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Home  /   Forum   /   Arrowhead Research   /   Forum Arrowhead Research geopend

Aandeel Arrowhead Pharmaceuticals OTC:ARWR.Q, US04280A1007

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Forum Arrowhead Research geopend

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Pagina: «« 1 ... 129 130 131 132 133 ... 429 »» | Laatste | Omlaag ↓
  1. Missolapola 24 november 2020 08:22
    Christopher Anzalone

    And when we first got into pulmonary, our first question or among of our first questions was whether not we are able to get through the mucus and our KOLs were non-plus by that. They said, you know what, given the size and charge of the molecule, we don't expect any problem to get the mucus and sure enough in animal models, whether it be rodents or NHPs or sheep, we've done that to be the case and so that was heartening.

    We then, asked what about CF mucus? We know that's dehydrated. We know that that's a bit different. Unfortunately, as Javier said, there is not a good animal model for that. However, we have done in vitro analysis using actual CF mucus and it does appear we are able to get to that. So we are optimistic. You never know until you know and so, look these – this first study will tell us an awful lot about the translatability of this platform. But we go into this reasonably confident given our good pre-clinical data.

    Shawn Egan

    Great. Thank you so much.

    Christopher Anzalone

    You are welcome.

    Operator

    Thank you. And our next question comes from the line of Maury Raycroft with Jefferies. Your line is now open.

    Maury Raycroft

    Hi, everyone. Congrats on the progress and thanks for taking my questions. First one is also on ENaC and HIF2alpha also so, for both programs can you provide more specifics on where are your outlook dosing. Are you at a therapeutically relevant dose? And is there anything else you can say on safety at this point?

    Christopher Anzalone

    Yes. So there is not so much we can say on that. It's been our policy, as you know Maury, not to give blow by blow. We have given some interim data before but in a more – in a different sort of environment. So, we can tell you that we are dosing patients in the early next study. We are at that portion of the study. So, that is encouraging. HIF2alpha of course we are dosing patients.

    Examples, I can tell you at this point, I don't think, with ARO-HIF2 we have not seen any data yet, those data are batch. And so at some point I hope in the near future we will see some early data that will indicate whether or not we are seeing knockdown at these first doses. But at this point, we just don't even know internally.

    With ARO-ENaC, we have just begun the patient portion and so we don't have data there yet to know we are in a therapeutic range. That's the big unknown for both these. We have a good idea about what the therapeutic range would be in animal models, but we'll just see how this translates. And this really is uncharted territory for us.

    We have a good idea about how things translate from rodents to NHP to humans in hepatocytes. This of course is our first foray into solid tumors and pulmonary epithelial cells. And so we'll learn a heck of a lot over the next few months.

    Maury Raycroft

    Got it. That's helpful perspective. And then, for the initial data updates mid-year 2021, have you decided if you are going to report at a conference or in a press release and then, any thoughts on the amount of patients you are going to include in those initial data updates?

    Christopher Anzalone

    Yes. It's really too early to tell there unfortunately. When we look at the calendar, we – it appears that we will have some at least preliminary data by the middle of the year. But how much we are going to have is not clear and therefore what sort of venue we can share these data are not clear. And so, unfortunately I can't give you a good answer for that at this point.

    Maury Raycroft

    Okay. Understood. Thanks for that.

    Christopher Anzalone

    Yes. You are welcome.
  2. Missolapola 24 november 2020 08:23
    Operator

    [Operator Instructions]

    Christopher Anzalone

    We appear to be having some technical difficulties and the question queue has disappeared. So, we'll give everyone a few minutes to get back into that queue, because right now it seems to be gone. Okay, now we can’t do it now. Go ahead operator. You can move on to the next question.

    Operator

    The next question comes from the line of Alethia Young with Cantor. Your line is now open.

    Alethia Young

    Hey guys. Thanks for taking my question. I got the whole thing went dead for a second. But I am glad to see that we are all back up and running. I just want to talk a little bit about and it's a little bit big picture, just, how you are kind of outside the extra-hepatic liver approach differs from some of your competitors?

    I know you don't want to give away the whole secret sauce, but I guess, we are like some inherent like big picture differences and things that you think about, I mean, many companies say this is something they are pursuing, you guys are pursuing it in a very robust way. So, just wanted to – I've gotten this question before. So, I just wanted to pose it to you guys.

    And then, also, can you talk a little bit about your confidence on going after HIF, I mean, as those studies get going, I know it's sometimes it's been a little tricky in RNA and kind of in that world of HEM, but just wanted to get kind of your perspective with your technology.

    Christopher Anzalone

    Sure. So, the first question, let's see, we have been thinking about, as you know Alethia, you have followed us for a bit, we've been thinking about and working on bringing RNAi outside the liver for probably a decade now. This spans our – even our prior platform that we are developing. We always knew this is going to be an important value inflection point.

    So we wanted to be there. So, a lot of this is just brute force. We've been working on this for a decade now and so, we looked like an overnight success, except for it's a bit of ten year overnight. So that's more broadly.

    More specifically, of course, part of that is building library of linker chemistry is that we can use to optimize delivery. It involves establishing a library of targeting MOIDs that we can use and maybe most importantly, it involves our ability to design these very potent RNAi triggers.

    Again, as you've heard us talk about in the past, Alethia, we have a set of algorithms and rules that are proprietary that enable us to design triggers that may not be potent in vitro, but will be potent in vivo. And look, that's important as it relates to getting to podocytes because it does allow us to make more potent podocyte-directed constructs.

    Look at the LP(a) data that Amgen showed. That was a very potent – appeared to be a very potent sequence. But it's absolutely critical when you're looking at going outside the liver, because we know that there is no GalNAc analog, if you will, in other cell types. There is nothing – there is no front door like that in other cells that we've ever found.

    And so, we need to squeeze all the potency we can out of these constructs. So that ability has been just critical in our ability to rapidly expand into long and solid tumor and next year at muscle cells. We hope to continue that as we talked about. This is a big part of our value proposition. This is a big part of our model.

    Now, the next question was around HIF2-alpha. So, are you asking about what we need to show vis-a-vis the Peloton Merck drug? Is that what you are curious as about?

    Alethia Young

    Well, a little bit, yes, kind of just to get a flavor and context of that. Yes.
  3. Missolapola 24 november 2020 08:24
    Christopher Anzalone

    Sure. So look, so that – that's been a great program. The data have looked pretty good and that has helped to further validate a target that we've been excited about also for, gosh, almost a decade. There is an opening, however. They have seen some anemia that we may see less of - it's too early to tell, but we may see less of, because we are targeted.

    But at the end of the day, I think we just need to show a well-tolerated and active drug. That's a big enough market that there is plenty of room for a couple of us. I don't – I am not absolutely focused on showing X percentage better responsiveness than the competitor drug. I think we just need to be on the board. And we are hopeful we can be there, because as again we've – as we talked about the past, that program has value for us in two ways.

    One, we think it's a good drug, and we think it could be a helpful drug in renal cell carcinoma, we think it could play well with others because we don't expect a lot of overlapping AEs, so that is exciting to us. But second, it's a good proof-of-concept.

    If we can show that we can knock out HIF2-alpha in these metastases, it will suggest to us that we have a platform, that we have a franchise and then we can go after other gene targets and potentially other solid tumor types. As we said in the past, our targeting strategy here is not specific to RCC metastases, but rather we believe it could allow us to get into solid tumors more broadly.

    Alethia Young

    Great. Thanks.

    Christopher Anzalone

    Sure. Thank you.

    Operator

    Thank you. And our next question comes from the line of Salveen Richter with Goldman Sachs. Your line is now open.

    Salveen Richter

    Thank you. Just another question here on extra-hepatic tissues you plan on targeting. Could you just walk us through your thoughts beyond the lung and muscle with your strategy? And on the skeletal muscle targeted asset, which is entering the clinic in mid-2021, when we might get to see pre-clinical data here? And any thoughts you could provide us on the initial indications that you may be targeting?

    Christopher Anzalone

    Boy! I apologize. You asked a lot of questions there and I really can't answer any of those. Again, we’ve talked about solid tumor of course, and skeletal muscle and lung. We are working on other cell types. We've not disclosed any of those yet. And so, we're not prepared to disclose any of those at this point. But we clearly have others that we're working on.

    As we talked about, this is a big part of our growth strategy. What we have done for the podocytes, we want to do for lung and solid tumor and muscle and for fill in the blank number of additional cell types.
  4. Missolapola 24 november 2020 08:24
    With respect to – gosh, I am sorry. What was the other question?

    Javier San Martin

    Targeted for muscle.

    Christopher Anzalone

    Target muscles. Sorry. Right. Again, we haven't talked about that yet. We gave some – we have mentioned some early data - I think, at our R&D Day last year. We haven't really shared any non-clinical data since then. I do expect that we will do it. But we're just not prepared to do it quite yet.

    And I am not being coy. I don't know when we are going to do it. We feel confident that sometime in the summer, I believe we will be filing at CTA for that asset. And so some more upstream of that we will talk about in more depth. But at this point, we are just not quite prepared to do that yet.

    Salveen Richter

    Thank you.

    Christopher Anzalone

    Sure.

    Operator

    Thank you. And our next question comes from the line of Ted Tenthoff with Piper Sandler. Your line is now open.

    Ted Tenthoff

    Great. Thanks guys, and congrats on the progress. Really exciting just to see how far the platform has come along and then to see the recognition. My questions really had to do with the cardiovascular programs. While it's interesting to see Amgen mentioned LP(a) on a – in the press release this morning.

    I am trying to get a sense for what the costs of these Phase 3 and Phase 2bs could be appreciating that you gave the guidance of $200 million to $250 million next year. When it comes to an outcome study, what kind of cost should we be thinking? Thanks very much.

    Christopher Anzalone

    Yes. I guess, I apologize, Ted. These are important questions. But I can't answer them. We've not given guidance on what we think those costs are going to be. At this point, we've talked about how large we think those phase could be. The Phase 2b studies for the large outcome study for ARO-ANG3 it's not even clear what the number of those patients are going to be yet.

    They probably range anywhere from 8,000, if you look at Ameren studies or Medicines Company studies, all the way up to may have 15,000. And so, we need to see what our Phase 2b data look like before we determine how large that phase is going to have to be and then, at that point, we might be able to give you a bit of guidance on what we think that's going to cost.

    For your model right now, I think you could plug in what those costs generally are for a company like us for the Ameren type study or The Medicines Company type study, but I can't give you better guidance than that unfortunately, I apologize.

    Ted Tenthoff

    No. That's okay. I think that makes sense with the potency of the molecule. Great. Thank you very much. Looking forward to exciting 2021.
  5. Missolapola 24 november 2020 08:25
    Christopher Anzalone

    You are welcome. Thanks, Ted.

    Operator

    Thank you. And our next question comes from the line of Mani Foroohar with SVB Leerink. Your line is now open.

    Mani Foroohar

    Hey guys. Thanks for taking the question. I guess, building off of what Ted asked earlier, so I know you can't give specific guidance around the cost of some of these trials, some of which were a few years away, so of course, pretty tough to -big estimate that far out.

    But you got a lot of trials going through early, mid, late stages and as you think about some of these assets moving forward, give us what your metrics are in terms of gating to move assets forward as opposed to deprioritizing or shutting down programs? And how do you think about that at each stage of development?

    Christopher Anzalone

    Sure. So, I think the real question there is strategic, right? I don't think we – that we have – I don't think that we are considering shutting down in the programs right now. I think the question is do we partner these programs or do we hold on to them internally. Right now, it feels like we can build out our commercial infrastructure for pulmonary and cardio metabolic.

    We have a good line of sight, I think, on half a dozen potential pulmonary drugs that we can develop. There are 16,000 pulmonologists in the U.S., and so we like that leverage of addressing a fairly larger market with only about 16,000 touch points where we can sell any number of drugs into it. That makes sense to us.

    Cardio metabolic as well, look, we think ARO-ANG3 and ARO-APOC3 are potentially big drugs and we could see ourselves building a sales force addressing cardiologists and lipid clinics to sell those two drugs that makes sense to us.

    As we go forward, those will not be the last two areas that we are going to build commercial infrastructure around, I think that's for sure. But right now, given our current clinical pipeline, we can make that forecast. As we bring in additional candidates into the clinic and as we address new cell types, we can expand that going forward. But right now, that makes sense to us.

    So, then, when you look at our assets outside of that, it doesn't mean that we are going to partner all those. It just means that that we've got a little bit of a higher bar I suppose when we think about building another sales force there. So, say take for instance HIF2-alpha, if that's our only oncology drug, it makes no sense for us to build a lot of sales force to just sell one drug.

    If that becomes a franchise, like we think it could, that could make sense for us to add on a commercial franchise there. It could also make sense to do a hybrid approach of finding the right oncology partner to help us build that out and also establish commercial jobs. It's a bit too early to tell at this point.

    Mani Foroohar

    Thanks guys.

    Christopher Anzalone

    You are welcome.
  6. Missolapola 24 november 2020 08:26
    Operator

    Thank you. And our next question comes from the line of Luca Issi with RBC Capital. Your line is now open.

    Luca Issi

    Terrific. Thanks for taking my question. Just two quick ones. The first one, I think I saw on clinicaltrials.gov that the size of the HIF2-alpha trial has been recently reduced from 40 patients to 80 patients. So, wondering if you have any color there? And maybe more broadly, saw some partnering I think you just articulated, but any thoughts there? Big picture thoughts would be helpful.

    And then the second is, I think it would seem some data for Ionis on the ENaC antisense oligonucleotide. Again, wondering if you have any thoughts on that data set. Thank you.

    Christopher Anzalone

    Sure. Javier, do you want to take the clin trials, as well as the ENaC? And then I'll circle back.

    Javier San Martin

    Sure. So, the HIF2 study, correct, we changed an amended the protocol early this year, I think was March or April and the reason was to reassess really what we wanted to learn from that study. And there is two really things that we care about. Number one, safety and number two, if we are able to get into the cells and knock down HIF2.

    In order to do that, we didn't need really 40 patients. Initially it was – I guess, very ambitious program to really evaluate different doses or sequences and then we made the decision to sell it to the first thing first, which is proof-of-concept that we get to the tumor and we knock down the gene as we've done with all of the liver targets. So that's the reason to do that, get the proof-of-concept and safety reg as early as possible.

    Christopher Anzalone

    Okay. And so, I piggy back, then I'll piggyback on that for the HIF2 partnering. So look, we are excited about that franchise and about that platform. Having said that, oncology is hard. And so, in a perfect world, we can achieve proof-of-concept for HIF2-alpha to show that we can do this and then bring in the right oncology partner to help us prioritize our next set of targets and then do some with our partner and then maybe some by ourselves.

    That's where we are right now. Do we have to partner HIF2 the candidate itself, not necessarily, but I do hope that the data will be compelling enough to enable us to blow out that platform, if you will, and the best way to do that would be, at least, in part with a partner. And so, Javier, do you want to talk about ENaC with Ionis?

    Javier San Martin

    Yes. So we look at that data carefully when we disclosed that a month or so ago. My opinion on the data is that it's not as consistent as initially, I think we thought, because it is four of those groups and only one show a movement within about 50% knock down and that was in the highest dose – was the second highest dose.

    So I think first glance, it's interesting. It got our attention and we are working on it. We decided to really work and see if we can replicate that and show our data. So we're in that process to think about or work on the development of the proper assay and we're thinking about how to do this in the clinical trial, whether it's going in normal healthy volunteers and/or patients. So, we're working on it. It was interesting. But again, as I said, I have my question mark about that data at this point.

    Luca Issi

    Terrific. Thank you.

    Christopher Anzalone

    You are welcome.
  7. Missolapola 24 november 2020 08:27
    Operator

    Thank you. And our next question comes from the line of Madhu Kumar with Baird. Your line is now open.

    Madhu Kumar

    Hey, everyone. Thanks for taking our questions. I guess my first one is kind of the elephant in the room, which is the REEF-1 trial with JNJ in hepatitis B. So, kind of by our back to the envelope calculations near the end of last year is what we might expect, kind of the 48 weeks of treatment from that trial to kind of conclude, plus some degree of number crunching.

    Do we expect to get visibility from JNJ about the kind of timing for the release of at least the 48-week treatment data from REEF-1? Like, how do you think about any kind of data cadence from that hepatitis B trial?

    Christopher Anzalone

    Thanks, Madhu. So that was funny. So you asked about – you mentioned the elephant in the room and I was thinking, which elephant is that and REEF-1 was not – didn't even come to my mind. Okay. So, I can't give you any guidance on that. You'll have to look at JNJ for that. As I recall, it was 48 weeks of treatment and then six months of follow-up. And so, so, that's the best I can give you at this point.

    I can tell you, and we've talked about it in the past, we are really excited about that drug candidate. We're really excited about JNJ. We think that they have been extraordinarily fast and thoughtful about all these trials and that they are starting its multinational. And so, all of that makes us really excited to be their partner, but I can't give you any guidance on when those data might come out.

    Madhu Kumar

    Okay. And then, moving onto AAT. So you mentioned - here you mentioned before this idea of streamlining kind of clinical development of AAT based on the effects you've seen in the open-label extension. So, I mean, how are you thinking about that? Are those some kind of like nominal precedence we should be looking at for kind of endpoint comparisons or kind of composite endpoints that might come to play in the trial in Alpha antitrypsin liver disease?

    Christopher Anzalone

    So, Javier is probably dying to answer that question, but I can't let him answer at this point. Here is the deal. We were so excited about those data for a lot of reasons. I believe that – which is that, is that, it suggests this drug is doing what we wanted it to do, in fact, doing a bit faster than we expected. And so, we are going with those data and probably some additional data to the FDA to talk about changing endpoints and changing size and maybe changing the duration of the study.

    Until we have those discussions, it's probably not appropriate for us to speculate on the specifics of what those changes could be. I don't want to get out in front of this conversation. We've had a very good collaborative relationship with the FDA as it relates to this program. We expect this to continue to be collaborative and I just don't want to jeopardize that. I want to have that discussion – an open discussion with them and then, come back to you and tell you what we have decided together.
  8. Missolapola 24 november 2020 08:27
    Madhu Kumar

    Okay. And then, stepping back on the macro, so, you mentioned at the beginning of the call, the idea of going after targets where there is kind of validation from the outside scientific community. So, what does that exactly mean? Like, are we talking kind of genetic validation? Are we talking like earlier kind of iterations of therapy? Like, how do you think would that be moving forward kind of what you need for a given target to get you all excited of it?

    Christopher Anzalone

    Yes. I think it's all those things, right? I think it is early data from some other drugs that looks good, but because of safety reasons – off-target safety reasons, they couldn't go forward. I think at GWAS analysis, with all of the increasing amount of GWAS data that are coming out, there is an awful lot of important genetic data that can validate a target.

    I think HSD, I think to a lesser extent, but still ENaC and also experimental data. There are a number of targets that have been studied in animal models, but for one reason or another it couldn't be druggable in humans. So look, we're just looking – this is a very – as you know, this is a business full of risk and we are just looking at where we can lop off risk.

    And we think if we can remove or at least limit target risk, that's a good thing for us. And so, we don't – you've heard me say this before. We should not be in the target validation business. When we are, you need to shake me by the lapels and remind me of that, because I think this is an important thing.

    This is an important luxury that we have, at least at this point, especially given that we can go outside the liver, we've got all these new tissues now. And so, we can go through an awful lot of validated targets before we have to start taking target risk, I think.

    Madhu Kumar

    Okay. And one last one. How do you think about multi-organ targeting? And what the opportunities pieces where you could go after targets that are expressed from more than one tissue type?

    Christopher Anzalone

    Multi-organ targeting, so, with one construct addressing different cell types, is that the question?

    Madhu Kumar

    Maybe not one, maybe it would be – I think the same target by targeting by going after knockdown of that gene across multiple different tissue types at once?

    Christopher Anzalone

    Sure. We are not doing that. Not right now. But yes, for some diseases certainly that would be of interest. That's –we try to limit complexity. What you talk about is elegant complex. And so, I don't think that – again, I think that there are enough good targets out there right now that we don't have to introduce that level of complexity. That may change at some point, but right now, that's not a real focus of ours.

    Madhu Kumar

    Got you.

    Christopher Anzalone

    Okay. Thanks very much.
  9. forum rang 5 Hulskof 24 november 2020 08:28
    Heeft iemand naar de earnings call geluisterd?

    Before I move on to 2021, I’d like to say a few words about the novel coronavirus. As with the rest of the world, we’re excited to see the interim results from some of the COVID-19 vaccines science. Multiple phase and effective vaccines will be a humanitarian triumph and we applaud the impressive work done by several companies.

    From an Arrowhead standpoint, some may ask that progress on the vaccines affects our internal program. The answer is, not really. We continue to make progress on an anti-viral approach that is designed work across different coronaviruses. The history of SARS, MERS and now the current coronavirus suggests that the world should expect some type of coronavirus outbreak approximately every seven years.

    As such, we are studying conserved regions in known coronaviruses with a goal of creating an inhalable antiviral that could be applied to future outbreaks, as well as the current virus should there be blind spots with the vaccines. We are still in early animal studies but I hope that we will have an idea about the feasibility of this approach in 2021.

    Moving to the future, there is lot you should expect from us during the final month of the year and into 2021. Our expectations include the following: one, we are on track to file a CTA for ARO-LUNG2 at the end of this year. This second program – this is a second program in our pulmonary franchise and is designed to treat COPD by pivoting an undisclosed target in pulmonary epithelia.

    Two, we are on pace to potentially have preliminary data readouts by the middle of 2021 for ARO-HSD, ARO-HIF2 and ARO-ENaC.

    Three, during the first half of 2021, we also intend to engage with the FDA and other regulators to discuss pivotal trial study design and endpoints for ARO-AAT.

    Based on the impressive data that came out of our 2002 open-label study, it appears that patients have large reductions in Z-AAT monomer, which we expected but also had improvements in other downstream markers such as polymer, globules, LFTs and others. These discussions may allow us to find a more streamlined and accelerated path to a potential approval.

    But there also maybe additional open-label data in 2021 for patients with 12 month and 18 month repeat biopsies.

    Four, we also intend to initiate multiple studies in first half of 2021 for both of our cardio metabolic programs. For ARO-ANG3 mixed dyslipidemia patients we are working on a Phase 2b dose-finding study.

    For ARO-APOC3, we are working to start three studies, a Phase 2b study – a Phase 2b dose-finding study in patients with triglycerides ranging from 150 to 499, a Phase 2b dose-finding study of patients with triglycerides over 500 and a Phase 3 study in patients with familial chylomicronemia syndrome or FCS.

    Five, in the second half of 2021, we intend to file a CTA for our first muscle targeted RNAi therapeutic. That program has moved forward very nicely and we are eager to talk more about that and what the data look like.

    Six, for our partnered program with Amgen and Janssen we can’t provide specific guidance on timing, but we continue to be pleased with their progress and look forward to additional future progress.

    Seven, lastly, we are working on several other undisclosed programs and we’ll likely have another CTA filed for another program in 2021.

    Data readouts van HIF2 en Enac halverwege 2021 vind ik ietwat teleurstellend, was dat eerder niet in Q1 2021? Enfin, op Twitter lees ik dat CA erg overtuigend klonk. Ze gaan er daar al vanuit dat Arrowhead een heuse bedreiging wordt (is) voor Vertex.
    Benieuwd hoeveel de koers vandaag terug zal vallen (want standaard na cijfers?) en hoe snel de longs deze gaan oppikken. Mocht de dip fors blijken, dan pik ik er zelf ook nog een paar op (zit al aan m'n plafond, maar dit is op termijn zo'n geldpers, niet normaal!)...
  10. Missolapola 24 november 2020 08:28
    Operator

    Thank you. And our next question comes from the line of Mayank Mamtani with B. Riley Securities. Your line is now open.

    Mayank Mamtani

    Hey. Good afternoon team. Thanks for taking our question and congrats on a productive quarter. So, if I may ask another elephant in the room type of question, so, which program do you think is going to be the first to market in your view?

    And how to really think about building a commercial organization across cardio metabolic and pulmonary franchises like, which program are you thinking would get – would cross the finish line first given all the different down charts you guys are looking at?

    Christopher Anzalone

    That's a good question. So, APOC3 against FCS could be a relatively near or relatively speaking near-term market opportunity. As we talked about on the KOL webinar, we are thinking that could be a 60 or so patient pivotal study. We are a bit ahead of ourselves now because we haven't started that study yet, but that feels to me like, like that could be near-ish term.

    A wildcard here could be ARO-ENaC. I don't – again I don't want to get out over my skis, because we haven't seen any data yet. But should those data be exciting, should they – should the data in this Phase 1/2 study suggest that we have something here, it could be that we could move directly into a Phase 2/3 study. The earliest that could be would be the end of next year, because we don't have tox coverage until then, but that's a possibility.

    And sorry, the other wildcard here would be partnered programs, of course, AAT a big possibility here is, we'll see how good Javier is. But once we have those discussions with the FDA and other regulators, we'll have a good idea about whether not we can shorten up that time to market.

    I think that we can make a very compelling argument as to – as to why we could do that and so that's another possible one. I don't know if you're talking only about wholly-owned or more broadly speaking, but I guess that runs the gamut of partnered and wholly-owned.

    Mayank Mamtani

    And also, how you build the commercial organization? I guess, the data on some of these inflection points really drive a lot of that? Is that kind of fair?

    Christopher Anzalone

    Is the question about when we start to build the commercial organization?

    Mayank Mamtani

    Yes, essentially. Like, I am thinking more about the spend, right? How to think about 2021, 2022 G&A and how should we think about that?

    Christopher Anzalone

    Yes, I can't give any guidance on that at this point. Let us get into the Phase 3 study with FCS. Let's see how fast that can enroll and then we can have a better idea about what we are looking at. Of course AAT nicely build commercial organization there we'll be working with the cadence with the commercial organization.

    And then, ENaC again, it's just a bit too early. Let's – give us a bit of time. Hopefully next year, we can have a better idea about timeframe and then have a better idea about spend for the commercial build out.

    Mayank Mamtani

    Understood. And then, just two quick follow-ups. Could you address the ARO-HSD trial progress and your in-patient cohort? But I am assuming you are seeing some liver enzyme data at the minimum. What is the data cadence disclosure?

    And confirm if only NASH cirrhosis patients are in there? There is no alcoholics cirrhotics. And my final question, if you've narrowed down your three-pronged R&D effort in COVID to just the value-added or are you doing other approaches also in COVID? Thanks for taking my questions.

    Christopher Anzalone

    Sure. Thanks for those questions. Let me start with COVID and go backwards. So, we are still interrogating some anti-inflammatory strategies in large part, because that coincides with developing these anti-inflammatory medicines for other disease areas. And so, that just works well and so we're still pursuing that as we pursue the antiviral approach for hopefully for broader coronaviruses. Now, son of a gun, what was the first question?

    Javier San Martin

    HSD.
  11. Missolapola 24 november 2020 08:29
    Christopher Anzalone

    HSD. Sorry, right. Okay. So, HSD, that's a tough one. As you may know, there is no known circulating biomarker and so, we are really – so we have to rely on biopsies and we are just looking forward for gene knockdown. This – in most of our - as you know, most of our Phase 1/2 studies we are looking for safety and finding a dose but we're looking for other activity measures. Here we are just looking to find a dose.

    And so we'll be taking biopsies and looking at knockdown and then based on that, we will take a dose or two forward into a Phase 2 study.

    James Hassard

    And for enrollment that's just NASH - expected NASH, no alcohol gets added.

    Christopher Anzalone

    Right. Thank you.

    Mayank Mamtani

    Great. Thank you.

    Christopher Anzalone

    You are welcome.

    Operator

    Thank you. And we have time for one more question. So, last question comes from the line of Patrick Trucchio with H.C. Wainwright. Your line is now open.

    Patrick Trucchio

    Thanks, good afternoon. I have a few follow-ups. First one is on NASH. So, just regarding the Phase I/2 trial in NASH. Can you remind us if participants in this study are expected to be confirmed now to your NASH patients and if it is to be confirmed by fiber scan or biopsy or some other methodology?

    And then, secondly, can you tell us how you think about the regulatory/NASH, specifically as it regards to 2018 guidance in Phase 2b and 3 trials against the backdrop of some of these recent challenges in drug development in the space? And then, finally, can you talk about what mechanisms do you believe if any, could be synergistic with ARO-HSD in potential combination treatment of NASH?

    Christopher Anzalone

    Javier?

    Javier San Martin

    Just repeat the first one of the three questions.

    Patrick Trucchio

    Yes. The first one is just on the Phase 1/2 trial in NASH. If you can remind us if the participants in the study are expected to be confirmed NAFLD or confirmed NASH patients?

    Javier San Martin

    Got it. So, thank you. We are enrolling patients that we have suspected NASH and that's a broad definition that include the MRI - so that others can - the MRI data in term of liver fat and metabolic syndrome and baseline LFD. So it's a combination of those three things that will not require to have confirmed NAFLD or NASH, but most of people who have those clinical features are likely to have NAFLD.

    If someone has a biopsy prior to the study that defined as NASH, then that patient will be enrolled in this study. Well, the broader question of our clinical development in NASH, of course, is a very complex situation and as you know, many, many large pharma companies or mid-sized pharma companies are working on this.

    The development of the guidance took easily a year – 10 years or so to get to where they are right now. And it is complex. The whole endpoint that they are asking for to be approved is complex, because the way people read this biopsy, the category of fibrosis level and all of those complexities. So, we are at the very beginning of our journey.

    We are looking at the proof-of-concept that the ARO-HSD is doing what it is supposed to and at that point we need to think carefully how to develop a drug for NASH and as we understand better perhaps the mechanism of action we may be able to select the patient population in a more smart fashion, but with regards to the overall development plan, Phase 2, Phase 3 biopsies and whether it is necessary to be approved, from now we may need to follow what is being proposed as guidance.
  12. Missolapola 24 november 2020 08:30
    Christopher Anzalone

    And last question on…

    Patrick Trucchio

    Synergies,

    A – Christopher Anzalone

    Synergy with other mechanisms or agents.

    Javier San Martin

    Well, NASH seems to be a disease that can start-up with different starting points and evolve via different mechanisms and when you look at broadly, all the drugs in development, you can try to target different aspects of the disease, those were more metabolic-oriented, more inflammation-oriented or more fibrotic-oriented.

    Where are we in that mix? We don't know. We don't think that maybe we are in the metabolic side. So that could be an interesting and clinically – like, in my opinion, like a scenario, how to go about this. But, I think we need to wait. We need to learn more about our own role and how the feel of NASH evolves in the next couple of years.

    Patrick Trucchio

    Yes. And if I may, just one follow-up on the imaging and biopsy and evaluation of patients for NASH. Can you talk about the advances in evaluation of non-invasive imaging or biomarkers that can enable potentially quicker enrollment of mid and later stage NASH studies, as compared to what we've been accustomed to historically and where we are in that process?

    Javier San Martin

    James, would you like to address that question?

    James Hassard

    Sure, sure. I can a take a stab at that. Yes, certainly, if there is another option, an alternative to liver biopsy, something like MRI, PDFF or MRE, that would be preferable. Those, at least in the setting of MRE that may not be something that's quite ready for prime time as an approvable endpoint.

    But looking down the road, I mean MRI PDFF is already used a lot in clinical studies, Phase II clinical studies. And I would suspect that MRE will become more commonly looked at as a key endpoint in NASH studies or other studies of liver disease broadly down the road.

    Patrick Trucchio

    That's helpful. Thank you very much.

    Operator

    Thank you. And this does conclude today's question and answer session. I would now like to turn the call back to Chris Anzalone for any closing remarks.

    Christopher Anzalone

    Okay. Well, thanks everyone for participating today and listening to the call. I hope that you all have a happy and safe Thanksgiving weekend.

    Operator

    Ladies and gentlemen, this concludes today's conference call. You may now disconnect. Thank you for participating
  17. Wil Helmus 24 november 2020 13:49
    quote:

    Hulskof schreef op 24 november 2020 11:08:

    [...]

    Zullen short zitten.
    Er zijn nog genoeg lieden (instituten) die goedkoop willen instappen.
    Idd, daar lijkt het wel op. Terwijl RBC en Cantor Fitzgerald beiden hun koersdoel verhogen naar $80, verlaagd Leerink hun al belachelijke koersdoel naar $ 34. Pure koersmanipulatie
  18. forum rang 5 Hulskof 24 november 2020 13:59
    quote:

    Wil Helmus schreef op 24 november 2020 13:49:

    [...]
    Idd, daar lijkt het wel op. Terwijl RBC en Cantor Fitzgerald beiden hun koersdoel verhogen naar $80, verlaagd Leerink hun al belachelijke koersdoel naar $ 34. Pure koersmanipulatie
    De verlaging met 1 dollar is op zich al veelzeggend. Daar zit venijn in, oud zeer misschien? Het heeft niks uitstaan met een oprechte analyse, maar alles met het negatief willen beïnvloeden van de koers of het willen schaden van het bedrijf.
  19. mvdln 24 november 2020 14:56
    Ik heb het hele transcript van de CC gelezen. Opnieuw interessante info. CA laat op veel vlakken het achterste van de tong niet zien, dat is duidelijk. Hij laat zich niets ontglippen over interne keuken.

    Diverse uitspraken over ARO-ENaC zijn voor mij wel een eyecatcher. Daar weet hij immers wel wat het doet bij mensen (gezonde weliswaar). Moest ARO-ENaC tegen eind H1/2021 met positieve data komen en doorstromen richting combo phase II / III dan zal dat een enorme boost geven aan de koers.

    Mijn gevoel blijft hetzelfde: gestaag bijkopen en minstens 5 jaar aanhouden.
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