PROTHENA CORP PUBLIC LTD CO — Call Transcript 2025

Thank you, guys, for being here. Super excited to have the management team from Prothena Biosciences with us. I feel like a lot has happened over the last few months, but all of a sudden there's also a lot of action coming up in short order. But I'll let you kick things off. Yeah, no, thanks. Well, I'll let Gene maybe give a little bit of overview here. But first, I wanted to just say thank you for having us. It's always great to be with you and happy to have the conversation. But, Gene, why don't you give a quick overview? Yeah, I mean, I think at a high level, in terms of what our focus is on, I mean, we're still creating value through being experts in protein dysregulation, which I think is represented in our robust pipeline. Clearly, we have two phase III programs, one being run in early Parkinson's disease patients through prasinezumab with Roche, and the other one is in ATTR cardiomyopathy with Novo. Novo has already initiated the phase III, and Roche is about to. They've basically already publicly disclosed they'll get it initiated here in the fourth quarter, and we're already in December. And then, of course, we're also working with Bristol on a phase II for Alzheimer's, targeting tau. And then we have X019 also partnered with Bristol in phase I that we're running, and we'll go into that a little bit more. But it's an undisclosed target, but it's for neurodegeneration, right? And so from there, we look forward to earning up to $105 million worth of clinical milestones in 2026 related to coramitug reaching a certain number of enrolled patients. And then, of course, the decision on X019 from Bristol later in the year. And then, of course, we just had a successful EGM where we approved our distributable reserves to support a share repurchase program for 2026. And then, of course, we'll look forward to putting out more data on CYTOPE. And we'll talk about CYTOPE a little bit more given the data we put out at Society for Neuroscience around the ALS program. But I think that captures all the things we're working on here towards the near-term in 2026. Yeah, I think the only thing I'd add is just that we continue to have a number of unpartnered programs that we've made some progress on. I know we'll talk a little bit about the Alzheimer's space and, obviously, our PRX012 molecule and some efforts to add transferrin to that based on some external data. So, yeah, we're looking forward to that and continuing to kind of progress the portfolio at large. Fantastic. So clearly, there's a pipeline we can talk through there. But maybe just before we get going, can you just remind us your amyloid beta? Is this alive, active, moving forward? Can you just catch us up on that? Yeah, I think earlier this year, as we were moving through the year and seeing the readout of different programs, one of the things we tried to communicate was that we felt like it would be advantageous to actually partner with that program to move it forward in a robust way. I think a great example is our partnership with Roche around prasinezumab for Parkinson's disease, where the ability to bring maybe a lower cost of capital to that and some bandwidth has really advantaged that program. And so, obviously, in Alzheimer's disease, we felt that that was the appropriate way to move forward as well. We looked at that data. The data with that molecule is really quite robust with respect to amyloid lowering, amyloid reduction. I think bringing in that study now with sub-Q once monthly dosing, we're seeing at 18 months in excess of 80% of the patients treated are amyloid negative. With that molecule, of course, there was some ARIA, which is a known effect that comes along with the removal of A beta, and clearly, one of the ways that in the field, the way the science is moving, is starting to think about ways to mitigate the ARIA effects, so clearly, we're looking closely at that, and we're watching the field closely. There are a couple of different approaches there. One we're going to be informed by in the not too distant future here, which is really moving to a pre-symptomatic patient population. Eli Lilly is conducting studies in that space with their molecule donanemab, so we're excited to see those results. We think not only does that increase the potential commercial opportunity, but it actually may be very informative with respect to these ARIA events as well and the propensity of those types of patients. What is the ARIA rate you guys have? I'm trying to remember what we reported in terms of the ARIA rates. Good. I was going to say it was around 40%. 40%. Okay. 400 mg. So we talked about a transferrin PRX012, which we'll put out data from our preclinical trials that we're running, our studies that we're running in 2026. And so I think that's a way for us to. Could that have phase I in 2027? I think for now, let's keep it to the preclinical data, and then we can think about a very financially, physically responsible phase I that you don't need actually a lot of patients for per cohort. You still need to define your dose, and you might need multiple cohorts, but you could need 10 patients per cohort. Got it. Could you maybe just for our purposes, so when you do that transferrin PRX012, the size of preclinical tox data, is that much more limited? Because transferrin is validated on its own. PRX has done all of it on its own. How much does the FDA need to see for to warrant an IND? Yeah, I mean, obviously, that's a point of conversation with the FDA, but you would expect a typical toxicology package in line with monoclonal antibody, which. De novo? It is a novel molecular entity, so you'd need some unique data around that construct. That said, I think we've just seen guidance coming from the FDA as recent as yesterday, where they're talking now about maybe avoiding the need to use, for example, non-human primates for testing of certain types of molecules and certain types of molecular entities. So I think there's still some work to do to understand exactly what that preclinical IND enabling tox package looks like. But clearly, there would need to be some. So if 400 mg is the dose where you were hitting all the objectives with a transferrin receptor on board, much more blood-brain barrier penetration, how much dose drop do you envision? Yeah, so I think what we can look to in the field is really the experience that Roche has with trontinemab, right? So trontinemab, obviously, the foundational antibody there is gantenerumab. And I think as you look at the transition from gantenerumab to trontinemab, the reduction in dose levels is pretty extreme. Somewhere around threefold. About threefold, yeah. So there you go. So that's kind of what they're seeing. Now, I think there's still some signs to be worked out in that space. Eli Lilly has recently talked a little bit about the idea that transferrin may be more exposed, for example, in the capillary structures as opposed to the larger arterial structures of the cerebral vasculature. And in fact, that if there is an impact on ARIA, it may be because there's a more preferential entry into the brain through the capillary structure. We don't know if that's true yet or not, but they've been presenting some data on that, which suggests it could be true. That would certainly be interesting and could explain maybe why you're getting a little better distribution into different areas of the CNS, as well as potentially having an ARIA-sparing effect. Got it. Okay, got it. So the preclinical doses you guys are using and the data sets we're going to see in due time, are they being done at a fraction of that or not because you want to put into the requirement? So that data will be coming, and we'll talk about that at the right time. But I don't think we're ready to talk about that data set yet. Okay, got it. And the half-life will still be more or less the same? We would anticipate so. I mean, obviously, with interaction with transferrin, depending on where that interaction lies, it could have a differential impact, as we've seen with gantenerumab and trontinemab. But I think clearly there are some newer technologies around transferrin targeting that are designed to target different epitopes that maybe play more or less a role at the level of the reticulocyte. Got it. So this is exactly the direction I was going to go because not all transferrin technologies are made the same. And I think we've seen some of the heme signals and some of the first-gen programs. But I'm not actually fully aware of what exactly are the nuanced differences. But is it just literally epitope and what epitopes overlap with reticulocyte sites? I think there's a number of components when you think about transferrin as a brain shuttle technology, not the least of which is affinity and making sure that you're dialing in the correct affinity so that it's not bound too tightly, so that when you get the transcytotic event at the blood-brain barrier, you're able to actually see release into the central nervous system. So that's a very important part of it. Epitopes are a very important part of it. So I think there's a number of components, and there are a number of companies working on different variants and different versions of it. Did you guys in-license transferrin technologies? Yeah, I think we're just going to allow for some of that data to speak for itself, and so we'll talk about that data at the right time, and we'll provide more details then. Just given your interest in the transferrin approach, do you think, what kind of data do you believe will be sufficient for a partner to really engage meaningfully? Is that at the preclinical level, or do you think they'll need to see phase I data at minimum? Yeah, I think it's hard to say. Different partners would value different data sets at different points. So it's a function of what value you're talking about at any given point in a collaboration. I think we've seen a number of deals and licenses that have happened in this space where people have looked at transferrin-based anti-A beta antibodies. I think one of the things that we feel is unique about PRX012 at this point is that we know what the foundational antibody can do. We have a good sense of what amyloid removal looks like as a sub-Q once monthly administration. I do think that sets it apart a little bit from maybe some of the other things we've seen in the field that have been brought in by companies where maybe that foundational antibody. It's not yet clear what that potentially offers with respect to amyloid removal in a clinical setting. But I think it also goes to deal value, right? And that's another way to think about it too. So I think at the end of the day, you go out and achieve the data sets you're trying to show that your construct works, right, and compare it to others, whether that is in humans or in animals. But that being all said, I think it's just about value at the end of the day. Got it. Got it. Just kind of moving on to prasinezumab and coramitug, as these programs kind of move forward to phase III, what indications have you seen from Roche and Novo in terms of how they're prioritizing and resourcing these programs? I mean. I'll say, I think in all cases, so we have some great collaborations, not just with Roche and Novo, but also with Bristol Myers Squibb. And I think in all cases, we've seen that these companies are rationalizing their internal portfolios. They're continuing to put, I think, pretty important gates and criteria around what programs move forward. So to see both in the Novo case with coramitug, that molecule, a decision made by Novo to move that forward. We've now seen the phase II data set that I think led to that decision-making, which we can talk about. And then also on the Roche side with prasinezumab, we've seen some of the data they've presented around the two phase II studies that have been completed. And obviously, that went through a rigorous evaluation criteria process within Roche. Clearly, they have a lot of things they could be working on. I think in both cases, it's great to see those things move forward. An indication of the potential of those is phase III programs. Got it. And I would just add on that that we had great presentations from data sets from both Roche and Novo this year relating and helping justify those phase III, right? So AD/PD 2025 for Roche, they presented some very compelling data on prasinezumab, especially at two-year duration and levodopa in the double-blind portion, which helps the justification for phase III. And then just recently at AHA 2025, a late-breaker presentation, very exciting data on NT-proBNP, about a 50% difference from placebo on that arm. And that small study really justifying them moving forward as well as some echo data. Yeah, well, a 50% change from placebo, but really, in my mind, something that was kind of interesting was a reduction from baseline. And I think if we look to the other agents in this space, we really haven't seen that, certainly not within a 12-month time period. So pretty remarkable there, the cardiac remodeling with the echocardiogram readouts, as you say, and at least not statistically significant, but across a 12-month time period, at least directionally, seeing an effect that goes in the correct direction relative to placebo on six-minute walk tests. So I think an encouraging overall weight of evidence data set with coramitug and obviously justifying that program moving into phase III. Got it. Now that Prothena is kind of largely focused on supporting partner programs, for PRX005 and coramitug, as they kind of head into phase III, what does that support look like if you kind of get more granular into that? Yeah, so we've been, I think, fortunate to have really great partnerships. And in the case of both Roche and Novo, we have engaged in, I think, pretty extensive dialogue with both of those companies around the science, around the clinical decision-making. And so we offer whatever support we can. And obviously, we're available to lend whatever support is needed. And obviously, we continue to work very closely with those partners as well as our partners at Bristol Myers Squibb. So with Bristol Myers Squibb, it's maybe a little bit more intensive. We're still conducting the phase I study for PRX019, where we expect them to potentially make a decision, which has some consequence relative to. That's MTBR? No, PRPRX019 is an undisclosed mechanism. So yeah, so the MTBR program is BMS-986446, which is in phase II. So they're conducting that. They have that fully enrolled. We expect that data according to ClinicalTrials.gov in 2017. 2027. 2027. By the way, are they going? Thank you. 2027. I feel like that trial's being run like a phase III and just slowing them down and you guys down with it as well. No, I mean, the primary thing is tau PET. Why? Week 76. They want to make. I mean, I think the whole field, in a sense, wants to correlate tau PET to clinical outcomes. I think they are actually running an appropriate phase II. There's no interim like first 50 patients out to week 76 that you could get much sooner? There's nothing like that? I don't believe that's how they've structured it, so it's data in 2027. Yeah, but I think the way that they're conducting that trial makes a lot of sense, right? So the key kind of element there is this is an MTBR targeting monoclonal antibody against tau. MTBR has recently come, I think, very center stage in terms of the pathology of tau in the context of Alzheimer's disease. Recent data from the ACI molecule, which targets a different part of the MTBR sequence, has shown that you see reductions of phospho tau-243, which is something that seems to correlate better with, for example, tau PET than maybe the pTau-181s and 217s, which correlate a little bit better with amyloid beta changes. And so I think there's a lot of excitement about what these MTBR agents can do. And the way that study is structured now is to look, I think, in a relatively definitive way at changes in tau PET. But with having functional measures as key secondaries, it allows you to also go in then and evaluate changes in tau PET and that relationship to any functional change. I think that's important, and it's very informative with respect to thinking about future studies. Excellent. Any thoughts on or comments on the recent J&J tau failure? Yeah, I mean, very different epitope, very different part of the molecule. Obviously, it was a phospho-specific antibody at pTau-217, which is more in the proline-rich repeat area of the tau protein relative to what we're talking about in terms of MTBR. I think if you look at the work of folks out there in the field like Marc Diamond and others, it's pretty clear from his work and related publications that this microtubule binding domain of the MTBR region really is responsible for making the key interactions with, if you will, unaffected neurons that allow for the internalization of tau fragments to start to seed and affect those neurons. It's through an interaction with a protein called heparan sulfate proteoglycan. And the best kind of narrowing of that interface region seems to be to the MTBR region. So the relevance of that proline-rich repeat region in terms of that kind of continuing pathogenic spread, I think, is a little bit more hypothetical. And I think what we're seeing is, at least on the top line, targeting those proline-rich repeat areas doesn't seem to be having the impact I think the sponsors had hoped it would. Whether then, in fact, with more data cuts and a little additional data analysis, there might be some important learnings that come from that, we certainly hope so. And that's something we'll be looking to. Got it. Got it. I know we're at time, Mike, so we might have to wrap it up. But why don't you ask your last? No, I mean, just one final question while we're on the subject of the tau. Phase II, they got fast-track status. What does that tell you about their level of conviction? Kind of, what do you need to see to view this as a potential registrational path? Yeah, so I think there's kind of two questions in there. The first is just around fast-track and what is the current kind of zeitgeist around tau and how do we think about that? And I think we've known for a long time that tau is very relevant in the context of Alzheimer's disease. Most in the field feel that A beta is an important kind of precedent and continuing event that leads to tau deregulation, and then you end up with neuroinflammation and some other components as well. So it's a multi-kind of component disease that is probably initiated by early dysfunction in A beta, but then A beta continues to have a toxic function throughout the lifespan of the disease space. So tau is very important. It's proximal to some of the functional deficits that you see in patients that show up. Most of those patients go through some period of rapid tau accumulation before you start to see subjective functional complaints. And so I think tau is a very interesting and important target from that perspective. So the idea of fast-track status makes sense from that lens. I think the second part of your question was. The registrational. Oh, registrational nature of that. Look, it's hard to say. I think all companies would advise that we should expect to run a robust phase III or phase IIIs in order to get registration from a full approval approach. If we look to the precedents in the field in Alzheimer's disease around A beta, what was required for aducanumab, for lecanemab to receive accelerated approval? Basically, the primary basis of approval were changes in imaging. So a biomarker that was reasonably likely to predict clinical benefit. That reasonable likeliness was exemplified through an understanding of how functional changes related, at least at a group level, to those changes in the biomarker. And at the end of the day, unless I'm mistaken, I believe the phase IIIs were fully or near fully enrolled at the time of those accelerated approvals. Again, if one wanted to allow themselves to wander down that path for a moment, hypothetically, I think the idea of having a primary outcome measure as an imaging marker, functional endpoints as a secondary outcome measure so that you can actually establish that relationship, at least put you in a good position to have those conversations. But again, I think the guidance certainly would be that the expectation, the base expectation is to run robust phase IIIs to prove out efficacy. Just before we wrap it up, Tran, in a scenario where Lilly hits 40%+ effect size in their preclinical Alzheimer's study, how do you guys intend to communicate to the street the continued commitment to the A beta space now with the transferrin receptor-based technology? I just want to sort of throw it out there because it's obviously important and you guys have a lot of experience here. Yeah, I mean, I think it shows through our preclinical studies that we are running and we'll share data on. And then after that, sharing a clinical plan, right, that would get to patient-level data that would show basically the positive characteristics of the construct. And I think from there, given the broader, I would say, development, because I think Lilly's running a great phase III for sub-Q remternetug in terms of dual population enrollment, right, in terms of pre-symptomatic and symptomatic, that would be something I think that could be attractive to a large pharma from that perspective. But I think go along that continuum and clearly work with large pharma along the way and try to, to what we discussed earlier with Mike, is where's the best value point. Makes sense. Fantastic. Excellent. Well, thank you guys. Thanks for joining. And certainly be in touch. Thanks for having us.

Speaker 4: Thank you, guys, for being here. Super excited to have the management team from Prothena Biosciences with us. I feel like a lot has happened over the last few months, but all of a sudden there's also a lot of action coming up in short order. But I'll let you kick things off. Thank you, guys, for being here. thank you guys for being here Super excited to have the management team from Prothena Biosciences with us. super excited to have the management team from prothena biosciences with us I feel like a lot has happened over the last few months, but all of a sudden there's also a lot of action coming up in short order. i feel like a lot has happened over the last few months but all of a sudden there's also a lot of action coming up in short order But I'll let you kick things off. but i'll let you kick things off

Speaker 2: Yeah, no, thanks. Well, I'll let Gene maybe give a little bit of overview here. But first, I wanted to just say thank you for having us. It's always great to be with you and happy to have the conversation. But, Gene, why don't you give a quick overview? Yeah, no, thanks. yeah no thanks Well, I'll let Gene maybe give a little bit of overview here. well i'll let gene maybe give a little bit of overview here But first, I wanted to just say thank you for having us. but first i wanted to just say thank you for having us It's always great to be with you and happy to have the conversation. it's always great to be with you and happy to have the conversation But, Gene, why don't you give a quick overview? but gene why don't you give a quick overview

Speaker 1: Yeah, I mean, I think at a high level, in terms of what our focus is on, I mean, we're still creating value through being experts in protein dysregulation, which I think is represented in our robust pipeline. Clearly, we have two phase III programs, one being run in early Parkinson's disease patients through prasinezumab with Roche, and the other one is in ATTR cardiomyopathy with Novo. Novo has already initiated the phase III, and Roche is about to. They've basically already publicly disclosed they'll get it initiated here in the fourth quarter, and we're already in December. And then, of course, we're also working with Bristol on a phase II for Alzheimer's, targeting tau. And then we have X019 also partnered with Bristol in phase I that we're running, and we'll go into that a little bit more. But it's an undisclosed target, but it's for neurodegeneration, right? Yeah, I mean, I think at a high level, in terms of what our focus is on, I mean, we're still creating value through being experts in protein dysregulation, which I think is represented in our robust pipeline. yeah i mean i think at a high level in terms of what our focus is on i mean we're still creating value through being experts in protein dysregulation which i think is represented in our robust pipeline Clearly, we have two phase III programs, one being run in early Parkinson's disease patients through prasinezumab with Roche, and the other one is in ATTR cardiomyopathy with Novo. clearly we have two phase iii programs one being run in early parkinson's disease patients through prasinezumab with roche and the other one is in attr cardiomyopathy with novo Novo has already initiated the phase III, and Roche is about to. novo has already initiated the phase iii and roche is about to They've basically already publicly disclosed they'll get it initiated here in the fourth quarter, and we're already in December. they've basically already publicly disclosed they'll get it initiated here in the fourth quarter and we're already in december And then, of course, we're also working with Bristol on a phase II for Alzheimer's, targeting tau. and then of course we're also working with bristol on a phase ii for alzheimer's targeting tau And then we have X019 also partnered with Bristol in phase I that we're running, and we'll go into that a little bit more. and then we have x019 also partnered with bristol in phase i that we're running and we'll go into that a little bit more But it's an undisclosed target, but it's for neurodegeneration, right? but it's an undisclosed target but it's for neurodegeneration right And so from there, we look forward to earning up to $105 million worth of clinical milestones in 2026 related to coramitug reaching a certain number of enrolled patients. And then, of course, the decision on X019 from Bristol later in the year. And then, of course, we just had a successful EGM where we approved our distributable reserves to support a share repurchase program for 2026. And then, of course, we'll look forward to putting out more data on CYTOPE. And we'll talk about CYTOPE a little bit more given the data we put out at Society for Neuroscience around the ALS program. But I think that captures all the things we're working on here towards the near-term in 2026. And so from there, we look forward to earning up to $105 million worth of clinical milestones in 2026 related to coramitug reaching a certain number of enrolled patients. and so from there we look forward to earning up to $105 million worth of clinical milestones in 2026 related to coramitug reaching a certain number of enrolled patients And then, of course, the decision on X019 from Bristol later in the year. and then of course the decision on x019 from bristol later in the year And then, of course, we just had a successful EGM where we approved our distributable reserves to support a share repurchase program for 2026. and then of course we just had a successful egm where we approved our distributable reserves to support a share repurchase program for 2026 And then, of course, we'll look forward to putting out more data on CYTOPE. and then of course we'll look forward to putting out more data on cytope And we'll talk about CYTOPE a little bit more given the data we put out at Society for Neuroscience around the ALS program. and we'll talk about cytope a little bit more given the data we put out at society for neuroscience around the als program But I think that captures all the things we're working on here towards the near- term in 2026. but i think that captures all the things we're working on here towards the near- term in 2026

Speaker 2: Yeah, I think the only thing I'd add is just that we continue to have a number of unpartnered programs that we've made some progress on. I know we'll talk a little bit about the Alzheimer's space and, obviously, our PRX012 molecule and some efforts to add transferrin to that based on some external data. So, yeah, we're looking forward to that and continuing to kind of progress the portfolio at large. Yeah, I think the only thing I'd add is just that we continue to have a number of unpartnered programs that we've made some progress on. yeah i think the only thing i'd add is just that we continue to have a number of unpartnered programs that we've made some progress on I know we'll talk a little bit about the Alzheimer's space and, obviously, our PRX012 molecule and some efforts to add transferrin to that based on some external data. i know we'll talk a little bit about the alzheimer's space and obviously our prx012 molecule and some efforts to add transferrin to that based on some external data So, yeah, we're looking forward to that and continuing to kind of progress the portfolio at large. so yeah we're looking forward to that and continuing to kind of progress the portfolio at large Fantastic. So clearly, there's a pipeline we can talk through there. But maybe just before we get going, can you just remind us your amyloid beta? Is this alive, active, moving forward? Can you just catch us up on that? Fantastic. fantastic So clearly, there's a pipeline we can talk through there. so clearly there's a pipeline we can talk through there But maybe just before we get going, can you just remind us your amyloid beta? but maybe just before we get going can you just remind us your amyloid beta Is this alive, active, moving forward? is this alive active moving forward Can you just catch us up on that? can you just catch us up on that Yeah, I think earlier this year, as we were moving through the year and seeing the readout of different programs, one of the things we tried to communicate was that we felt like it would be advantageous to actually partner with that program to move it forward in a robust way. I think a great example is our partnership with Roche around prasinezumab for Parkinson's disease, where the ability to bring maybe a lower cost of capital to that and some bandwidth has really advantaged that program. And so, obviously, in Alzheimer's disease, we felt that that was the appropriate way to move forward as well. We looked at that data. The data with that molecule is really quite robust with respect to amyloid lowering, amyloid reduction. Yeah, I think earlier this year, as we were moving through the year and seeing the readout of different programs, one of the things we tried to communicate was that we felt like it would be advantageous to actually partner with that program to move it forward in a robust way. yeah i think earlier this year as we were moving through the year and seeing the readout of different programs one of the things we tried to communicate was that we felt like it would be advantageous to actually partner with that program to move it forward in a robust way I think a great example is our partnership with Roche around prasinezumab for Parkinson's disease, where the ability to bring maybe a lower cost of capital to that and some bandwidth has really advantaged that program. i think a great example is our partnership with roche around prasinezumab for parkinson's disease where the ability to bring maybe a lower cost of capital to that and some bandwidth has really advantaged that program And so, obviously, in Alzheimer's disease, we felt that that was the appropriate way to move forward as well. and so obviously in alzheimer's disease we felt that that was the appropriate way to move forward as well We looked at that data. we looked at that data The data with that molecule is really quite robust with respect to amyloid lowering, amyloid reduction. the data with that molecule is really quite robust with respect to amyloid lowering amyloid reduction I think bringing in that study now with sub-Q once monthly dosing, we're seeing at 18 months in excess of 80% of the patients treated are amyloid negative. With that molecule, of course, there was some ARIA, which is a known effect that comes along with the removal of A beta, and clearly, one of the ways that in the field, the way the science is moving, is starting to think about ways to mitigate the ARIA effects, so clearly, we're looking closely at that, and we're watching the field closely. There are a couple of different approaches there. One we're going to be informed by in the not too distant future here, which is really moving to a pre-symptomatic patient population. Eli Lilly is conducting studies in that space with their molecule donanemab, so we're excited to see those results. I think bringing in that study now with sub-Q once monthly dosing, we're seeing at 18 months in excess of 80% of the patients treated are amyloid negative. i think bringing in that study now with sub-q once monthly dosing we're seeing at 18 months in excess of 80% of the patients treated are amyloid negative With that molecule, of course, there was some ARIA, which is a known effect that comes along with the removal of A beta, and clearly, one of the ways that in the field, the way the science is moving, is starting to think about ways to mitigate the ARIA effects, so clearly, we're looking closely at that, and we're watching the field closely. with that molecule of course there was some aria which is a known effect that comes along with the removal of a beta and clearly one of the ways that in the field the way the science is moving is starting to think about ways to mitigate the aria effects so clearly we're looking closely at that and we're watching the field closely There are a couple of different approaches there. there are a couple of different approaches there One we're going to be informed by in the not too distant future here, which is really moving to a pre-symptomatic patient population. one we're going to be informed by in the not too distant future here which is really moving to a pre-symptomatic patient population Eli Lilly is conducting studies in that space with their molecule donanemab, so we're excited to see those results. eli lilly is conducting studies in that space with their molecule donanemab so we're excited to see those results We think not only does that increase the potential commercial opportunity, but it actually may be very informative with respect to these ARIA events as well and the propensity of those types of patients. We think not only does that increase the potential commercial opportunity, but it actually may be very informative with respect to these ARIA events as well and the propensity of those types of patients. we think not only does that increase the potential commercial opportunity but it actually may be very informative with respect to these aria events as well and the propensity of those types of patients What is the ARIA rate you guys have? What is the ARIA rate you guys have? what is the aria rate you guys have I'm trying to remember what we reported in terms of the ARIA rates. I'm trying to remember what we reported in terms of the ARIA rates. i'm trying to remember what we reported in terms of the aria rates

Speaker 1: Good. I was going to say it was around 40%. Good. good I was going to say it was around 40%. i was going to say it was around 40% 40%. Okay. 40%. 40% Okay. okay 400 mg. So we talked about a transferrin PRX012, which we'll put out data from our preclinical trials that we're running, our studies that we're running in 2026. And so I think that's a way for us to. 400 mg. 400 mg so we So we talked about a transferrin PRX012, which we'll put out data from our preclinical trials that we're running, our studies that we're running in 2026. 400 mg so we talked about a transferrin prx012 which we'll put out data from our preclinical trials that we're running our studies that we're running in 2026 And so I think that's a way for us to. and so i think that's a way for us to Could that have phase I in 2027? Could that have phase I in 2027? could that have phase i in 2027 I think for now, let's keep it to the preclinical data, and then we can think about a very financially, physically responsible phase I that you don't need actually a lot of patients for per cohort. You still need to define your dose, and you might need multiple cohorts, but you could need 10 patients per cohort. I think for now, let's keep it to the preclinical data, and then we can think about a very financially, physically responsible phase I that you don't need actually a lot of patients for per cohort. i think for now let's keep it to the preclinical data and then we can think about a very financially physically responsible phase i that you don't need actually a lot of patients for per cohort You still need to define your dose, and you might need multiple cohorts, but you could need 10 patients per cohort. you still need to define your dose and you might need multiple cohorts but you could need 10 patients per cohort Got it. Could you maybe just for our purposes, so when you do that transferrin PRX012, the size of preclinical tox data, is that much more limited? Because transferrin is validated on its own. PRX has done all of it on its own. How much does the FDA need to see for to warrant an IND? Got it. got it Could you maybe just for our purposes, so when you do that transferrin PRX012, the size of preclinical tox data, is that much more limited? got it could you maybe just for our purposes so when you do that transferrin prx012 the size of preclinical tox data is that much more limited Because transferrin is validated on its own. because transferrin is validated on its own PRX has done all of it on its own. prx has done all of it on its own How much does the FDA need to see for to warrant an IND? how much does the fda need to see for to warrant an ind

Speaker 2: Yeah, I mean, obviously, that's a point of conversation with the FDA, but you would expect a typical toxicology package in line with monoclonal antibody, which. Yeah, I mean, obviously, that's a point of conversation with the FDA, but you would expect a typical toxicology package in line with monoclonal antibody, which. yeah i mean obviously that's a point of conversation with the fda but you would expect a typical toxicology package in line with monoclonal antibody which De novo? De novo? de novo It is a novel molecular entity, so you'd need some unique data around that construct. That said, I think we've just seen guidance coming from the FDA as recent as yesterday, where they're talking now about maybe avoiding the need to use, for example, non-human primates for testing of certain types of molecules and certain types of molecular entities. So I think there's still some work to do to understand exactly what that preclinical IND enabling tox package looks like. But clearly, there would need to be some. It is a novel molecular entity, so you'd need some unique data around that construct. it is a novel molecular entity so you'd need some unique data around that construct That said, I think we've just seen guidance coming from the FDA as recent as yesterday, where they're talking now about maybe avoiding the need to use, for example, non-human primates for testing of certain types of molecules and certain types of molecular entities. that said i think we've just seen guidance coming from the fda as recent as yesterday where they're talking now about maybe avoiding the need to use for example non-human primates for testing of certain types of molecules and certain types of molecular entities So I think there's still some work to do to understand exactly what that preclinical IND enabling tox package looks like. so i think there's still some work to do to understand exactly what that preclinical ind enabling tox package looks like But clearly, there would need to be some. but clearly there would need to be some So if 400 mg is the dose where you were hitting all the objectives with a transferrin receptor on board, much more blood-brain barrier penetration, how much dose drop do you envision? So if 400 mg is the dose where you were hitting all the objectives with a transferrin receptor on board, much more blood-brain barrier penetration, how much dose drop do you envision? so if 400 mg is the dose where you were hitting all the objectives with a transferrin receptor on board much more blood-brain barrier penetration how much dose drop do you envision Yeah, so I think what we can look to in the field is really the experience that Roche has with trontinemab, right? So trontinemab, obviously, the foundational antibody there is gantenerumab. And I think as you look at the transition from gantenerumab to trontinemab, the reduction in dose levels is pretty extreme. Yeah, so I think what we can look to in the field is really the experience that Roche has with trontinemab, right? yeah so i think what we can look to in the field is really the experience that roche has with trontinemab right So trontinemab, obviously, the foundational antibody there is gantenerumab. so trontinemab obviously the foundational antibody there is gantenerumab And I think as you look at the transition from gantenerumab to trontinemab, the reduction in dose levels is pretty extreme. and i think as you look at the transition from gantenerumab to trontinemab the reduction in dose levels is pretty extreme

Speaker 1: Somewhere around threefold. Somewhere around threefold. somewhere around threefold

Speaker 2: About threefold, yeah. So there you go. So that's kind of what they're seeing. Now, I think there's still some signs to be worked out in that space. Eli Lilly has recently talked a little bit about the idea that transferrin may be more exposed, for example, in the capillary structures as opposed to the larger arterial structures of the cerebral vasculature. And in fact, that if there is an impact on ARIA, it may be because there's a more preferential entry into the brain through the capillary structure. We don't know if that's true yet or not, but they've been presenting some data on that, which suggests it could be true. That would certainly be interesting and could explain maybe why you're getting a little better distribution into different areas of the CNS, as well as potentially having an ARIA-sparing effect. About threefold, yeah. about threefold yeah So there you go. so there you go So that's kind of what they're seeing. so that's kind of what they're seeing Now, I think there's still some signs to be worked out in that space. now i think there's still some signs to be worked out in that space Eli Lilly has recently talked a little bit about the idea that transferrin may be more exposed, for example, in the capillary structures as opposed to the larger arterial structures of the cerebral vasculature. eli lilly has recently talked a little bit about the idea that transferrin may be more exposed for example in the capillary structures as opposed to the larger arterial structures of the cerebral vasculature And in fact, that if there is an impact on ARIA, it may be because there's a more preferential entry into the brain through the capillary structure. and in fact that if there is an impact on aria it may be because there's a more preferential entry into the brain through the capillary structure We don't know if that's true yet or not, but they've been presenting some data on that, which suggests it could be true. we don't know if that's true yet or not but they've been presenting some data on that which suggests it could be true That would certainly be interesting and could explain maybe why you're getting a little better distribution into different areas of the CNS, as well as potentially having an ARIA-sparing effect. that would certainly be interesting and could explain maybe why you're getting a little better distribution into different areas of the cns as well as potentially having an aria-sparing effect Got it. Okay, got it. So the preclinical doses you guys are using and the data sets we're going to see in due time, are they being done at a fraction of that or not because you want to put into the requirement? Got it. got it Okay, got it. okay got it So the preclinical doses you guys are using and the data sets we're going to see in due time, are they being done at a fraction of that or not because you want to put into the requirement? so the preclinical doses you guys are using and the data sets we're going to see in due time are they being done at a fraction of that or not because you want to put into the requirement So that data will be coming, and we'll talk about that at the right time. But I don't think we're ready to talk about that data set yet. So that data will be coming, and we'll talk about that at the right time. so that data will be coming and we'll talk about that at the right time But I don't think we're ready to talk about that data set yet. but i don't think we're ready to talk about that data set yet Okay, got it. And the half-life will still be more or less the same? Okay, got it. okay got it And the half-life will still be more or less the same? and the half-life will still be more or less the same We would anticipate so. I mean, obviously, with interaction with transferrin, depending on where that interaction lies, it could have a differential impact, as we've seen with gantenerumab and trontinemab. But I think clearly there are some newer technologies around transferrin targeting that are designed to target different epitopes that maybe play more or less a role at the level of the reticulocyte. We would anticipate so. we would anticipate so I mean, obviously, with interaction with transferrin, depending on where that interaction lies, it could have a differential impact, as we've seen with gantenerumab and trontinemab. i mean obviously with interaction with transferrin depending on where that interaction lies it could have a differential impact as we've seen with gantenerumab and trontinemab But I think clearly there are some newer technologies around transferrin targeting that are designed to target different epitopes that maybe play more or less a role at the level of the reticulocyte. but i think clearly there are some newer technologies around transferrin targeting that are designed to target different epitopes that maybe play more or less a role at the level of the reticulocyte Got it. So this is exactly the direction I was going to go because not all transferrin technologies are made the same. And I think we've seen some of the heme signals and some of the first-gen programs. But I'm not actually fully aware of what exactly are the nuanced differences. But is it just literally epitope and what epitopes overlap with reticulocyte sites? Got it. got it So this is exactly the direction I was going to go because not all transferrin technologies are made the same. so this is exactly the direction i was going to go because not all transferrin technologies are made the same And I think we've seen some of the heme signals and some of the first-gen programs. and i think we've seen some of the heme signals and some of the first-gen programs But I'm not actually fully aware of what exactly are the nuanced differences. but i'm not actually fully aware of what exactly are the nuanced differences But is it just literally epitope and what epitopes overlap with reticulocyte sites? but is it just literally epitope and what epitopes overlap with reticulocyte sites I think there's a number of components when you think about transferrin as a brain shuttle technology, not the least of which is affinity and making sure that you're dialing in the correct affinity so that it's not bound too tightly, so that when you get the transcytotic event at the blood-brain barrier, you're able to actually see release into the central nervous system. So that's a very important part of it. Epitopes are a very important part of it. So I think there's a number of components, and there are a number of companies working on different variants and different versions of it. I think there's a number of components when you think about transferrin as a brain shuttle technology, not the least of which is affinity and making sure that you're dialing in the correct affinity so that it's not bound too tightly, so that when you get the transcytotic event at the blood-brain barrier, you're able to actually see release into the central nervous system. i think there's a number of components when you think about transferrin as a brain shuttle technology not the least of which is affinity and making sure that you're dialing in the correct affinity so that it's not bound too tightly so that when you get the transcytotic event at the blood-brain barrier you're able to actually see release into the central nervous system So that's a very important part of it. so that's a very important part of it Epitopes are a very important part of it. epitopes are a very important part of it So I think there's a number of components, and there are a number of companies working on different variants and different versions of it. so i think there's a number of components and there are a number of companies working on different variants and different versions of it Did you guys in-license transferrin technologies? Did you guys in-license transferrin technologies? did you guys in-license transferrin technologies Yeah, I think we're just going to allow for some of that data to speak for itself, and so we'll talk about that data at the right time, and we'll provide more details then. Yeah, I think we're just going to allow for some of that data to speak for itself, and so we'll talk about that data at the right time, and we'll provide more details then. yeah i think we're just going to allow for some of that data to speak for itself and so we'll talk about that data at the right time and we'll provide more details then Just given your interest in the transferrin approach, do you think, what kind of data do you believe will be sufficient for a partner to really engage meaningfully? Is that at the preclinical level, or do you think they'll need to see phase I data at minimum? Just given your interest in the transferrin approach, do you think, what kind of data do you believe will be sufficient for a partner to really engage meaningfully? just given your interest in the transferrin approach do you think what kind of data do you believe will be sufficient for a partner to really engage meaningfully Is that at the preclinical level, or do you think they'll need to see phase I data at minimum? is that at the preclinical level or do you think they'll need to see phase i data at minimum Yeah, I think it's hard to say. Different partners would value different data sets at different points. So it's a function of what value you're talking about at any given point in a collaboration. I think we've seen a number of deals and licenses that have happened in this space where people have looked at transferrin-based anti-A beta antibodies. I think one of the things that we feel is unique about PRX012 at this point is that we know what the foundational antibody can do. We have a good sense of what amyloid removal looks like as a sub-Q once monthly administration. Yeah, I think it's hard to say. yeah i think it's hard to say Different partners would value different data sets at different points. different partners would value different data sets at different points So it's a function of what value you're talking about at any given point in a collaboration. so it's a function of what value you're talking about at any given point in a collaboration I think we've seen a number of deals and licenses that have happened in this space where people have looked at transferrin-based anti-A beta antibodies. i think we've seen a number of deals and licenses that have happened in this space where people have looked at transferrin-based anti-a beta antibodies I think one of the things that we feel is unique about PRX012 at this point is that we know what the foundational antibody can do. i think one of the things that we feel is unique about prx012 at this point is that we know what the foundational antibody can do We have a good sense of what amyloid removal looks like as a sub-Q once monthly administration. we have a good sense of what amyloid removal looks like as a sub-q once monthly administration I do think that sets it apart a little bit from maybe some of the other things we've seen in the field that have been brought in by companies where maybe that foundational antibody. It's not yet clear what that potentially offers with respect to amyloid removal in a clinical setting. I do think that sets it apart a little bit from maybe some of the other things we've seen in the field that have been brought in by companies where maybe that foundational antibody. i do think that sets it apart a little bit from maybe some of the other things we've seen in the field that have been brought in by companies where maybe that foundational antibody It's not yet clear what that potentially offers with respect to amyloid removal in a clinical setting. it's not yet clear what that potentially offers with respect to amyloid removal in a clinical setting

Speaker 1: But I think it also goes to deal value, right? And that's another way to think about it too. So I think at the end of the day, you go out and achieve the data sets you're trying to show that your construct works, right, and compare it to others, whether that is in humans or in animals. But that being all said, I think it's just about value at the end of the day. But I think it also goes to deal value, right? but i think it also goes to deal value right And that's another way to think about it too. and that's another way to think about it too So I think at the end of the day, you go out and achieve the data sets you're trying to show that your construct works, right, and compare it to others, whether that is in humans or in animals. so i think at the end of the day you go out and achieve the data sets you're trying to show that your construct works right and compare it to others whether that is in humans or in animals But that being all said, I think it's just about value at the end of the day. but that being all said i think it's just about value at the end of the day Got it. Got it. Just kind of moving on to prasinezumab and coramitug, as these programs kind of move forward to phase III, what indications have you seen from Roche and Novo in terms of how they're prioritizing and resourcing these programs? Got it. got it Got it. Just kind of moving on to prasinezumab and coramitug, as these programs kind of move forward to phase III, what indications have you seen from Roche and Novo in terms of how they're prioritizing and resourcing these programs? got it just kind of moving on to prasinezumab and coramitug as these programs kind of move forward to phase iii what indications have you seen from roche and novo in terms of how they're prioritizing and resourcing these programs I mean. I mean. i mean

Speaker 2: I'll say, I think in all cases, so we have some great collaborations, not just with Roche and Novo, but also with Bristol Myers Squibb. And I think in all cases, we've seen that these companies are rationalizing their internal portfolios. They're continuing to put, I think, pretty important gates and criteria around what programs move forward. So to see both in the Novo case with coramitug, that molecule, a decision made by Novo to move that forward. We've now seen the phase II data set that I think led to that decision-making, which we can talk about. And then also on the Roche side with prasinezumab, we've seen some of the data they've presented around the two phase II studies that have been completed. And obviously, that went through a rigorous evaluation criteria process within Roche. I'll say, I think in all cases, so we have some great collaborations, not just with Roche and Novo, but also with Bristol Myers Squibb. i'll say i think in all cases so we have some great collaborations not just with roche and novo but also with bristol myers squibb And I think in all cases, we've seen that these companies are rationalizing their internal portfolios. and i think in all cases we've seen that these companies are rationalizing their internal portfolios They're continuing to put, I think, pretty important gates and criteria around what programs move forward. they're continuing to put i think pretty important gates and criteria around what programs move forward So to see both in the Novo case with coramitug, that molecule, a decision made by Novo to move that forward. so to see both in the novo case with coramitug that molecule a decision made by novo to move that forward We've now seen the phase II data set that I think led to that decision-making, which we can talk about. we've now seen the phase ii data set that i think led to that decision-making which we can talk about And then also on the Roche side with prasinezumab, we've seen some of the data they've presented around the two phase II studies that have been completed. and then also on the roche side with prasinezumab we've seen some of the data they've presented around the two phase ii studies that have been completed And obviously, that went through a rigorous evaluation criteria process within Roche. and obviously that went through a rigorous evaluation criteria process within roche Clearly, they have a lot of things they could be working on. I think in both cases, it's great to see those things move forward. An indication of the potential of those is phase III programs. Clearly, they have a lot of things they could be working on. clearly they have a lot of things they could be working on I think in both cases, it's great to see those things move forward. i think in both cases it's great to see those things move forward An indication of the potential of those is phase III programs. an indication of the potential of those is phase iii programs Got it. Got it. got it

Speaker 1: And I would just add on that that we had great presentations from data sets from both Roche and Novo this year relating and helping justify those phase III, right? So AD/PD 2025 for Roche, they presented some very compelling data on prasinezumab, especially at two-year duration and levodopa in the double-blind portion, which helps the justification for phase III. And then just recently at AHA 2025, a late-breaker presentation, very exciting data on NT-proBNP, about a 50% difference from placebo on that arm. And that small study really justifying them moving forward as well as some echo data. And I would just add on that that we had great presentations from data sets from both Roche and Novo this year relating and helping justify those phase III, right? and i would just add on that that we had great presentations from data sets from both roche and novo this year relating and helping justify those phase iii right So AD/PD 2025 for Roche, they presented some very compelling data on prasinezumab , especially at two-year duration and levodopa in the double-blind portion, which helps the justification for phase III. so ad/pd 2025 for roche they presented some very compelling data on prasinezumab especially at two-year duration and levodopa in the double-blind portion which helps the justification for phase iii And then just recently at AHA 2025, a late-breaker presentation, very exciting data on NT-proBNP, about a 50% difference from placebo on that arm. and then just recently at aha 2025 a late-breaker presentation very exciting data on nt-probnp about a 50% difference from placebo on that arm And that small study really justifying them moving forward as well as some echo data. and that small study really justifying them moving forward as well as some echo data

Speaker 2: Yeah, well, a 50% change from placebo, but really, in my mind, something that was kind of interesting was a reduction from baseline. And I think if we look to the other agents in this space, we really haven't seen that, certainly not within a 12-month time period. So pretty remarkable there, the cardiac remodeling with the echocardiogram readouts, as you say, and at least not statistically significant, but across a 12-month time period, at least directionally, seeing an effect that goes in the correct direction relative to placebo on six-minute walk tests. So I think an encouraging overall weight of evidence data set with coramitug and obviously justifying that program moving into phase III. Yeah, well, a 50% change from placebo, but really, in my mind, something that was kind of interesting was a reduction from baseline. yeah well a 50% change from placebo but really in my mind something that was kind of interesting was a reduction from baseline And I think if we look to the other agents in this space, we really haven't seen that, certainly not within a 12-month time period. and i think if we look to the other agents in this space we really haven't seen that certainly not within a 12-month time period So pretty remarkable there, the cardiac remodeling with the echocardiogram readouts, as you say, and at least not statistically significant, but across a 12-month time period, at least directionally, seeing an effect that goes in the correct direction relative to placebo on six-minute walk tests. so pretty remarkable there the cardiac remodeling with the echocardiogram readouts as you say and at least not statistically significant but across a 12-month time period at least directionally seeing an effect that goes in the correct direction relative to placebo on six-minute walk tests So I think an encouraging overall weight of evidence data set with coramitug and obviously justifying that program moving into phase III. so i think an encouraging overall weight of evidence data set with coramitug and obviously justifying that program moving into phase iii Got it. Now that Prothena is kind of largely focused on supporting partner programs, for PRX005 and coramitug, as they kind of head into phase III, what does that support look like if you kind of get more granular into that? Got it. got it Now that Prothena is kind of largely focused on supporting partner programs, for PRX005 and coramitug, as they kind of head into phase III, what does that support look like if you kind of get more granular into that? now that prothena is kind of largely focused on supporting partner programs for prx005 and coramitug as they kind of head into phase iii what does that support look like if you kind of get more granular into that Yeah, so we've been, I think, fortunate to have really great partnerships. And in the case of both Roche and Novo, we have engaged in, I think, pretty extensive dialogue with both of those companies around the science, around the clinical decision-making. And so we offer whatever support we can. And obviously, we're available to lend whatever support is needed. And obviously, we continue to work very closely with those partners as well as our partners at Bristol Myers Squibb. So with Bristol Myers Squibb, it's maybe a little bit more intensive. We're still conducting the phase I study for PRX019, where we expect them to potentially make a decision, which has some consequence relative to. Yeah, so we've been, I think, fortunate to have really great partnerships. yeah so we've been i think fortunate to have really great partnerships And in the case of both Roche and Novo, we have engaged in, I think, pretty extensive dialogue with both of those companies around the science, around the clinical decision-making. and in the case of both roche and novo we have engaged in i think pretty extensive dialogue with both of those companies around the science around the clinical decision-making And so we offer whatever support we can. and so we offer whatever support we can And obviously, we're available to lend whatever support is needed. and obviously we're available to lend whatever support is needed And obviously, we continue to work very closely with those partners as well as our partners at Bristol Myers Squibb. and obviously we continue to work very closely with those partners as well as our partners at bristol myers squibb So with Bristol Myers Squibb, it's maybe a little bit more intensive. so with bristol myers squibb it's maybe a little bit more intensive We're still conducting the phase I study for PRX019, where we expect them to potentially make a decision, which has some consequence relative to. we're still conducting the phase i study for prx019 where we expect them to potentially make a decision which has some consequence relative to That's MTBR? That's MTBR? that's mtbr No, PRPRX019 is an undisclosed mechanism. So yeah, so the MTBR program is BMS-986446, which is in phase II. So they're conducting that. They have that fully enrolled. We expect that data according to ClinicalTrials.gov in 2017. No, PRPRX019 is an undisclosed mechanism. no prprx019 is an undisclosed mechanism So yeah, so the MTBR program is BMS-986446, which is in phase II. so yeah so the mtbr program is bms-986446 which is in phase ii So they're conducting that. so they're conducting that They have that fully enrolled. they have that fully enrolled We expect that data according to ClinicalTrials.gov in 2017. we expect that data according to clinicaltrials.gov in 2017

Speaker 1: 2027. 2027. 2027

Speaker 2: 2027. 2027. 2027 By the way, are they going? By the way, are they going? by the way are they going Thank you. 2027. Thank you. 2027. thank you 2027 I feel like that trial's being run like a phase III and just slowing them down and you guys down with it as well. I feel like that trial's being run like a phase III and just slowing them down and you guys down with it as well. i feel like that trial's being run like a phase iii and just slowing them down and you guys down with it as well

Speaker 1: No, I mean, the primary thing is tau PET. No, I mean, the primary thing is tau PET. no i mean the primary thing is tau pet Why? Week 76. Why? why Week 76. why week 76 They want to make. I mean, I think the whole field, in a sense, wants to correlate tau PET to clinical outcomes. I think they are actually running an appropriate phase II. They want to make. they want to make I mean, I think the whole field, in a sense, wants to correlate tau PET to clinical outcomes. i mean i think the whole field in a sense wants to correlate tau pet to clinical outcomes I think they are actually running an appropriate phase II. i think they are actually running an appropriate phase ii There's no interim like first 50 patients out to week 76 that you could get much sooner? There's nothing like that? There's no interim like first 50 patients out to week 76 that you could get much sooner? there's no interim like first 50 patients out to week 76 that you could get much sooner There's nothing like that? there's nothing like that I don't believe that's how they've structured it, so it's data in 2027. I don't believe that's how they've structured it, so it's data in 2027. i don't believe that's how they've structured it so it's data in 2027

Speaker 2: Yeah, but I think the way that they're conducting that trial makes a lot of sense, right? So the key kind of element there is this is an MTBR targeting monoclonal antibody against tau. MTBR has recently come, I think, very center stage in terms of the pathology of tau in the context of Alzheimer's disease. Recent data from the ACI molecule, which targets a different part of the MTBR sequence, has shown that you see reductions of phospho tau-243, which is something that seems to correlate better with, for example, tau PET than maybe the pTau-181s and 217s, which correlate a little bit better with amyloid beta changes. And so I think there's a lot of excitement about what these MTBR agents can do. And the way that study is structured now is to look, I think, in a relatively definitive way at changes in tau PET. Yeah, but I think the way that they're conducting that trial makes a lot of sense, right? yeah but i think the way that they're conducting that trial makes a lot of sense right So the key kind of element there is this is an MTBR targeting monoclonal antibody against tau. so the key kind of element there is this is an mtbr targeting monoclonal antibody against tau MTBR has recently come, I think, very center stage in terms of the pathology of tau in the context of Alzheimer's disease. mtbr has recently come i think very center stage in terms of the pathology of tau in the context of alzheimer's disease Recent data from the ACI molecule, which targets a different part of the MTBR sequence, has shown that you see reductions of phospho tau-243, which is something that seems to correlate better with, for example, tau PET than maybe the pTau-181s and 217s, which correlate a little bit better with amyloid beta changes. recent data from the aci molecule which targets a different part of the mtbr sequence has shown that you see reductions of phospho tau-243 which is something that seems to correlate better with for example, tau pet than maybe the ptau-181s and 217s which correlate a little bit better with amyloid beta changes And so I think there's a lot of excitement about what these MTBR agents can do. and so i think there's a lot of excitement about what these mtbr agents can do And the way that study is structured now is to look, I think, in a relatively definitive way at changes in tau PET. and the way that study is structured now is to look i think in a relatively definitive way at changes in tau pet But with having functional measures as key secondaries, it allows you to also go in then and evaluate changes in tau PET and that relationship to any functional change. I think that's important, and it's very informative with respect to thinking about future studies. But with having functional measures as key secondaries, it allows you to also go in then and evaluate changes in tau PET and that relationship to any functional change. but with having functional measures as key secondaries it allows you to also go in then and evaluate changes in tau pet and that relationship to any functional change I think that's important, and it's very informative with respect to thinking about future studies. i think that's important and it's very informative with respect to thinking about future studies Excellent. Any thoughts on or comments on the recent J&J tau failure? Excellent. excellent Any thoughts on or comments on the recent J&J tau failure? any thoughts on or comments on the recent j&j tau failure Yeah, I mean, very different epitope, very different part of the molecule. Obviously, it was a phospho-specific antibody at pTau-217, which is more in the proline-rich repeat area of the tau protein relative to what we're talking about in terms of MTBR. I think if you look at the work of folks out there in the field like Marc Diamond and others, it's pretty clear from his work and related publications that this microtubule binding domain of the MTBR region really is responsible for making the key interactions with, if you will, unaffected neurons that allow for the internalization of tau fragments to start to seed and affect those neurons. It's through an interaction with a protein called heparan sulfate proteoglycan. And the best kind of narrowing of that interface region seems to be to the MTBR region. Yeah, I mean, very different epitope, very different part of the molecule. yeah i mean very different epitope very different part of the molecule Obviously, it was a phospho-specific antibody at pTau-217, which is more in the proline-rich repeat area of the tau protein relative to what we're talking about in terms of MTBR. obviously it was a phospho-specific antibody at ptau-217 which is more in the proline-rich repeat area of the tau protein relative to what we're talking about in terms of mtbr I think if you look at the work of folks out there in the field like Marc Diamond and others, it's pretty clear from his work and related publications that this microtubule binding domain of the MTBR region really is responsible for making the key interactions with, if you will, unaffected neurons that allow for the internalization of tau fragments to start to seed and affect those neurons. i think if you look at the work of folks out there in the field like marc diamond and others it's pretty clear from his work and related publications that this microtubule binding domain of the mtbr region really is responsible for making the key interactions with if you will unaffected neurons that allow for the internalization of tau fragments to start to seed and affect those neurons It's through an interaction with a protein called heparan sulfate proteoglycan . it's through an interaction with a protein called heparan sulfate proteoglycan And the best kind of narrowing of that interface region seems to be to the MTBR region. and the best kind of narrowing of that interface region seems to be to the mtbr region So the relevance of that proline-rich repeat region in terms of that kind of continuing pathogenic spread, I think, is a little bit more hypothetical. And I think what we're seeing is, at least on the top line, targeting those proline-rich repeat areas doesn't seem to be having the impact I think the sponsors had hoped it would. Whether then, in fact, with more data cuts and a little additional data analysis, there might be some important learnings that come from that, we certainly hope so. And that's something we'll be looking to. So the relevance of that proline-rich repeat region in terms of that kind of continuing pathogenic spread, I think, is a little bit more hypothetical. so the relevance of that proline-rich repeat region in terms of that kind of continuing pathogenic spread i think is a little bit more hypothetical And I think what we're seeing is, at least on the top line, targeting those proline-rich repeat areas doesn't seem to be having the impact I think the sponsors had hoped it would. and i think what we're seeing is at least on the top line targeting those proline-rich repeat areas doesn't seem to be having the impact i think the sponsors had hoped it would Whether then, in fact, with more data cuts and a little additional data analysis, there might be some important learnings that come from that, we certainly hope so. whether then in fact with more data cuts and a little additional data analysis there might be some important learnings that come from that we certainly hope so And that's something we'll be looking to. and that's something we'll be looking to Got it. Got it. I know we're at time, Mike, so we might have to wrap it up. But why don't you ask your last? Got it. got it Got it. got it I know we're at time, Mike, so we might have to wrap it up. i know we're at time mike so we might have to wrap it up But why don't you ask your last? but why don't you ask your last No, I mean, just one final question while we're on the subject of the tau. Phase II, they got fast-track status. What does that tell you about their level of conviction? Kind of, what do you need to see to view this as a potential registrational path? No, I mean, just one final question while we're on the subject of the tau. no i mean just one final question while we're on the subject of the tau Phase II, they got fast-track status. phase ii they got fast-track status What does that tell you about their level of conviction? what does that tell you about their level of conviction Kind of, what do you need to see to view this as a potential registrational path? kind of what do you need to see to view this as a potential registrational path Yeah, so I think there's kind of two questions in there. The first is just around fast-track and what is the current kind of zeitgeist around tau and how do we think about that? And I think we've known for a long time that tau is very relevant in the context of Alzheimer's disease. Most in the field feel that A beta is an important kind of precedent and continuing event that leads to tau deregulation, and then you end up with neuroinflammation and some other components as well. So it's a multi-kind of component disease that is probably initiated by early dysfunction in A beta, but then A beta continues to have a toxic function throughout the lifespan of the disease space. So tau is very important. It's proximal to some of the functional deficits that you see in patients that show up. Yeah, so I think there's kind of two questions in there. yeah so i think there's kind of two questions in there The first is just around fast-track and what is the current kind of zeitgeist around tau and how do we think about that? the first is just around fast-track and what is the current kind of zeitgeist around tau and how do we think about that And I think we've known for a long time that tau is very relevant in the context of Alzheimer's disease. and i think we've known for a long time that tau is very relevant in the context of alzheimer's disease Most in the field feel that A beta is an important kind of precedent and continuing event that leads to tau deregulation, and then you end up with neuroinflammation and some other components as well. most in the field feel that a beta is an important kind of precedent and continuing event that leads to tau deregulation and then you end up with neuroinflammation and some other components as well So it's a multi-kind of component disease that is probably initiated by early dysfunction in A beta, but then A beta continues to have a toxic function throughout the lifespan of the disease space. so it's a multi-kind of component disease that is probably initiated by early dysfunction in a beta but then a beta continues to have a toxic function throughout the lifespan of the disease space So tau is very important. so tau is very important It's proximal to some of the functional deficits that you see in patients that show up. it's proximal to some of the functional deficits that you see in patients that show up Most of those patients go through some period of rapid tau accumulation before you start to see subjective functional complaints. And so I think tau is a very interesting and important target from that perspective. So the idea of fast-track status makes sense from that lens. I think the second part of your question was. Most of those patients go through some period of rapid tau accumulation before you start to see subjective functional complaints. most of those patients go through some period of rapid tau accumulation before you start to see subjective functional complaints And so I think tau is a very interesting and important target from that perspective. and so i think tau is a very interesting and important target from that perspective So the idea of fast-track status makes sense from that lens. so the idea of fast-track status makes sense from that lens I think the second part of your question was. i think the second part of your question was The registrational. The registrational. the registrational Oh, registrational nature of that. Look, it's hard to say. I think all companies would advise that we should expect to run a robust phase III or phase IIIs in order to get registration from a full approval approach. If we look to the precedents in the field in Alzheimer's disease around A beta, what was required for aducanumab, for lecanemab to receive accelerated approval? Basically, the primary basis of approval were changes in imaging. So a biomarker that was reasonably likely to predict clinical benefit. That reasonable likeliness was exemplified through an understanding of how functional changes related, at least at a group level, to those changes in the biomarker. And at the end of the day, unless I'm mistaken, I believe the phase IIIs were fully or near fully enrolled at the time of those accelerated approvals. Oh, registrational nature of that. oh registrational nature of that Look, it's hard to say. look it's hard to say I think all companies would advise that we should expect to run a robust phase III or phase IIIs in order to get registration from a full approval approach. i think all companies would advise that we should expect to run a robust phase iii or phase iiis in order to get registration from a full approval approach If we look to the precedents in the field in Alzheimer's disease around A beta, what was required for aducanumab, for lecanemab to receive accelerated approval? if we look to the precedents in the field in alzheimer's disease around a beta what was required for aducanumab for lecanemab to receive accelerated approval Basically, the primary basis of approval were changes in imaging. basically the primary basis of approval were changes in imaging So a biomarker that was reasonably likely to predict clinical benefit. so a biomarker that was reasonably likely to predict clinical benefit That reasonable likeliness was exemplified through an understanding of how functional changes related, at least at a group level, to those changes in the biomarker. that reasonable likeliness was exemplified through an understanding of how functional changes related at least at a group level to those changes in the biomarker And at the end of the day, unless I'm mistaken, I believe the phase IIIs were fully or near fully enrolled at the time of those accelerated approvals. and at the end of the day unless i'm mistaken i believe the phase iiis were fully or near fully enrolled at the time of those accelerated approvals Again, if one wanted to allow themselves to wander down that path for a moment, hypothetically, I think the idea of having a primary outcome measure as an imaging marker, functional endpoints as a secondary outcome measure so that you can actually establish that relationship, at least put you in a good position to have those conversations. But again, I think the guidance certainly would be that the expectation, the base expectation is to run robust phase IIIs to prove out efficacy. Again, if one wanted to allow themselves to wander down that path for a moment, hypothetically, I think the idea of having a primary outcome measure as an imaging marker, functional endpoints as a secondary outcome measure so that you can actually establish that relationship, at least put you in a good position to have those conversations. again if one wanted to allow themselves to wander down that path for a moment hypothetically i think the idea of having a primary outcome measure as an imaging marker functional endpoints as a secondary outcome measure so that you can actually establish that relationship at least put you in a good position to have those conversations But again, I think the guidance certainly would be that the expectation, the base expectation is to run robust phase IIIs to prove out efficacy. but again i think the guidance certainly would be that the expectation the base expectation is to run robust phase iiis to prove out efficacy Just before we wrap it up, Tran, in a scenario where Lilly hits 40%+ effect size in their preclinical Alzheimer's study, how do you guys intend to communicate to the street the continued commitment to the A beta space now with the transferrin receptor-based technology? I just want to sort of throw it out there because it's obviously important and you guys have a lot of experience here. Just before we wrap it up, Tran, in a scenario where Lilly hits 40%+ effect size in their preclinical Alzheimer's study, how do you guys intend to communicate to the street the continued commitment to the A beta space now with the transferrin receptor-based technology? just before we wrap it up tran in a scenario where lilly hits 40%+ effect size in their preclinical alzheimer's study how do you guys intend to communicate to the street the continued commitment to the a beta space now with the transferrin receptor-based technology I just want to sort of throw it out there because it's obviously important and you guys have a lot of experience here. i just want to sort of throw it out there because it's obviously important and you guys have a lot of experience here

Speaker 1: Yeah, I mean, I think it shows through our preclinical studies that we are running and we'll share data on. And then after that, sharing a clinical plan, right, that would get to patient-level data that would show basically the positive characteristics of the construct. And I think from there, given the broader, I would say, development, because I think Lilly's running a great phase III for sub-Q remternetug in terms of dual population enrollment, right, in terms of pre-symptomatic and symptomatic, that would be something I think that could be attractive to a large pharma from that perspective. But I think go along that continuum and clearly work with large pharma along the way and try to, to what we discussed earlier with Mike, is where's the best value point. Yeah, I mean, I think it shows through our preclinical studies that we are running and we'll share data on. yeah i mean i think it shows through our preclinical studies that we are running and we'll share data on And then after that, sharing a clinical plan, right, that would get to patient-level data that would show basically the positive characteristics of the construct. and then after that sharing a clinical plan right that would get to patient-level data that would show basically the positive characteristics of the construct And I think from there, given the broader, I would say, development, because I think Lilly's running a great phase III for sub-Q remternetug in terms of dual population enrollment, right, in terms of pre-symptomatic and symptomatic, that would be something I think that could be attractive to a large pharma from that perspective. and i think from there given the broader i would say development because i think lilly's running a great phase iii for sub-q remternetug in terms of dual population enrollment right in terms of pre-symptomatic and symptomatic that would be something i think that could be attractive to a large pharma from that perspective But I think go along that continuum and clearly work with large pharma along the way and try to, to what we discussed earlier with Mike, is where's the best value point. but i think go along that continuum and clearly work with large pharma along the way and try to to what we discussed earlier with mike is where's the best value point Makes sense. Fantastic. Excellent. Well, thank you guys. Thanks for joining. And certainly be in touch. Makes sense. makes sense Fantastic. fantastic Excellent. excellent Well, thank you guys. well thank you guys Thanks for joining. thanks for joining And certainly be in touch. and certainly be in touch

Speaker 2: Thanks for having us. Thanks for having us. thanks for having us