Hi, everyone. My name is Maury Raycroft, and I'm one of the biotech analysts at Jefferies. Thanks for joining us today. I'd like to welcome our guest, Chris Anzalone, the CEO of Arrowhead. Thanks so much for joining us, Chris.
Sure. It's great to be here. Thanks for having me.
To start off, for those who may be new to the story, if you want to give a one-minute intro to Arrowhead.
We are a hard company to give a one-minute intro about. We have. We are an RNAi company. We have an initiative that we call 20 in 25, which predicts that we will have 20 individual drug candidates in clinical trials or at market by the year 2025. We are on track to meet that, and so we are, we, we have a very large pipeline across a variety of areas, not only therapeutic areas, but also variety of, of cell types. You know, we have, we have essentially 5 platforms right now targeting the liver, CNS, adipose, skeletal muscle, and pulmonary. And we're moving forward on all of those now, as next year.
Our , you know, if we, if we would have a lead product, it would be plozasiran. The target there is APOC3. We have one phase 3 study that's ongoing now that will read out middle of next year. We expect an NDA towards the end of next year, and we'll have two additional phase 3 that we will start, you know, sometime in the Q1, I believe, in 2024. That's against cardiovascular disease. We think it's a powerful target, addressing a variety of needs within the cardiometabolic markets.
Great! T hat's pretty good. You got a lot in one minute there, I'd say. And start off with cardiometabolic. You just had an updated AHA recently and also did a company event afterward. You're pursuing a fast path for APOC3 for approval in FCS, which is a smaller indication. And the APOC3 phase III is supposed to read out in Q2 of 2024. Can you talk about the status of the phase III, types of patients you're enrolling into the study, and highlight any notable differences between this study and your phase II?
Sure. So that phase 3 is in patients with familial chylomicronemia syndrome or FCS. These are folks generally with triglycerides in the thousands. We are, you know, with guidance from the FDA, we are defining this not just genetically, but also, you know, patients, you know, with very high triglycerides that may not have the traditional FCS mutation. It is a relatively small market, as you mentioned, but what's attractive to us is A, you know, this is still, you know, a grossly underserved patient population. You know, these are patients, as I mentioned, you know, with triglycerides in the thousands.
You know, many of them will have bouts, continued bouts with pancreatitis, and there's just no good treatment for them other than changing the way that they eat. You know, they're allowed essentially you know, a similar amount of fat as, like, 7 or 8 almonds every day. And so we think we have something that can really help them. So it's very attractive from that perspective, but it's also attractive, you know, from a market serving perspective. Because what plozasiran does, it's the name of this drug candidate. What it does is a number of things. It lowers triglycerides, but also lowers remnant cholesterol, it increases HDL.
It does a number of things that we think can address multiple markets. So FCS is the smallest and most in nearest term. We'll be starting a phase III program, as you mentioned, early next year against severe hypertriglyceridemia. We think that's a very interesting market. We think there are 3-4 million of those people in the U.S. alone. These are people with trigs about 500 and above, and about 1 million of those are above 880, and that's also a very underserved market, we think, but a large market. That'll be a one-year-long clinical study, at least one year for one year of treatment.
So, you know, it's we will get into market first with this very small FCS market and then expand the label, assuming we get approved, in SHTG, a few years after that. And then ultimately, we anticipate entering the ASCVD market. You know, this is a much broader population of individuals. We think there are probably tens of millions of these in the United States. And again, you know, in a space that has been treating people only by lowering LDL, we'll be offering something that moves different lipid parameters, and we think, you know, can extend the life of a number of people. That is a much longer clinical study. It's a clinical.
It's a CVOT, so we'll start that sometime next year, and that will be a you know several-year study. You know, we have plenty of time to you know conduct that study because we'll be entering FCS and an SHTG market upstream of that.
Got it. Makes sense. S o it's a steppingstone-type strategy where FCS is gonna be the first approval and first phase 3 readout, too, which could de-risk some of the other opportunities you're going after. What are your expectations for results for this FCS readout, and what do you have to show to ensure that you get approved and get commercial uptake?
Yep. Yes, it's a great question. So, you know, our I think that our biology risk on this across at least the FCS market and the severe hypertriglyceridemia markets, you know, are low indeed, because we have seen now in literally hundreds of patients that we lower triglycerides by, you know, depending upon the patient population, between 80% and 90+%, and it works in virtually everybody. And so our chances of failure, we think, are quite low. You know, the approval endpoint for FCS is simply lowering triglycerides. The approval endpoint for SHTG is simply lowering triglycerides, and we've seen that now in hundreds of patients in a well-tolerated manner. And so this for us feels like blocking and tackling.
You know, we just we need to spend the time, we need to do these studies, but we think that the risk of failure is quite low given what we've seen. And of course, given the theoretical, you know, given the, the theoretical mode of action here, we, we've not been surprised by that, by that, you know, consistent results. You know, this is it is attributed to two things. One, it is a good target, it is well-validated. We, we expect it if you can, if you can reduce expression of, of APOC3, these things should follow, and they have. And second, it is a tribute to RNAi as a platform, as a, as a modality.
You know, this is a reliable technology that's mature, and we in particular, as it relates to hepatocyte-directed constructs, it just works, and it works in essentially 100% of patients, and that's what we're seeing. The greater risk will be in the larger population, the CVOT trial that we expect to do. There is an awful lot of evidence to suggest that remnant cholesterol and other lipid parameters that APOC3 moves are substantial risk factors in cardiovascular disease. No one's been able to move them, however, and so there's good theoretical basis for that, but less therapeutic basis. Look, you know, we are bullish about that, but there's still unknown. Upstream of that, FCS and SHTG, you know, we think is fairly straightforward.
Got it. At your company event, you talked about the pivotal designs for SHTG, SHASTA-3 and SHASTA-4. Can you clarify if those designs are based on FDA feedback? And also, would these studies qualify for a label expansion and approval, or would you need that CVOT study first?
So I'll go backwards. No, we do not need the CVOT study first. In fact, you know, we are doing the CVOT study for an orthogonal population, but for the SHTG population, that's not necessary. Our protocol is still in flux a bit. We had our end of phase II meeting recently with the FDA, and we're still discussing this with the FDA, and so the precise parameters are not yet clear. But the basic size is becoming increasingly clear, and yes, that this is all a result of discussions with the FDA.
Got it. And, can you talk about timelines for the Shasta studies with getting those fully enrolled and getting into data? And how important is it to have the reduction in pancreatitis risk on the label for commercial uptake?
Sure. So, having pancreatitis on the label is not, or showing a reduction in pancreatitis risk is not necessary for approval. But we think is important, and certainly from a payer perspective, we think it's important. Maybe not critical, but important. And so we will be collecting those data. But we think also that that's, you know, upstream of pancreatitis, there's an awful lot of things that are happening with these patients, that we will be monitoring. You know, we know these patients have brain fog.
We know these patients have abdominal pain, and so we will be building out that story, you know, as we are conducting that phase 3 study, because it's important for payers to understand that, it's important for prescribing physicians to understand that. You know, we've got a drug that will. Gosh, if I remember my numbers correctly, in the phase 2 study, in several hundred patients, you know, I think that 96% of those patients had triglycerides that lowered beneath the 500 threshold, where you start to see pancreatitis, and over 80% of them, we reduced their triglycerides to normal levels. I mean, it's really stunning.
You know, compare that to the fish oils, which is the only other treatment right now, where they are lowering triglycerides by, you know, 20%-30%. You know, this is an absolute game changer, and, and, and it is our job not only to show that, A, we reduce triglycerides substantially; B, we reduce ApoC3 substantially; C, we reduce the risk of pancreatitis, but D, you know, we are also reducing these other, these other sequelae that are associated with severe hypertriglyceridemia.
Got it. Based on that, what are your latest insights into certain patient populations where results could be more predictable for your SHTG studies?
Sure. So, I think that we've seen substantial reductions in triglycerides in 100% of patients, and so that'll just be a blanket effect, you know? However, the extent to which you see reductions does differ a bit from patient type to patient type. It appears that, for instance, the FCS patients, you know, see a greater degree of triglyceride reduction than those patients who come in with a baseline triglyceride level that's a bit lower than that. You know, and with respect to pancreatitis, we know that those patients who have had pancreatitis in the past are more likely to have it, and those who have had it, say, in the last year, are even more likely than that.
You know, there seems to be a, you know, a downward cycle, you know, with these patients, that once they start to get pancreatitis, they get it more often.
Got it. And maybe talk a little bit more about the CVOT study. So you're planning to discuss that with FDA Q1 of next year. Can you bookend what the size and scope of that study could be, and how does that factor into the Arrowhead story and just building the value proposition? I think The Medicines Company is an interesting comp in this space, and you look at how that played out with with their CVOT study.
Sure. So you're right. We have not had discussions with the FDA about that study yet. We do expect to do that sometime in the Q1. So I don't have too much guidance on what that should look like. To bookend it, you know, depending upon if you're looking at only secondary prevention versus secondary and primary or only primary prevention, you know, the size could be as small as, I don't know, 3,000 or 4,000 individuals, could be as large as 12,000 or 13,000 or 15,000 individuals. We are probably skewing to the smaller end of that, you know, to at least enrich for secondary prevention and maybe entirely secondary prevention for this first CVOT study.
So how does this fit in with our strategy? Y ou know. The way that we believe we can create an awful lot of value for our shareholders is, you know, is by making sure that we have, you know, a fair number of wholly owned assets, right? You know, we are really good at pushing new clinical candidates into the clinic, that have a high, you know, probability of success. So much so that we can't commercialize all of those that we are developing. As I mentioned, I think we'll have, you know, more than 20 in clinical studies, by the year 2025.
And so there's an awful lot of room for us to do business development to outlicense these, you know, in order to bring in capital so we can support our own wholly owned projects. But ultimately, you know, we create a lot of value by having these wholly owned assets. APOC3 is a cornerstone of that, I think. And it's a good one for us for a lot of reasons. You know, first, again, our probability of success is very high. You know, we know that this works, it works consistently. It does things that are important in these patient populations, so at least FCS and SHTG, you know, we have a high confidence of success, and it's well tolerated. You know, the CVOT, we'll see.
We are bullish about that, but there's a bit more biology risk there. So this is a good center asset, if you will, you know, to build around. And then around that, you know, we'll have, gosh, everything from pulmonary candidates to other liver candidates to muscle candidates and the like.
Got it. A nd last question for cardiometabolic. Can you talk about the phase III plan for ANGE3 and homozygous FH? And what are your latest thoughts on partnering to run phase III for larger indications?
Sure. So, we are still developing our strategy for HoFH with ARO-ANGPTL3. You know, with respect to business development, that it might make some sense to find a partner for that at some point. You know, we are not in a position where we would do multiple CVOTs across multiple compounds. We are prepared to do a CVOT for APOC3, for ARO-ANGPTL3. It's, you know, it's probably a bit of a broader market, right? You know, what's great about APOC3 is it allows us to leg into larger markets, FCS to SHTG to ASCVD. ARO-ANGPTL3 doesn't really have that.
It's got, you know, it's got this very small indication of HoFH, and then, and then, you know, you would, one would do a broad CVOT to, you know, to address a very large population. That may make sense to find, you know, to find a company that, that, that has experience doing that and, and, and would extract full value from that and bring that to patients who need it. Whereas in our hands, we probably would not bring that to all the patients that, that, that would need it. And so, so that might make some sense for us at some point to find a partner.
Got it. Okay, so let's shift gears to pulmonary. For your pulmonary program, starting with RAGE, can you provide a status update on enrollment and talk about the relevance of the FeNO reduction cohort and set expectations for this cohort, which I believe should be about 25 patients?
Sure. Boy, RAGE is a really exciting compound for us. You know, it, it is, it is, you know, the sharp end of a spear of our pulmonary franchise. You know, it is the furthest along, and we have, we have already shown some data in healthy volunteers showing that we get good knockdown, you know, you know, on the order of, of greater than 80% knockdown, in some patients, greater than 90% knockdown, in healthy volunteers, sorry, not patients, but, but healthy volunteers and human subjects. And so and it's been well-tolerated so far. So that, so that's been encouraging. Between now and the end of the year, I expect that we will have the complete chronic tox data.
We expect that to be benign, but you never know until you know, and so that's gonna be, I think, I think, a bit of an inflection point for us, you know, if, if in fact that holds. Second, we will show additional knockdown data in patients. We—I think at our Analyst Day, we had a small, small amount of, of knockdown data in patients. It was at a lower dose. And the good news there was, as expected, it was tracking almost exactly on top of the knockdown in healthy volunteers, as we would expect. But again, you never know until you know, and so that was good news.
By the end of the year, I expect that we'll have a more complete data set there, and our expectation, and certainly hope, is that we continue to see that good knockdown. I think that's, and that's another inflection point that suggests that this drug is doing what we intend to do in asthmatics, you know, in patients, not just in healthy volunteers. And then, as you mentioned, we have created additional cohorts of high FeNO asthma patients that we are dosing as we speak. We won't have data this year. I expect we'll have data sometime, maybe towards the middle of next year. And that will be a next step further. You know, step one would be, you know, good tolerability. Step two is knockdown in patients.
Step three is a measure that suggests that we are seeing clinical benefit, and I think FeNO can do that.
Got it. Makes sense. And so it sounds like, for the chronic tox, you could update on that by the end of this year?
Yes.
And then also have some additional patient data .
Exactly. Yes.
Got it. Could that be on your earnings update? Would-
It's possible.
Okay. Okay. And, for the RAGE update, and for the FeNO cohort in particular, what's the bar for success there to show clinical benefit? And are you also gonna be looking at FEV1 ?
We are. You know, I think that we. You know, look, we need to be competitive with, you know, with the, with the Dupixents of the world. And so I think that, you know, that depending upon, you know, on how high the baseline FeNO is for these patients, you know, we would be looking for, you know, 30%-40% reduction. Again, depending upon, you know, the baseline, you know, what they have shown is that the higher the baseline, the higher the reduction of FeNO you get. And so we'd be, you know, looking at ours versus theirs and seeing how we fit in. We're bullish, of course, but I think we'll know a lot more over the next several quarters.
Got it. Are you saying anything more about the type of baseline you anticipate enrolling?
I don't think we have talked about that.
Okay. Okay, and for the RAGE program, can you discuss the relationship between bronchial lavage data and RAGE serum P biomarker data, and whether you're seeing directional or correlative trends there?
So in healthy volunteers, what we have generally seen is deeper knockdown in the BALF. This is the bronchoalveolar fluid that we can flush. And unsurprisingly, I guess, you know, we see a deeper knockdown in the BALF versus in circulating in serum. Again, probably not surprising because we know there are extrapulmonary sources of RAGE, not a ton, but some. And so you'd expect that. And we in fact we again, we've seen that in healthy volunteers. I mean, so you know, the 80+% knockdown figure that I mentioned in healthy volunteers was in circulating in serum. And so we are seeing even deeper knockdown in the BALF.
We expect that to continue in patients, but you know, once those data come in, we'll see.
Got it. And, based on those data, can you make adjustments to your MUC5AC and MMP7 programs to better set them up for success?
You know, the short answer is yes. The longer answer is, is that each one is a little bit different. You know, the potency will be a little bit different, and so, for instance, we haven't even started the chronic tox studies in MUC5AC because we don't know what the, you know, what the duration is gonna be. You know, we want to get some knockdown data in patients, and, and watch how long that lasts before we, we, you know, before we, we, we do the chronic tox. Because, again, you know, we don't know if, if we, if we should dose that once a month, once every two weeks, once every other month.
You know, I think that the way the data are looking, at least in healthy volunteers for RAGE, is that that'll be once every two month, you know, dosing schedule. Depending upon what that timeframe looks like, of course, that would affect the timing of the GLP tox dosing.
Got it. Makes sense. And you also added a new COPD cohort to your MUC5AC program earlier this year. Maybe talk about the rationale for that for adding that before you have some initial asthma data, and provide a status update on how the asthma cohorts are enrolling.
Sure. So the asthma cohorts are enrolling. We are probably a step behind MUC5AC compared to RAGE, but we're progressing, and I expect to have data next year in patients. As you mentioned, we added a COPD cohort because that just makes sense. You know, it's it you know this is in any mucobstructive disease it would make sense to knock down MUC5AC. This is the component of mucin that is upregulated. And so we're not talking about knocking down MUC5B, which is that which you need for normal mucociliary clearance. There is no reason that at least the RKOs know of to upregulate MUC5AC. It's just a bad thing.
And so if you can knock that down, you know, you get at the root cause of these diseases. You know, people die of mucus plugs. If you can decrease the production of that mucus, then you can decrease the incidence of those situations. You know, they could also be used for CF. You know, you think of those patients who don't have any CFTR to correct, you know, those null nulls, they have very few options. If we are able to really reduce production of MUC5AC, you know, that could be a place to go. There's also smaller indications, you know, non-CF bronchiectasis.
Anyway, there are other smaller indications that we can go after and get and see data on, you know, on a fairly rapid basis, in addition to the larger markets of asthma and COPD.
Got it. And maybe provide a quick update on the status update on the MMP7 program, and for the platform as a whole. You talked about the RAGE updates, so we can expect in the near term what other updates from the pulmonary platform should we expect?
Sure, S o, as I mentioned, you know, nothing by the end of this year for MUC5AC, just because, again, you know, we need to get those data in patients, and we don't have enough yet. Same thing with MMP7. We're probably a half a step. With MMP7, we're probably half a step behind MUC5AC, and so we have just started dosing patients. As with MUC5AC, you know, we did treat healthy volunteers, but that's just a safety measure. MMP7 levels are very low in non-IPF, you know, in healthy volunteers, right? As you know, as the MUC5AC is very low in healthy volunteers. And so we have just started to recruit IPF patients, and I expect sometime in 2024 to have MMP7 data.
Got it. Let's talk about your CNS platform . For this program, talk more about the approach and the targeting ligand you're using for intrathecal delivery and how that's differentiated from Alnylam's strategy. And, when do you expect to have 9-month NHP chronic tox study data from this program?
S o I don't know that we've given guidance on chronic tox time. We have initiated a CTA for, you know, against a type of ALS patient. The target there is SOD1. I expect we'll start dosing patients maybe by the end of this year, certainly by early, you know, Q1 of next year. We'll just see how fast we can pull these patients in. It's a really good way of seeing proof of concept. I expect that we will have additional, at least one, additional clinical candidate in clinical trials next year, with the intrathecal approach.
We also have been developing systemic delivery for CNS, and that's, of course, been a holy grail for, you know, for various researchers for decades. But I think we're close. You know, we showed some data at our R&D day back in June, and while I don't think we'll be in the clinic in 2024, I think we're close, and so I think you'll hear more about that in 2024. And that's a really exciting approach, and that could be, you know, that could be seriously disruptive if we can get that to work.
Got it. Interesting. And I also wanted to ask about your adipose program. You see more durable and robust knockdown after a single dose with this program relative to the liver-based ones, where you need two doses to reach the KD trough. Can you recap the preclinical data for this one, and just what are next steps?
Sure, w e're seeing incredible data with the adipose platform. After a single dose, we are seeing deep, deep knockdown through 6 months, and we're still following. I wouldn't be surprised if we have good, deep knockdown through 12 months. Doesn't mean that it'll be once every 12-month dosing, but it certainly, it certainly could mean that we are, that we are once every 6-month dosing, maybe, maybe 9 months. We'll see. It's an incredible opportunity. You know, this is the largest endocrine organ in the body, and we are clearly making a play for cardiometabolic exposure.
You know, APOC3 is the, is the cornerstone of that, but we see an awful lot of good targets coming out of our adipose platform, and you'll see the first one in the clinic next year.
Got it. I think we're pretty much out of time. Maybe last question, if you can talk about ramp up in R&D that you're expecting with the future of clinical trial plans, and then reiterate what are the key catalysts ahead that investors should be focused on?
Sure. So we'll be spending more money next year on R&D than we did last year. I expect that we'll be bringing in additional capital to help fund that, primarily through business development. I think we have an awful lot of catalysts ahead of us. You know, in no particular order, you know, the chronic tox for the RAGE program will be important. That will be between now and the end of the year. Good knockdown data in asthma patients with RAGE, you know, will be before the end of the year. FEV1 data coming out of RAGE will be more towards the middle of next year. That's gonna be important. Look, you know, with APOC3, I think we'll have our first NDA next year.
As I mentioned, adipose will enter the clinic next year, or our adipose platform with our first candidate next year. CNS will have—we will add an additional candidate in the clinic next year. Skeletal muscle, I expect that we will have a new candidate in the clinic by the end of this year. We've got an awful lot of things coming up.
Very good. T hanks so much for joining us today, Chris.
Thank you.