Good afternoon, everyone. Welcome to our second day at our Piper Sandler Healthcare Conference. My name is Yasmeen Rahimi. I'm a Senior Biotech Analyst here at Piper Sandler. Really thrilled to have the Prothena team here with us. Thank you again for traveling and being here with us and spending the time. We have lots to cover over the next 25 minutes, so let's just get started. I think a great place to start off is you really have a pipeline of phenomenal assets that you partnered. So maybe help us understand what is the overall pipeline strategy for the company as we look into 2026. No, Tran, please. I think, thank you for that, and Yas, thank you for inviting us and having us out at your conference. We always appreciate it every year. The weather's holding up nicely, so appreciate that. From a value perspective, we continue to drive value with our protein dysregulation expertise, which, as you said, shows up in our robust pipeline. We have two late-stage programs in Phase III, Prasinezumab for early Parkinson's that we're partnered with Roche, and they've publicly stated they're going to initiate that trial here in the fourth quarter, and then, of course, Coramitug, which is our ATTR cardiomyopathy program that's in Phase III with Novo. They have initiated that Phase III, so we're very excited by our late-stage programs. Of course, also we have Phase II that's ongoing with Bristol going after early Alzheimer's disease, symptomatic Alzheimer's disease patients with targeting Tau, right, MTBR. Then, of course, we have another program that's partnered with Bristol called PRX019, undisclosed target, but for neurodegeneration. We're conducting the Phase I. Of course, Bristol, we'll see that data next year. Then, of course, we'll make a decision. Mark will cover this in the milestones. But, of course, that's a clinical milestone we can receive upon that decision-making. That being said, in terms of our kind of near-term focus for 2026 would be we have folks at Prothena focused on achieving the $105 million of clinical milestones for Coramitug and for PRX019. Coramitug is earned when a certain number of patients are enrolled in the Phase III. We'll clearly announce that if and when that occurs. Of course, they've already initiated. Of course, we're also working on. We just put out a poster at the Society for Neuroscience for a technology called CYTOPE. We can go more into that a little bit later. But we're also excited by that because we're going to look for unpartnered programs and technologies such as CYTOPE to partner out in 2026. We'll be working towards that. And that could be anywhere from a business development deal to a research agreement to further elucidate, let's say, the technology platform for CYTOPE. And, of course, we just had a successful EGM where we passed to give ourselves the ability to do a share repurchase program next year. So we'll be targeting to announce that around, let's say, the fourth quarter announcement in 2026. So it gives you kind of a snapshot of where we are out strategically. Okay. Perfect. Thank you, team. Let's maybe go through program by program as much as we can cover in a short period of time. Maybe Prasinezumab and PD. I think investors who haven't paid attention maybe help walk us through the alpha-synuclein antibody approach and why it makes sense for Parkinson's disease, especially overlaying it with what we know about the pathophysiology of Parkinson's. Yeah. Prasinezumab is the molecule that you're referring to. And as Tran had mentioned, that's partnered with Roche. And they've just moved that into a Phase III study on the back of two Phase II studies that were conducted, showing, I think, very consistent biological effect across those two studies. So we're excited about that. Prasinezumab is a monoclonal antibody that targets a protein, alpha-synuclein. Alpha-synuclein is more or less the smoking gun with respect to cause and progression of Parkinson's disease. And obviously, the approach here would be a disease or potentially disease-modifying approach. And if successful, would represent the first disease modifier for this disease. Why is that important? Well, Parkinson's is the fastest growing neurodegenerative disease globally, so about 10 million patients today. But growing actually at a rate faster than even Alzheimer's disease, which today is a higher prevalence rate. So we think it's a very important program. What we've shown with Roche to date across these two Phase II studies is a delay in time to progression of motor dysfunction. Using some open label data, Roche has also shown a slowing of progression over time, again, on a functional measure of motor progression, the MDS-UPDRS Part III, and shown other components of that, including biomarkers and ways of measuring movement dysfunction that correlate with those changes as measured by MDS-UPDRS Part III. So we're excited to see that move into a Phase III program. We think it represents kind of first-in-class and state-of-the-art in terms of how you target alpha-synuclein. We spent a lot of time even in the preclinical phase making sure that we targeted that 140+ amino acid protein in the right way and in the right place. Now we're starting to see some of those clinical data become more consistent. That's actually very encouraging. And, team, obviously, you have a Phase IIb PADOVA study. You had this year the Phase II PASADENA study that read out. Maybe help us understand what have we learned from the learnings of the study? Because your partner obviously has publicly communicated, Roche, that they're advancing and starting a Phase III study at year-end, right around the corner this month. So maybe you could contrast the learnings that will sort of inform decision in regards to Phase III. Yeah. So why don't I get started? Maybe we can talk about the Phase III trial design and how they've incorporated some of the learnings from those Phase IIs, including the open-label extension from the PASADENA study that's gone out over four years, showing a really nice slowing of progression of disease. So the Phase III clinical trial design is very similar to the Phase IIb PADOVA study. For instance, the primary endpoint is still time to motor progression. That's a worsening of MDS-UPDRS Part III, so time-to-event study. But it's also going to be better powered. It's 900 patients as opposed to 586. And that patient population is early Parkinson's disease patients on stable symptomatic treatment with levodopa. And why that's important is in PADOVA, 75% of patients who are on levodopa actually performed better and actually were nominally statistically significant in that trial. The other learning that they have incorporated into Phase III is the trial design duration is now going out to two years before the primary endpoint. All patients have to be in the trial for at least two years. When we looked back at the PADOVA data, Phase IIb data, that was an 18-month time point. There they just slightly missed the p-value of 0.06 in the overall population. When you looked at the patients who were in the trial for two years in the double-blind portion, there was a nominally statistically significant effect there. Taking those learnings and applying it to Phase III to increase the probability of success, that's what Roche has done. What has Roche communicated around positioning of this asset in Parkinson's disease and what this opportunity presents? I think the focus right now is in patients that are relatively early in their disease course. And obviously, for disease-modifying agents, that's where you'd expect to have the biggest impact over time. But again, in terms of overall, I think they're talking about potential market opportunity of upwards of $3.5 billion. And so it's a sizable opportunity, as you would expect, for a first-in-class disease modifier in a patient population of this size. I think one of the ways we can start to think about this is time saved, right? So as you think about a progressive disease like Parkinson's disease, where the progressive neurodegeneration continues to occur and that underlies the symptoms and the progressive symptomatology that you see, what you really want to see is that you're actually saving time. You're actually slowing down that progression. You can start to calculate that saved time over a period. So as I think Roche continues to share data from the two Phase II studies, we'll continue to see additional data cuts, additional rationale as to why they've made the decision to move forward into Phase III. We look forward to those additional data shares. What are the economic terms of this partnership as you obviously are going to be entering? Yeah. The deal with Roche is very attractive. To date, we have received $135 million in upfront and clinical milestone payments. What's remaining on the deal is another $620 million in milestone payments. Now, that's mostly going to be around success-based with regulatory and sales milestones. And that's tiered. And then there's also an attractive royalty structure. Royalties on Prasinezumab, on sales, would be tiered up to high double-digit teens. Pretty exciting. That's wonderful. Now, another partnered program with Coramitug, right, in ATTR-CM recently was concurrently published during the AHA conference. Congrats for that. That was a very as well as a late breaker at the session. So maybe a good place to start is just maybe reminding people about the mechanism of PRX004 Coramitug in ATTR and maybe also comparing and contrasting it to other approved therapies that are available. Great question. So Coramitug is really placed for ATTR amyloidosis and in particular ATTR cardiomyopathy. And so folks that are familiar with that field will recognize that there are several key therapeutics in that space. What those therapeutic classes do is really act to either inhibit the synthesis of the offending protein, which in this case is transthyretin, or to stabilize that protein. And so transthyretin in its normal form and function actually forms a heterotetramer. So four units of transthyretin are put together that underlies its normal structure and its normal function. And so the current approaches, what they tend to do is, again, either decrease the production of transthyretin or stabilize that homotetramer. Where we differentiate in terms of Coramitug is it's really targeted to the deposited forms, the resident amyloid that's already there in the heart or in other organs and causing dysfunction. The way that Coramitug was developed was to look at the structure of that homotetramer and to identify areas that were key to the interface. And in so doing, what you could do is target abnormal forms of transthyretin, but leave the normal form and structure and function in place. So that was the goal. We took that through a Phase I study and ultimately partnered with our colleagues at Novo. Mark can talk a little bit about the structure of that business development deal. But they've now, as you say, taken that into a Phase II and reported data. The data we found to be very encouraging. First, looking at NT-proBNP, which is a marker of cardiac health and function, they actually saw at the highest dose level just under a 50% change relative to placebo. And not only that, if you look at the change from baseline, you actually saw a decrease from baseline, which at least to my knowledge in this field is the first time that that's been demonstrated, particularly within the first 12 months of treatment. So very rapid effect and actually starting to see a measure that would be at least directionally consistent with improvement. On top of that, using echocardiogram, they showed different signs and signals of cardiac remodeling that would be, again, consistent with an effect on the offending amyloid in the cardiac system. And although not significant, at least at the highest dose level, saw a separation from placebo in the correct direction, if you will, on six-minute walk test. So again, consistent data, relatively robust compared to what's been published, certainly on NT-proBNP with these other classes of molecules. Ultimately, as you allude, Novo made the decision and communicated the advancement of that into a Phase III study this year. And how does the data from the study, the Phase II data, compare to existing data sets? You noted to the NT-proBNP was something that we've not seen with any other classes. But maybe just have we seen remodeling with other agents? Even though the study wasn't powered for six-minute walk tests, but how does it? Yeah. I think what I can say generally, and Mark, maybe you want to expand on this, is that you tend to see the effects separate at a later time point with some of these other classes of therapies and maybe not to the same level or degree of delta of change that we observed in this study. But I don't know if you want to. No, no. That's absolutely right. And one thing I wanted to add to about the Phase II results is this was on top of stabilizers. So over 80% of the patients were on stabilizers. Actually, even more patients in the high dose of 60 mg, I think it was about 86% were on stabilizers. So you're seeing this effect above and beyond the current standard of care, which is very exciting. Wow. And, team, that's very, very helpful. Thank you. That's a very important distinction, right, that the benefits are on top of the standard. I think that follows through, and Mark will cover this, in the way they designed the Phase III too. Yeah. No, no. I think Novo was very clear, not only concurrently publishing it, sharing it as a late breaker, but their commitment even ahead of that data saying that going to Phase III with their CLEOPATRA study. So maybe help us understand. Mark did a great job kind of highlighting with Bristol. Yeah. So the CLEOPATRA study, that's their Phase III. And as you said, Novo has already initiated this study. This is in approximately 1,280 patients, one-to-one randomization. And what's interesting is Novo is actually looking at all New York Heart Association classes from one to four. So it's kind of an all-comers study on that. And the patients come in, and they can continue to receive their treatments as they would be prescribed by a doctor. So you're going to see that combination therapy approach on top of standard of care there as well. The primary endpoint is what you would expect. They're looking at a composite endpoint of number of events. And those events are cardiovascular death as well as recurrence of cardiovascular-related events such as hospitalizations or urgent heart failure visits. The total study time should take up to about four years for them to collect all of these events. They've started now, and we're looking forward to what happens there. I think another point you made an important point, right, which is this is kind of all stages of disease, including patients that may be a little bit more advanced. I think that is something also that distinguishes this approach, this depleter approach, if you will, from maybe some of the other classes of therapeutics. We saw first with tafamidis that as you move to more advanced patients with more advanced cardiac involvement, you didn't see as robust an impact as you saw with, for example, New York Heart Association class one and two patients. I think we saw a bias towards enrolling maybe patients a little bit more mild in terms of cardiac involvement as we saw the follow-on studies happening with those classes of therapies. Here, the rationale would tell you that going after resident amyloid should be helpful across a broader range of classes of involved patients. And so having this open to New York Heart Association classes across the board, I think, is a little bit differentiated. Then team, what is the economic terms for this partnership, and what are sort of the key milestones left? Yeah, so I think. You know the 100 and something. Yeah. Going into the Novo deal, but first just the commercial potential, right? This is a branded ATTR-CM space. You'd be hard-pressed to find anyone that doesn't have consensus that's around multi-billion dollars for each one of these branded opportunities, including the tafamidis, which I think is somewhere around $5 billion alone for ATTR-CM. So that is a backdrop for what this could potentially be. You then look at our deal with Novo. So our deal with Novo is a little unique. It was actually a sale of the business in 2021. So far, we've received $100 million of milestone payments. We do have another clinical milestone, which is part of the $105 million we expect to receive by the end of next year. But total remaining on the deal is $1.13 billion. A unique aspect of that $1.13 billion is that because of the way we sold the business in 2021, it's not a taxable event. There's no more future taxes on that $1.13 coming in. That would be based on success of, obviously, the clinical start, regulatory, and then tiered sales milestones. Just to add to the uniqueness of it, because of being tax-free with the Irish IRS, basically, they don't deal with royalties really well. You have to basically include larger sales milestones to include the royalties in there. As you get to certain sales thresholds, you get a lump sum for crossing that threshold. That's why it's the $1.1 billion. Okay. Thank you, team. Very helpful. Next one is PRX005 in AD, which is also partnered with Bristol. So maybe there talk to us about the target, right? And it specifically targets the MTBR region of Tau. What is the mechanistic rationale to work in Alzheimer's? Let's start maybe there. Yeah. So Tau, of course, is a complex target. So it's 440 amino acids. There are six major forms of Tau. There are splice variants and the like. So thinking about how to target Tau, we know in a protein that's maybe a little bit more simplistic of 38-42 amino acids, protein like amyloid beta, where you target matters a lot with respect to the biological activity. So certainly, that's the case with Tau as well. What we did many years ago now was to take an approach where we like to call it empirical epitope mapping. So we basically made antibodies against the different parts of Tau. And we looked in a series of preclinical models really for robustness and consistency with respect to biological response in a correct direction as we kind of predefined it. It wasn't until we got to the MTBR region, the microtubule binding region of the Tau protein, that we saw very consistent and robust effects across a number of models. One great example is cell-to-cell transmission, where we saw in terms of the ability of Tau to transmit from an affected cell to an unaffected cell, you've got almost complete blockade by targeting this MTBR region. We think we understand that now. We didn't at the time. And so what we've seen to date in the field now are folks that have tested molecules that target either the amino terminus of Tau or more recently, the proline-rich repeat regions of Tau haven't been successful, at least with the primary outcome measures. We're still learning more about what those trials have shown at a more detailed level. But I think at least on the primary level, they've been reported to be unsuccessful. We and at least one other company out there have kind of moved to this or focused on this MTBR region. We think it's differentiated. There's some research out there, for example, showing that this MTBR region is a critical region to bind to a protein on unaffected cells, called heparan sulfate proteoglycan, and mediate the transmission from cell to cell. And so on reflection now with additional data, it probably makes sense as to why this region might be preferred from a biological effect perspective. We also know from data in the literature that a phospho-tau243 assay seems to track well with changes in tau PET. And obviously, that's very adjacent to this MTBR region. We think in terms of the modifications of tau that happen, maybe secondary to amyloid beta-induced changes, are leading to changes that in this MTBR region are particularly important. So we've taken that molecule forward. We're working with Bristol Myers Squibb, as I think you pointed out. They're now testing that in a Phase II study and looking specifically at changes in Tau PET and additional biomarkers. I don't know, Mark, if you want to talk a little bit about that study design. Yeah. Yeah. I think it's important. So it's a 310 approximate patient study, three arms, so placebo, low dose, and high dose. It's 18 months in duration. And so that's helpful for the imaging and biomarker of Tau PET of the primary endpoint, but also secondaries of clinical outcomes. So CDR sum of boxes and iADRS, they're also looking at as well. Okay. And what is enrollment completion? You said it's like 20. We're on ClinicalTrials.gov. Primary completion is early 2027. Okay. And then team, maybe same, what is the commercial opportunity for this asset? And also, what are the economic terms left at that data? Yeah. So So I think it would be pretty fair to say that the AD with an anti-tau agent would be a multi-billion dollar global market. If we look at the specifics on the economics, so this actually started with a broader partnership with Bristol, where we have $100 million as an upfront payment plus a $50 million equity investment that they still have. And then the programs that we're moving forward is the anti-tau, so the BMS-986446 and PRX019. For 986446, we've received an $80 million and a $55 million clinical milestone to date. They take the rest of the development. And then we have another $562.5 million in milestones, regulatory sales milestones that would be due back, including royalties up to high double-digit teens. Similar on PRX019, we've received $80 million to date. We're running a Phase I. There's another clinical milestone that could be payable to us if BMS decides to advance that, which we would expect that decision by the end of next year. And then beyond that, or sorry, inclusive of that, there is $617.5 million in remaining milestone payments and also a similar royalty structure. Okay. So when you step back, as you think about all these milestones and opportunities, right, you think about over the next time horizon of four years, right, four to five years, all of these key programs are going to continue to mature and set. So how do you think about when you think about an investor, as you're thinking about they're looking for ideas for 2026, this is a huge value creation opportunity without taking really clinical risk, right? So maybe if you could just kind of highlight how the smart strategy of this pipeline and the milestones associated, which the stock doesn't really reflect on. Yeah. I think it shows through in our near-term strategy of focusing on, again, earning the $105 million worth of clinical milestones from both Coramitug and PRX019 and working with our partners on that. And I think from a Coramitug perspective, right, we think that has a high probability. On PRX019, clearly, Bristol still needs to make their decision after they see the data. So we'll continue to work with them on that. And then, of course, also in the near term, we just had our successful EGM, right? And we'll announce a share repurchase program here in 2026 that we'll act upon. So that'll help support the shares in 2026. Again, part of our kind of like let's execute, right? And financially prudent. We'll do this in a financially prudent way. So we'll put out our guidance for 2026 here on our fourth quarter call for 2025. And I think it'll be in the February time period of 2026. And then, of course, technology that we haven't had a chance to talk about, which we can do more later. There's unpartnered programs, of course. And there's our CYTOPE technology, which we'll be working with and discussing it with other potential partners. And that's another way for because any BD deal or any even research agreement is business-wise accretive to shareholders. And so we'll continue to focus on that in the near term. And then that bridges us, of course, to 2027, which, of course, will be when the Tau data reads out. No, that's great. And then team, how big is the infrastructure at Prothena now as you guys are operating through all these partner portfolio? I think we're in the 50s, right, in terms of folks. And of course, we reduced a lot of the folks and kept folks that are supporting activities to the value-enhancing activities that we have. So we think we have the right mix of folks right now. And that could change later, up or down. It just depends on the activity. Often we get the question because you have a strong balance sheet and you have the opportunity to all these additional capital through the partnership, if you're also concurrently seems like you're very good in selling things, whether you're also exploring opportunities to purchase things. Yeah. I'm not purchasing. We have a very robust business development both in and out, right? So we'll take a look at everything. But I think the most important thing to hear is CYTOPE itself can be applied to targets that we think can be proprietary to us. But for now, we're clearly prioritizing. Yeah. I think that technology we haven't talked about it, but I think that technology has the potential to be much broader than even our scope and interest, and so, working with others to really expand that application of that technology, I think, is something that is a near-term focus for us and we're excited about. Wonderful. Well, let's say thank you to the team for a great discussion. I'm very much looking forward to 2026. Thank you. Yeah. Thank you. Thank you.