Arrowhead Pharmaceuticals, Inc. (ARWR) Earnings Call Transcript & Summary

And thank you for joining us at the UBS Virtual Healthcare Conference. We are lucky to have Chris Anzalone from Arrowhead Pharmaceuticals for this fireside chat. And without much ado, I'll go ahead and hand over to him to maybe set us up for this call, and then we'll jump into Q&A. [Operator Instructions] So with that, Chris, why don't you just sort of walk us through what we should be expecting for the rest of the year and some of the key catalysts?

Sure. So thanks very much for having us, Esther. It's really a pleasure to be here. So the good news, bad news, with us is that we have a ton going on. We'll have -- we're going to have 10 clinical programs in no time. I think we'll double that to 20 in the next few years. And so we always have a lot to think about, a lot to talk about and a lot to look forward to. Over the next couple of months, we have a number of interesting potential catalysts, in no particular order, I don't think we'll have -- we expect to have a more complete data set on the AAT open-label study at EASL, sometime towards the end of June. We expect to have HSD data. That's our NASH drug candidate, also at EASL towards the end of June. We'll have preclinical data on our first muscle-targeted program, this is against DUX4, at the FSHD patient meeting sometime in, I guess, the middle or late June. We will -- sometime towards the end of the month or maybe even into early July, we will have the first taste of our HIF-2 alpha data. That's our first solid tumor targeting program against renal cell carcinoma. Around the same time, we'll have our first taste of our ENaC data. That's our first lung-targeted program against cystic fibrosis. Now we think both the ENaC as well as the HIF-2 alpha data are important, not just as they relate to those drug candidates, but as they relate to broader franchises, our ability to address the lung and our ability to address solid tumors. Should those data be positive, I think it means a lot in terms of value creation for those 2 franchises. By the middle of the year, we expect to push our first muscle candidate in the clinic, again, this is against DUX4 against FSHD. So we have a lot going on over the next few months, that's for sure.

Got it, okay. What I'll do is I'll start off with ENaC, and then we'll go through some of the programs here. So ENaC has always been a tough target in cystic fibrosis. And we just recently saw another one of your competitors' programs getting pulled back. So what are your thoughts on how you're differentiated? And what are some of the pros and cons here of targeting ENaC for cystic fibrosis?

Right. So it's been a tantalizing target for a long time to treat cystic fibrosis because the idea here is that CF lungs have dehydrated mucus. And so the idea of inhibiting ENaC or epithelial sodium channel in the lung has been tantalizing because you can do that. You can potentially increase the hydration of that mucus and allow for better mucociliary clearance. That should, in theory, help out with the lung disease. And in fact, there have been patients that are essentially heterozygote ENaC knockouts, who also have cystic fibrosis, who don't have the lung disease at all or not until later in life and even then, it's mild. And so it's been this really interesting looking target that has been undruggable. And so we think we have something that can drug it. We think it's -- our animal data have been very compelling across rodent models, across nonhuman primate models, across sheep models. And so this is -- this first human data will be the first time that we get to look at translation into humans. And we're cautiously optimistic that we have something that can really help out these patients. As I mentioned though, the real value, I think, of this is not only what we can do in cystic fibrosis but as a proof of concept, that we are able to knock down any gene product in the lung. We view the lungs as a target-rich environment. And once we show that we get good and consistent knockdown of ENaC, it will say to us that we've got to franchise. And then we can go after multiple targets in asthma, in COPD, in IPF. We've got multiple programs that we're developing as we speak that are -- earlier, that will piggyback on, hopefully, the positive data coming out of ENaC.

Got it. And have you done -- you referred to some preclinical models and studies. So have you done any long-term tox studies? And what kind of data have you seen there to give you confidence?

It's a good question. So we have begun chronic tox studies. Those aren't complete yet. We have -- we, of course, done acute tox that allow us to get into the clinic for the current program, which we really -- we're now just interrogating 2 dose cycles. The chronic tox, which will be done towards the end of this year will allow us to treat chronically. And so we don't have any data on that yet.

And when would you expect to have that data?

We should have that in the fourth quarter of this year, I believe. The clinical data have been encouraging so far in terms of safety. We still don't know what the activity looks like. We hope to see that over the next month or so. But from a safety standpoint, we've gone all the way through the highest dose in healthy volunteers, and we haven't seen anything that's been concerning to us. We have begun dosing in patients. We've only done the first dose cohort so far. We have started the second dose cohort. Again, we haven't seen any safety concerns so far. So we are cautiously optimistic. We have something that will be well tolerated, and we'll find out again over the next month or so, how active we are.

Got it. Okay. So can you walk us through this data that you're expecting over the next month? I mean there are 88 healthy volunteers, I believe. And then you had added another 12 or 15 healthy volunteers specifically to do BAL, And then you have 3 or 4 cystic fibrosis patients. Is that correct? So kind of -- so what should we be expecting to see in the 88 versus the new 12 healthy volunteers and in the cystic fibrosis patients?

Right. So we're not going to have a complete data set by any stretch of the imagination. Our hope here was that we had something that is interpretable and that we could push out to The Street to see -- to hopefully show The Street that we have something that appears to be working or at least we're on the right track. So I expect to have -- we will have BAL or bronchio-alveolar lavage data in healthy volunteers at the highest dose by the end of next month thereabouts. What we're looking for there is knockdown. What we're looking for present knockdown of ENaC. That's going to be helpful to us, right? That is going to tell us if we are getting into these proper cell types, if we are able to engage in these epithelial cells, if we are able to initiate this RNAi process and get knockdown. Again, if that's successful, it means we've got a franchise, as far as I am concerned. We will also have a very limited amount of patient data, really just the first-dose cohort. It's the lowest dose in patients. We only have 4 patients on active drug, 2 on placebo. And so that's probably only valuable as it relates to safety profile. We will be taking FEV1 readings, but FEV1 is such a noisy measure that I don't think that it will be interpretable with just 4 patients on active drug. Now going forward, as we fill out the study, we certainly will be looking for changes in FEV1. But I just think that it's probably too early to take too much from that. And so we're really focusing on the healthy volunteer data.

Understood. And you said the BAL is going to be done in the patients -- at the highest dose levels. And what is -- what are the number of -- what's the number of cycles and the dosing frequency relative to the other 88 healthy volunteers?

Right. Right. So again, it's not -- that's not patients, it's only healthy volunteers. And that's only a single-dose cycle. So for us, right now, we are testing a dose cycle is 3 daily doses. And so then sometime after that, we will be doing the bronchio lavage to look at knockdown. Over time, we expect to look at knockdown after 2 dose cycles. We also expect to do other studies where we can look at the duration of knockdown. But this first small data set will just tell us what the knockdown looks like at a single time point.

Got it. So 3 doses or 1 cycle of 3 doses.

That's correct.

And then the BAL. Got it. And in terms of some of the data that you've seen with your animal studies, how does the dosing in these patients tie into that, what you have seen there?

Yes. So it's -- we'll see how this translates to humans. The -- we have published some knockdown data in sheep at the same dose, and we were able to see as high as 70% knockdown in ENaC in those sheep that translated into about a doubling of mucociliary clearance. That's a big thing. That -- if we're able to achieve that in humans, I think that is substantial. Now I don't think we even have to be that good to be totally honest, in order to have a drug. I think that our threshold here is somewhere around 50% knockdown. If we can hit that, it -- I think that, that will be helpful for the CF patients. And the reason I use the 50% number is that, that's consistent with these heterozygotes that have been studied in the past, right, these folks who only make about half as much ENaC as a normal wild-type person. And that seem to have -- that seems to relate to a positive phenotype. So while look, more knockdown is better. I think as long as we can jump 50% knockdown, we really have something that can help these patients that really have nothing else right now. The -- our -- at least initially, our target patient population in CF are those patients who are null/nulls, who have no CFTR to correct. We think that's about 10% of the population. They have no real therapeutic options right now. And so if we can just increase their FEV1 by 3% to 5%, that's a big thing for them. So again, I'd like to go higher, but at the very least, if we can show that we have something that is helpful to them. Similarly, we can treat those patients who are refractory to Trikafta or who don't have -- who are not indicated for Trikafta because of the wrong mutation, et cetera. Those patients have limited options as well. And so as long as we can show some limited improvement in FEV1, I think we have something that can help them. And again, as a proof of concept, if we can just show consistent, even 50%, knockdown, there are clearly some -- a large number of targets that we can go after in asthma, COPD, IPF, that could be helpful. Again, my hope is we can go beyond 50%, but if we can just hit that, we have something that is really valuable as far as I'm concerned.

Understood. So can you talk a little bit about these 4 CF patients? Are they null/nulls? Or are they Trikafta refractory? What -- can you just characterize them for us?

Right. So I don't know about -- I don't know the specifics of those first 4 patients. The study is blinded and I haven't seen any of that yet. But I can tell you broadly, the study is bringing in all comers. And so presumably, there could be some null/nulls. It's a small percent of the population. So it wouldn't shock me if we don't have any of them in the study, but it's open to them if they do -- if we do find them. Some of these folks could be on Vertex drugs. I assume at least so far, none of them will be on Trikafta because we're doing this in Australia, New Zealand, where until recently, that was not an approved drug. But we're taking any CF patients who have a certain threshold of pulmonary impairment. So we've got room to help them. We think this drug should -- if it works as design and it works as we saw in the animal models, we think it will work equally well across genotype, equally well on top of existing drugs or as a single agent, we think it could be helpful.

Understood. And in terms of -- just kind of conceptually, the -- if it is being tested on top of standard of care, can you sort of discuss the considerations of ENaC, the balance of ENaC versus CFTR modulation and how that might play out over a longer time period of chronic therapy?

Sure, sure. So whether or not someone is on a CFTR modulator, should not decrease the activity of our drug, assuming that they still have impaired lung function. If they can come back to normal, then, of course, there's nowhere to go. But as long as the -- there's still impaired lung function, at least in theory, reducing ENaC expression should improve mucociliary clearance, and therefore, it should improve FEV1.

Got it. Okay. So maybe we can move on to the HIF-2. So there is a small molecule HIF-2 program in the clinic. And can you talk about siRNA approach and how that's potentially differentiated from the small molecule approaches to targeting HIF-2 and some of the advantages and concerns in set of patients?

Sure. So look, so we like this target. HIF-2 alpha, we know is important for the overwhelming majority of renal cell carcinoma patients because we know that they have this Von Hippel-Landau mutation. But there are also other tumor types that can be treated in this manner. And we're seeing it in the Merck-Peloton drug expanding beyond or we expect them to expand beyond RCC. We think that's a good increased validation for this target. We're excited about the target. So where would we fit in? Well, it appears that, that's a good drug. One of their issues is they see anemia in an awful lot of patients, as you would expect, given that you're knocking out HIF-2 alpha, this is an on-target effect. The opening there is that ours is a targeted approach. And so we should be accumulating our ARO-HIF2 preferentially around the solid tumor. And it should not go everywhere like a small molecule would. And so it's possible that we could expect less anemia than a small-molecule approach. That's a potential advantage to us. But look, I don't think that we have to be best-in-class here to have a drug. I think we have to be good. It's a good pathway. It's going to -- there are a number of patients that it can help, and I think having multiple approaches to this target is a good thing for oncologists and a good thing for patients. And so we just have to be on the board. We have to show that we're active, we have to show that we are well tolerated, and then I think we've got a drug. Also, as I said, the longer-term value of this study is as a proof of concept that we are able to address solid tumors. Our delivery strategy here is not specific to renal cell carcinoma, but rather is designed to work across solid tumors. And so to the extent that we can show that we get into solid tumors and we can knock down a gene target, we think we can bring this approach to a variety of new gene targets in a variety of different tumors. And so we think it's a potential real value creation moment if we see consistent knockdown.

Got it. Okay. So in terms of what we should be expecting to see from a data perspective, you talked about biopsies. So can you contextualize that for us a little bit? Have the biopsies been completed and set the bar for us a little bit there?

So some biopsies have been depleted, but not all of them. We haven't seen data yet. We expect to have biopsies from the first 2 dose cohorts, obviously, the 2 lowest doses. These are paired biopsies, we are biopsy metastases. And so we'll be looking for a knockdown of HIF-2 alpha. I don't expect that we will -- actually, I know that we're not going to have a complete data set because we know that there have been some patients where we just couldn't get enough tissue in the second biopsy. But my hope is that we'll have enough data that will be interpretable. So if, in fact, we are able to get consistent knockdown, we can see it in these 2 cohorts.

Got it. And what is the n for those 2 lowest doses?

That's a good question. I don't know how many we're able to -- I don't know how many patients we were able to biopsy the second time. It's probably in the 4 to maybe -- 4 to 5-or-so patients per cohort, thereabouts. Again, I'm not sure how many got a second -- a positive second biopsy.

Understood. And you've talked about the bar here as about 50% knockdown for some therapeutic benefit. Can you help us understand sort of what preclinical data or what you've seen that kind of gets you to that 50% knockdown number?

Yes. So that's -- the 50% knockdown is really just to tell us that we are on the board. I don't know how much knockdown you need to get to have a therapeutic effect. When we think of what success is, right now, it's 50% because it gets us on the board. These are 2 low doses if we can be around there, then it says to us that if that's not enough, we can continue to dose escalate to see higher knockdown because also, it's -- again, the value here is not just in HIF-2 alpha, but the value here is a proof of concept that we can get into the solid tumors, and that threshold of knockdown percent in terms of therapeutic benefit will be different from target to target. And so if we're consistently seeing enough -- seeing 50% knockdown in HIF-2 alpha, that says to us that we will be able to find a number of good targets that the 50% knockdown is going to be helpful because, like -- as with most cancer drugs, I expect this will be part of a cocktail. Cancer is hard. And so more knockdown is better. And so to the extent that we can get -- that we can increase that above 50%, that's even better. But as long as we can get some knockdown, that tells us we're on the board, and we can work with that and see where we are going forward.

Got it. And I have a question here on e-mail. And the listener wants to know just in terms of on-target effect of ENaC outside of the lung, how are you -- what data do you have to sort of be comfortable that there's not enough leakage out of the lung?

Yes, it's a great question. So that's been one of the reasons that this has been an undruggable target because people have had a hard time reducing it enough in the lung, but spare it in the kidney. We know that if you reduce this, if you reduce ENaC in the kidney, you induce hyperkalemia, which is toxic, of course. So we did it. We've done exhaustive studies in animal models, looking for -- first, looking for changes in potassium, we just never saw it. We then went even deeper and looked for any kind of knockdown in the kidneys. We just didn't see it. We then -- and we weren't shocked by that, right, because this is administered via inhalation. And so not a ton of material is going to get into the peripheral set. But we then said to ourselves, okay, what if we inject this directly in the blood stream, IV or subcu? And even then, we didn't see any knockdown in the kidney. And we think the reason is we know that the oligos are cleared -- when they're cleared by the kidneys, they're cleared generally in the proximal tubule. So we don't think very much oligo that gets in the circulation, gets to the distal tubule where knocking out ENaC could be problematic. And so look, there's a thousand reasons why this program may fail. I don't expect that renal tox is going to be one of those reasons.

Got it. Okay. And I'm not going to ask you to list the 999 other reasons that this might fail. All right, so just going back to HIF-2 here for a bit. Assuming you have -- you see that 50% knockdown level, what is your strategy here? Because you've always sort of talked about pulmonary and cardiometabolic as the 2 areas where you can go independent. With oncology, how are you thinking about that platform if you see a signal?

Right, right. So first, and let's be clear, if we see 50% knockdown, that means we're successful at this point, but we're not quitting. We'll continue to dose escalate. And hopefully, we can continue to see even better knockdown because that just gives us more potent drugs and gives us more targets we can go after. But -- so the question is what do we do with this? Look, oncology is hard. And so we would, at some point, like to have a good partner to help us to expand this platform. We think it's potentially a powerful franchise. If we see good data in the HIF-2 alpha program, it will suggest to us we've got a franchise. We'd like to exploit that, at least partially with a real oncology partner. We're not even looking for that partner right now, and let's see what the data look like and if they're positive, let's go out and see if we can find the right partner. With HIF-2 or without it, frankly, we're really looking to build out that platform. So in the long term, look, I wouldn't be surprised if we have -- if we commercialize some oncology drugs ourselves. But at least early on, it would be helpful if we could bring in a good partner to help prioritize targets, et cetera.

Got it. So you think the ligand conjugation chemistry you have, that could be applied outside of HIF-2? Or are you talking about HIF-2 expression in other solid tumor types?

Yes, yes. So our -- we are targeting integrins. And so we know that solid tumors upregulate integrins. Specifically, we're targeting alpha(v)beta(3) and alpha(v)beta(5) integrins. Again, we know that the solid tumors upregulate those. And so there are a whole host of solid tumors that we think we can go after with the same basic targeting strategy. Now, we can go after them with HIF-2 alpha with ARO-HIF2, some of them, but also -- but others that are -- that might not be HIF-2-alpha-dependent, there are any number of gene targets that we can go after. Again, this is a good proof of concept if it works that we're able to get into the solid tumors and knock down any gene product. Once we see that, there should be, gosh, dozens of follow-on possible drugs there that we could go after, I think.

Got it. Okay. I'm going to move on to AAT here. So one of the big questions we often get on the AAT program, and you've had really great data, but sort of the patient segment that you're targeting with liver diseases, and if you end up knocking down AAT over the long period of time in depleting it, what are the implications for the long really?

Yes. That's a good question. So the lung disease is a slow progressing disease. We know that. And when we first got into this, that was a concern of ours. If we are knocking down expression of AAT in this population, are we maybe trading liver disease for lung disease? In other words, are we treating the liver disease but then making -- exacerbating the lung disease? And what our KOLs thought was, you know what, probably not for a few reasons. Reason one is that these patients are producing a very small amount of bioactive -- I'm sorry, a very small amount of AAT anyway. And so knocking that down further may not have any real long-term effect. Second, that which gets out of the liver, these misfolded proteins are only about half as bioactive as the wild-type protein. So not only are they low levels, but they're not very bioactive. So again, we're not -- we're probably not changing their protective -- their protections very much. Third, we are not knocking this down in the lungs. We know there is some local production of AAT and we only knock down AAT in the liver. And so that's retained. And then finally, because it's a slow progressive disease, if we knock it down for a short period of time, and then even if you have a longer-term intermittent therapy, our KOLs didn't think that this is going to have an effect on lung disease. So that's all in theory, that made us comfortable. We went forward. And now we've been in a large number of patients between our open-label study and the SEQUOIA study. We will we're around 50 patients so far. And we give the sites pretty wide berth on using enzyme replacement therapy if they believe that they need it. And not a single -- to my knowledge, not a single person has been initiated with this enzyme replacement therapy. No one's needed it so far. So that's hard. Now, some patients came on study with enzyme replacement therapy, and of course, they stay on therapy. But there's been, again, to my knowledge, there's been no need for rescue therapy. So that also gives us some confidence. And then finally, look, I think people have thought of AAT as a lung disease first and a liver disease second. I think we are in the process of turning that on its head because now we are in a generation of patients who might have never smoked in their life. And so we know that altering behavior like not smoking, like staying away from environmental pollutants, can keep people from having severe lung disease. And so I think that going forward, keeping that in mind, I think this becomes primarily a liver disease rather than a lung disease, because the liver disease is untreatable. There's no behavioral means, there's nothing short of liver transplant to treat that. And so I think that as patients are living longer because they're not dying of the lung disease, you're going to start to see much more often, the liver disease. And so that's why our therapy, we think, is a really important one for these folks who just have nothing right now.

Got it. Let me turn that question around a little bit and ask you in a different way. If you're knocking down the protein and -- to essentially clean up the liver. Is it possible? Or have you seen any data to show that in patients with liver disease, basically enabling correct folding of the protein would clear liver disease? Or would it just prevent further deterioration of the tissue?

Yes. So we've seen stunning data, as you know, that, frankly, between you and me and anyone who is watching this, the market has not fully appreciated. What we saw is after only 6 months of therapy, 2 of 4 patients had a reversal of fibrosis. And oh, by the way, those 2 were cirrhotic. We rescued them from cirrhosis after only 6 months of therapy, shocking. And then after 12 months of therapy, 4 of 5 patients showed a reversal of fibrosis. If you were to see that in NASH, it would be everywhere because it's such a powerful and vast therapy. The reason we're seeing that is because our drug is so good at turning off the production of this mutant protein. We know the biology here is clear. It is the misfolded protein accumulated in liver that causes that liver disease. And so we stop it in its tracks and allow the liver to heal itself. If the approach here is to fix the misfolding, there's a few challenges there. Challenge one is that this is an extraordinarily -- this is a protein that is made at extraordinarily high levels. It's thought that the liver makes about 2 grams a day. So it is inconceivable that you could correct 2 grams of protein a day. The stoichiometry just doesn't work. So now you're looking at correcting a very small percentage of that. And I think that's where this approach will be very difficult for liver disease because at the end of the day, we are taking away essentially 100% of the insulting protein compare that to taking away a small percentage. I just don't think that's competitive as it relates to the liver disease.

Understood. Okay. Great. That's a great summary. So maybe you could talk about your muscle-targeting agent now. It's sort of the newest -- you've been talking about it for a long time, and you finally sort of disclosed what it is, the DUX4. Can you share a little background here in terms of what the process was to identifying this as a target? And then how did you decide on FSHD as an indication?

Right. So we have been trying to develop a muscle-targeted approach for a while. As you know, we've got -- we now have lung-targeted approach. We have a solid-tumor-targeting approach. We were working on muscle for some time. We finally got there, I think. We expect to file CTA sometime by the end of the summer for this first program, and we'll have our first slug of animal data that will be published sometime in June. So we're excited for that to be out. So FSHD is an interesting opportunity. On the face of it, it's a very difficult first approach, right, because there's no circulating biomarker. The way to figure out if you're working is you're going to have to do biopsies, that's not so easy. So that's the bad news. The good news, though, here is that -- for these patients, is that we don't have to be perfect here to help these patients. And so what I mean by that is that FSHD is caused by the expression of this DUX4 that should not be expressed in your body anywhere. And so if, in fact, we are not terribly specific or not surgically specific in this first attempt, that's okay because there should be no DUX4 expressed anywhere else in your body that you want to to allow to continue to express. So the bar there is fairly low for us. Second, there's no treatment for these patients. This is a fairly significant muscular dystrophy. And these patients just have no real therapeutic options. And so again, we don't have to play perfect baseball to really to provide them some relief. That was all very attractive to us. So we're cautiously optimistic. Our animal data have been quite good. You'll see some of that next month. And now it's time to see if we can translate into humans. If we can, again, view this in a similar fashion, as I'm asking you to view ENaC and HIF-2 alpha. Look at this as a drug. I think ARO-DUX4 could be a powerful drug against FSHD, but also view this as a proof of concept. If we show good knockdown in these patients, it suggests to us that we've got yet another franchise. And there are a number of other muscle targets we can go after to treat other diseases going forward.

Got it. Okay. I just realized there's a whole host of questions here on the chat. So I'm going to take a moment to kind of run through some of them, and then we can hop back on to mine. So the first one here is on the AAT. Is there still a strong case for filing an early NDA accelerated approval, how is the data progressing?

Yes. So I'll tell you where we are. We are filing for RIG therapy. I think we have a good argument as to why we should get it. We'll see if the FDA agrees with us. We will be presenting data from the 6-month paired biopsy group, from the 12-month paired biopsy group. And given the data that we -- that's already public, you know that -- it feels to us like we have a good shot there. If we get that, then we can start to have a dialogue with the FDA, and it is our position that an approval endpoint could reasonably be simply lowering hepatic burden of ZAAT protein. The biology here is clear, as I said, we know that the accumulation of that protein causes the liver disease. And so to the extent that we can show that we can reduce that, in fact, almost entirely remove it, that should be an approvable endpoint. Now we're also happy to have, as a key secondary endpoint, the reversal of fibrosis, given that we -- that, that seems to happen much more rapidly than we expected. So look, we think we have a good argument as to why that should be our path, and we'll see what the FDA says. In the past, we've spoken with them about this disease. And we've had a very good collaborative relationship with them, and so we expect that going forward. They appreciate the severity of this disease. They appreciate that there's no therapy for the liver disease associated with it. So I think that we have a good productive partner in this. And so we'll just see where this goes this year, but that's our near-term strategy.

Got it. Okay. And kind of staying on AAT, are you recruiting cirrhotic patients? Or is that something that you're planning to do going forward?

I think we would probably do a study -- a second study that only treat cirrhotics. The open-label study, as you know, we had 2 cirrhotics in the 6-month paired biopsy cohort. And we rescued both of them, 2 for 2. One was F4 and after 6 months, it was F3, one was F4 and after 6 months, it was F2. So we are -- we were surprised about how well this seems to work. Now it's a small -- and, of course, so we'll have to do larger studies. But yes, we will do studies in cirrhotics.

Got it. Okay. And then kind of moving on to ENaC, here is a question. How long does it take to dose ARO-ENaC with a nebulizer?

Yes. So we'll see what -- we're dose escalating. And we'll see what dose we end up with. But depending upon the dose, it's not so long. I believe it's in the 10- to 15-minute range, thereabouts. But again, we'll see what the ultimate dose is going to be, and that will tell us how long we're nebulizing. Look, I think there's a lot we need to learn still with ENaC obviously. But if we see good knockdown over the next month or so, that will lead us to do a number of follow-on studies really throughout the rest of this year to look at durability and the like. I'm cautiously optimistic that we should have good durability given what we know about RNA interference. It's a catalytic process. Once we get into a cell, we should be able to continue to knockdown any gene product for a fairly long period of time. I don't believe that these epithelial -- these pulmonary epithelial cells are going to turn over very rapidly. And so it tells me that we should have a good, durable approach. If that's the case, when you start to think about not just cystic fibrosis, but severe asthma, severe COPD, IPF, it's not crazy to think that we could be treating patients fairly infrequently. It's a pretty light touch to think of a 10- or 15-minute nebulizing event once every 2 weeks or 4 weeks or beyond that. We feel pretty good about our anticipated dosing schedule.

Got it. Okay. I have a question here on ARO-JNJ1. What disease is that targeting? And where -- what's the update on that program?

Yes. I don't have much update on that. So as you know, they -- as part of the HBV collaboration with Janssen, they had an option on 3 additional targets. Now they had to bring us those targets. They couldn't come from our pipeline, it couldn't be anything that we're working on. These are true novel targets. They -- as I said, gosh, on a conference call, sometime ago, that we had given them everything that we are required to give them. And now -- and at that point, going forward, they have some period of time to choose to take an option or not. And they took an option on the first one so far, JNJ1, they have not allowed us to disclose what that target is. My hope is that they'll announce that or allow us to announce it sometime later, but right now, we have to stay mum on that.

Got it. Okay. And then any update on the ARO-COV program, the COVID program? Is that...

Yes. So we're generating data in animal models. And look, I think we're on the board. I think we're -- the data so far are encouraging. But let's talk about what that is, and what that isn't. The good news for the whole world is that we have some vaccines that work very well. That's great news. We are now looking to displace those vaccines because they're quite good. What we're looking at here is, is there an opportunity for us to create a therapeutic or prophylactic that could work across other SARS viruses. If there's one thing we learned is that there will be a coronavirus outbreak every 7-or-so years. And it looks like they're really severe. Those are going to be SARS-related coronaviruses. And so our hope is that we could find well-conserved regions that could work across various SARS, known and unknown to use prophylactically or therapeutically for the current one or for future ones. So that's where we're still working. We are still far from having something that is clinic-ready. But we're on the board, and I think we're moving in the right direction. This -- there's also an opportunity for the current coronavirus in those patients, who are unable to take -- immunosuppressed patients that wouldn't benefit from vaccine. There's a possibility there. But again, our long-term approach here is a broader approach across other SARS viruses and also as a proof of concept, that we can go after respiratory viruses. I talked about these franchises, right, the pulmonary franchise broadly, the solid tumor franchise, the muscle franchise. Think of pulmonary viruses as its own franchise, going after influenza, parainfluenza, RSV, things of that nature. And so this is -- this will be a good proof of concept, I think, about whether or not we can think about that kind of franchise.

Understood. Okay. Kind of switching back to DUX4 here. Is it a conjugated siRNA?

It is. Yes, yes. So everything we do is structurally simple. It's an RNAi backbone that is chemically modified with a targeting moiety conjugated directly to it, so yes, that's the approach we're taking for DUX4.

Got it. And just from a competitive standpoint, there are other -- 2 other agents in early stages of development. How -- and it's a fairly small patient population, so how are you sort of thinking about the competitive positioning of your agent versus the others?

So we have no control over those. What we what we can control, or what we can focus on is making the best drug that we can and moving as quickly as we can to patients. We are going to be -- I expect that we're going to be the first one by, I think, a lot into the clinic against FSHD. And so that's going to mean something. And I think we're going to have a good drug. That's the only thing we can focus on right now.

Got it. Okay. So in terms of the partnership, that you have outside of Takeda, are there -- what are some meaningful milestones or catalysts that we should be looking at from your partnered programs?

Sure. So the partner programs are, as you know, HBV with Janssen. I don't know when they're going to have data from the first Phase IIb study. They are doing a number of Phase IIb studies internationally. They have moved very quickly into these large studies. And so far, we are thrilled to have them as a partner. We haven't seen any data yet. And so we're optimistic that, that drug is going to work across patient populations, but we'll see. Again, I can't give you any guidance on when that -- on when we'll see that, but we're crossing our fingers. So we're looking forward to seeing those data. We have a partnership with Amgen on Lp(a). They are conducting the Phase II study right now that I think they believe will be complete early next year. Again, I haven't seen any data there from the current Phase II, we did see data from the Phase I study. And boy, that's a good-looking drug, appears to be very potent. They're using low doses. We'll find out what the durability is going to be, but we're excited about that. And again, they appear to be the right partner, and they appear to be as motivated to move that forward quickly as we would be. And then Takeda with AAT, they are -- we're still controlling the assets. We are still doing the Phase II studies, but we're in close contact with them. The next data set would be at EASL, which will be a larger, more complete data set from what we top lined a few weeks ago.

Got it. Okay. So just taking a step back, and you've talked about sort of setting up these different franchises with the same technology platform. And one of the biggest untapped challenges is in CNS. So how are you about that because some of your -- some of the other RNA players are talking about conjugated approaches of getting siRNA into the CNS. So have you done any work on it? Is that something that we should be keeping an eye out for the future?

Yes. So we are -- that's not a focus of ours right now. It's too large an opportunity for us not to focus on it in the future. But right now, it's not a big focus for us. We've got our hands full with pulmonary, solid tumor, muscle and some others. But I'm sure we'll get there. Look, we -- I like -- I can say right now that if you go down our pipeline, every one of our clinical programs, we were the first RNAi player in that -- against that target. I like that model. We'll continue to do that. We'll get to CNS eventually. But right now, I think we can create the most amount of value by really focusing on these other areas where we are alone, muscle, solid tumor and pulmonary and build value there.

Great. Awesome. So we are -- our time is up, but questions are a lot. So we look forward to having you back here sometime again. And good luck with upcoming catalysts.

It's been a real pleasure. Thanks so much, Esther.

Yes. Talk soon. Bye-bye.