market for us. We have ongoing phase III studies right now in that population.
We expect those to be fully enrolled. They're one-year studies. We expect those to be fully enrolled by the middle of 2025 and so done by the middle of 2026, and then file sNDA end of 2026 to launch in 2027. That's how it feels to us now. Now, look, we'll see if we stay on track with enrollment, but that's how we see it now. And this FCS market allows us to really start to talk to physicians and patients about what we think Plozasiran can bring to the SHTG market. And look, we think there's a three to four million people there. It's a real block of patients that are unserved right now that we think we can make a real impact on.
Got it. So FCS will lay the groundwork for this broader market opportunity eventually. For FCS specifically, how do you see that commercial launch looking from a revenue standpoint? I guess if you think about year one, year two, year three, what could that look like, especially when you think about Ionis out there as a competitor?
Yeah, so we haven't given any guidance on that at this point. Let's see what this label looks like. We are building out our commercial infrastructure as we speak, but we have not given revenue guides at this point.
Got it. And anything you can comment on as it relates to strategy for part B versus part D? That's something that Alnylam has had a lot of debate around that with their drug. Could there be some sort of strategic advantage there versus Ionis based on that?
Yeah, we haven't given any guidance on that either at this point.
Got it. Okay. And you talked about the larger indications for SHTG, and you're running a couple of other phase III s, the SHASTA-3, SHASTA-4, and then also MUIR-3 as well. Talk about the status of those studies. Where are you at with enrollment so far, and what's the purpose of those studies?
Sure, yeah. We are on track with all those studies to be fully enrolled by the middle of 2025. The MUIR study that you referenced is really just for safety. We are grossly overpowered for showing decreases in triglycerides, but we need a number of patients. And so the MUIR study is just to give us that. We also have a concurrent acute pancreatitis study that we think will be important for payers and also probably important here in Europe. It's not gating from a regulatory standpoint, but we think it will be important to have. And so that also has just kicked off.
Got it. Okay. And for these studies, could you potentially do an interim analysis? You mentioned the timeline with launching in 2027. Could you do an early look and potentially accelerate that to some extent?
Nope, no. It's a year-long study. That's all it gets. I mean, it's one of those times when the phase III is a little bit not terribly exciting because we know what the story is going to be. The drug works in essentially everybody. It's well tolerated. It decreases triglycerides by a very large extent, and so we have a strong expectation of success for these studies. We just need to do them, and so we are on that horse.
Got it. Okay. And then going back to the competition, and you said you're getting ready for the commercial launch. Maybe talk about where you're at with commercial preparedness and also what you're thinking about pricing too versus Ionis?
Sure. So we expect it to be priced as an ultra-orphan. It is a small population. We think that's appropriate because presumably, if we are lucky enough to get approved, it's a small market. And so that's an appropriate route. We do expect, if we're to get approved in the much broader SHTG market, to then lower the price, commensurate with that much broader market. But the initial ultra-orphan pricing also really enables us to talk about the drug. I don't think that we can be accused of off-label marketing because it will be priced as an ultra-orphan, and we'll be talking to a larger population to help them understand what this drug might be able to do for them. So we are often running on building out the commercial enterprise.
We are also often running on, actually, we've completed building out the med affairs at least to this point, and they are out and about talking to folks. This is to some extent. It is an education play because there's been no real way to lower triglycerides. Fibrates and fish oils and such can maybe lower triglycerides by around 20%. But that doesn't really move the needle for a lot of these patients and doesn't get them out of the danger zone, and traditionally, you don't measure so much what you can't move. And so when we all look at our lipid panels, we look at LDL, we don't so much look at triglycerides. We think that's sort of the next shoe to drop for people to focus on that.
Having said that, for in the severe hypertriglyceridemia market at least, there is some understanding that this can be a ticking time bomb. And we think around 75% in that population is using some fish oil or fibrate or something of that nature. That's a really great start for us. That suggests to us that there is a potentially broader understanding than we first anticipated of the problems with severely elevated triglycerides. And so that may help us launch more quickly. For FCS, it is clear to these folks, certainly for the genetically defined folks, and less so, but still relatively clear for the clinically defined folks, I believe.
Got it. And to demonstrate how high triglycerides could lead to mortality, you're planning on running a cardiovascular outcome study at some point as well. Talk about how you envision that study starting and playing out and the timeline for what that could look like as well. So if you do the label expansion in 2027, when could the next label expansion be? And maybe talk about commercial inflection.
Sure, sure. So we can't give you good timing guidance on that because we're not going to start that CVOT until we've got better clarity on additional capital. That just seems the prudent route for us. And so stay tuned on that. On the SHTG side, though, I think we need people to understand that's a serious economic block. We think that's a $2 billion-$3 billion a year drug just in SHTG alone. And so we think that's a substantial drug in and of itself. Once we've got better clarity on how we can pay for a CVOT, then we can better forecast when the label could be expanded even more.
Got it. And with the outcomes data, I guess that will enhance the value proposition. You mentioned the high triglycerides, that could be three to four million people.
Yes.
With the CVOT study, that would basically be something that you add to the label.
Yes, yes. The population that we would be addressing via the CVOT could be 10 or 20 million people. And so it's substantially larger than the three to four SHTG folks.
Got it. Okay. And for the SHASTA-5 study, you mentioned that's for pancreatitis, primarily for payers and also for value proposition. We're wondering if it's possible that with SHASTA-3 and SHASTA-4, you could get enough insight into pancreatitis from those studies where you wouldn't have to run that SHASTA-5 study. Is that part of the strategy or?
It's not, actually. We could get some clarity on or some data on pancreatitis in those studies, but we really wanted to make sure to design a study that was intended to show an improvement in pancreatitis. But we didn't want to slow down the regulatory studies, right? So it made sense for that to be a separate study.
Got it.
We are quite confident that we'll see it in the phase III studies for FCS. We saw a statistically significant improvement in pancreatitis. The biology makes sense. We know that these elevated levels of triglycerides can cause pancreatitis. We know that once you have pancreatitis, once you've got a greater chance of having it in the future, we also know that triglyceride-related pancreatitis is a more serious condition than broader forms of pancreatitis. We think we've got a very good chance of showing improvement.
Got it. And for the CVOT study, at your R&D day in June, you talked about running that study in a primary prevention and secondary prevention populations of patients. We're wondering if you have final approval from the steering committee on the study design and then what the anticipated sample size, powering assumptions, and costs could be for the study?
Yeah, so we do have a protocol that's pretty well set. We have not given guidance on those things. Although let's just be clear, it'll be secondary prevention and then high-risk primary prevention, not just all-comers, necessarily primary prevention. And so we are still running down exactly what that budget is going to be. We have communicated with regulators. And so we've got a pretty good idea of what that's going to look like. We'll provide better guidance once we have a better idea about when that could start.
Got it. And we've looked to just precedent examples. The Medicines Company, they ran a CVOT study based on some estimates out there. It seems like that could have cost about $150 million. Does that seem appropriate for what a CVOT study would cost?
The Medicines Company, a CVOT costs substantially more than $150 million. These are expensive studies. These are large, expensive studies. I think we can do it more cheaply than Big Pharma has traditionally done them. We have worked with regulators to strip away ephemera that doesn't really help the story. I think we can do some of that. I think our drug's going to be powerful. And so it's not going to be a 20,000-person study. But at the end of the day, you just got to put the time in and you've got to study the patients. And so it will be an expensive study.
Got it. Okay. And the plan is to keep this in-house, keep APOC3 100% wholly owned, or could you potentially partner this to help out with expenses in some way?
Yeah. So we are really focusing our pipeline in on cardiometabolic, and this is an important piece of that, and so we don't have any interest right now in partnering that. Having said that, we could use some help internationally at some point, and so I could see doing one or multiple ex-U.S. partnerships, but this is an important drug for us. It's a powerful drug, and we intend a whole lot of this.
Got it. Okay, let's shift gears to your pulmonary platform, focusing on ARO-RAGE. How did the data so far inform your phase IIa plans and severe asthma patients? And wondering if you have completed the regulatory interactions needed to start the phase II study?
We have not. We have not completed those yet, so look, as a target, RAGE is well validated, though not yet clinically validated because it's been undruggable, and so we have been going off knockdown. We've seen very good knockdown in both healthy volunteers as well as in patients, and so we've seen enough to suggest to us that we could see a clinical benefit. We just need to show that now, and so we are kicking around various ideas for a phase II . Look, there are two broad ways you could do that. You could move into a large dose-finding traditional phase II study that allow you to roll directly into a phase III study. Or you could do it a bit more cheaply and show some clinical benefit to essentially act as an inflection point for value for that program.
We have not decided which way is the right way to go. We've also not decided if we're going to do that ourselves or partner it. As it looks like now, as we're building out our cardiometabolic franchise, which is really going to be our primary franchise, we are actively wondering how much bandwidth we have for large asthma studies, and so that could be an attractive asset to partner, at least at some point.
Got it. Okay. Well, for getting additional proof of concept around the mechanism there, you've talked about the FeNO-high patient cohort, and you were enrolling some of those patients in your study. You said the screen failure rate was challenging. Can you talk about what types of asthma patients you could enroll into the phase II a study and how will this design be different or similar to other phase II studies?
Yeah. Again, I can't give you too much guidance on that yet. We have not laid that out yet. We do believe that at least the target looks like it should be helpful for most asthma patients. It wouldn't be just a small subsection. We don't think of asthma patients. And we also think it could be helpful for COPD. And so those are all being kicked around internally right now.
Got it. Okay. Maybe last question here, just based on what you've seen in your preclinical data and also in the initial clinical work as well, what would you expect on a measure like FEV1 in severe asthma patients just with RAGE? I guess what would the goal be? What would you have to show?
I have no idea what we would show. I can't hazard a guess on that because we just haven't done those studies yet, and so ask me that over the next 18 or so months, and I may have a better answer for you.
Okay. Okay. Fair enough, and wanted to check on MUC5AC and MMP7 as well. What should we expect to see from those programs in 2025, and maybe talk about how you're setting expectations for COPD and asthma cohorts and then the IPF patients for the initial study.
Sure. So look, so I think that we should have data in the first half of 2025 from all three of those programs, MUC5AC, MMP7, and RAGE. And then we'll just see where we take them from there. Again, RAGE has been a very interesting target, undruggable, and one that we've been excited about. And we look forward to moving that into a phase II study. MMP7 has been a well-validated IPF target, obviously an underserved market. And so we're getting knockdown data right now in patients. You really can't interrogate that in healthy volunteers. And so I expect we'll have those data over the next quarter or so, and we'll share them once we can. And then based on that, we'll see where we go from there. Same thing with MUC5AC. It's a very interesting target for asthma, potentially COPD as well.
We'll just see what those data look like. Again, we've gone through the healthy volunteer cohorts, but there's just nothing you can see in either MUC5AC or in MMP7. You really need to interrogate that in patients, and that's where we are right now.
Got it. Okay. And I think one of the key things about your platform that resonates is that you're able to deliver to the lung, get a lung target, knockdown, show dose dependency there. For potentially partnering this out, would you partner all three assets? Would you go to a pharma company, have them pick their own targets, or how could that look?
We'll see. I like the idea. So I think we have a platform that works. And I like the idea of working with a more traditional respiratory company that has deep experience in these late-stage studies and biology of various respiratory diseases, etc., to partner to find new targets. That makes a lot of sense. Whether we would also partner all three of those programs or some subset, who knows? We'll see what the appetite would be. But we think we have created a lot of potential value with the pulmonary programs. And I think our best path forward is to extract value from that with partners.
Got it. Okay. Okay, that's helpful. And let's shift gears and talk about the muscle platform that you're developing as well. For the FSHD and DM1 muscle programs, where do you see room for differentiation versus competitor antibody ASO approaches?
Sure. So look, so based on our animal data, we are hopeful that we could have best in class in both those, DUX4 and DM1. We'll see what the data look like. We are good at RNAi. And so we would expect to have very potent drugs for both of those. There is a technology advantage generally in RNAi versus ASO in terms of durability. And so we would expect that to play out. That could be helpful from a dose and schedule standpoint and also could be helpful from a depth of knockdown standpoint. So we'll see what those look like. We also know that the antibody approaches use an awful lot of drug, an awful lot of drug, grams of drug. And so we think there's an opportunity there to use. We'll see.
Somewhere, I think, between a tenth and maybe a hundredth of the amount of overall drug used, we think that could be helpful from a safety standpoint. But we'll see. It's very early for us. We're excited about those two programs. I think we are optimistic that those will truly be drugs.
Got it. Okay. And for your two clinical programs, can you talk on timing for initial data for both of these programs?
Yeah. Again, they're early, but I would certainly expect data in 2025, not in the first half of 2025 probably, but sometime in the second half of 2025. I think DUX4 is a little bit ahead. So yeah, I would say that towards the end of next year, maybe third quarter, maybe fourth quarter, we should have data.
Got it. And just from some of the competitors in the space, you mentioned the high amount of drug needed for those competitors. Any observations that you've learned just on dose and potency and where competitors have failed and how you could do better with development?
Yeah. So we have learned a lot. For instance, in the DUX4 program from other companies, that is expressed in a pulsatile manner. And so it can be difficult to catch depth of knockdown. And so we are looking at downstream genes. It appears that those can give you an idea about how much knockdown you're getting. So that's all very helpful. Most of what we do, we've been the first ones in a space. And so we have to be the pioneers. And that's good and bad. And so it's been a bit of a luxury to be able to be behind some folks and learn from their process.
Got it. Yeah. And also wanted to check briefly on AATD with Takeda. I don't know if there's a status update you can provide there and also talk about the strategy for your CNS programs.
Sure. And with a minute to go, I'm also going to throw in obesity there. So AATD, Takeda has said publicly that they believe that phase III should be fully enrolled in 2025. It's a two-year study to primary endpoint. And so we think that's the rough timing of getting that out. That drug seems to work. We had very good data in phase II . We saw a decrease in fibrosis, a drastic decrease in production of AAT. And so I would expect that to work. We have 50/50 profits here in the U.S., and then 20%-25% royalties ex-U.S. And so it's a real economic opportunity for us. On the CNS side, we will be in the clinic in 2025 with our systemic delivery platform. We'll be delivering via subQ injection. MAPT is one of the targets. HTT for Huntington's is one of the targets.
Alpha-synuclein is one of the targets, and so we're excited about that. I think that is very disruptive. If in fact it translates from animals to humans and the animal data were quite compelling, and then finally, on the obesity side, we will have our first two obesity drugs in the clinic shortly. And INHBE is a liver-expressed gene target. That should be dosing in January, I think. ALK7 is our first adipose-directed construct. That'll be in the clinic sometime around the end of the first quarter, I believe. We've already filed the CTA for that. Those are very exciting programs that we will be interrogating both as monotherapies as well as in conjunction with tirzepatide, and the animal studies have been very compelling. We've seen good quality weight loss where animals are losing fat but not losing lean muscle mass.
We also see that these animals eat the same amount of food as control, and so we were just able to ramp up their metabolism. They ate the same amount of food but didn't gain weight. It's really compelling. We're looking forward to seeing how that translates.
Got it. Yeah. Definitely would like to talk about the obesity ones more, but we're out of time. It's been a great conversation. Maybe to close out, if you want to highlight key catalysts that investors should be focused on.
Sure. Look, this NDA was a big catalyst for us. We will have data throughout 2025. We expect to launch into FCS somewhere around the middle of the year. We'll see what our PDUFA date is. We will be in the clinic with our systemic delivery for CNS. We'll be in the clinic with adipose. We'll be in the clinic for another obesity program. We have an awful lot going on in 2025.
Got it. Thanks so much for joining us, Chris.
Yep. Thank you.