Ladies and gentlemen, thank you for standing by, and welcome to the Prothena Fourth Quarter and Full Year 2020 Financial Results Conference Call. At this time, all participants are in a listen only mode. After the speaker's presentation there will be a question and answer session. To ask questions during this session, you will need to press star then one on your telephone. Please be advised that today's call is being recorded. If you require any further assistance, please press star then zero. I would now like to hand the conference over to one of your speakers today, Ellen Rose, Head of Communications. Please go ahead. Thank you, Michelle. Good morning, everyone, and welcome to Prothena's investor conference call to review our business progress and our fourth quarter and full year 2020 financial results, and our 2021 financial guidance. Please review the press release we issued earlier today, which is available on our website at prothena.com and is also attached to a Form 8-K filed today with the SEC. On today's call, Dr. Gene Kinney, our President and Chief Executive Officer, will highlight Prothena's recent and 2020 pipeline progress, what distinguishes our scientific platform, and our path for sustainable growth. Following Gene's comments, Tran Nguyen, our Chief Operating Officer and Chief Financial Officer, will review our financial results and performance for the fourth quarter and full year of 2020 and 2021 financial guidance. Gene will provide an overview of our near-term milestones. We will then open the call for Q&A and be joined by Dr. Wagner Zago, our Chief Scientific Officer, and Dr. Radhika Tripuraneni, our Chief Development Officer. Before we begin, I would like to remind you that during the course of today's presentation, we will be making forward-looking statements that are subject to certain risks, uncertainties, and other factors that could cause actual results to differ materially from those referred to in any forward-looking statements. For a discussion of the risks and uncertainties associated with our forward-looking statements, please see our press release issued today, as well as our most recent filings with the SEC. We disclaim any obligation to update our forward-looking statements. With that, I'd like to turn the call over to Gene. Thank you, Ellen, and thank you all for joining us this morning to review our 2020 financial results. It's been an exciting and transformational year for Prothena. As Tran will highlight shortly, we met our 2020 financial guidance and ended the year with a strong cash position. When combined with up to $140 million in potential payments stemming from our collaborations with Roche and Bristol Myers Squibb, this enables us to fund our pipeline through key upcoming milestones. Over the past year, we've made significant progress advancing new medicines with the potential to change treatment paradigms in multiple indications. In our rare peripheral amyloid disease portfolio, we recently announced plans to initiate the phase III AFFIRM-AL study of birtamimab in Mayo Stage IV patients with AL amyloidosis under a Special Protocol Assessment, or SPA agreement with FDA at the unprecedented P value of 0.10. The significant survival benefit observed in our VITAL study made this SPA agreement possible. We expect to initiate the AFFIRM-AL study by mid 2021. We also announced results from our phase I study of PRX004, including improvements in neuropathy and cardiac function in patients with ATTR amyloidosis. We expect to advance this program into a phase II, III study in the fourth quarter of this year. In our neurodegenerative disease pipeline, we advanced two programs in our Alzheimer's disease portfolio. PRX005, our anti-tau antibody being developed under our global neuroscience collaboration with Bristol Myers Squibb, and PRX012, our proprietary next generation subcutaneous anti-Aβ antibody. We continue to expect that the Biogen molecule, aducanumab, will be approved later this year, and we are developing PRX012 to offer a next generation treatment in order to enhance patient compliance and access. Last year, we also announced the results from part one of the phase II PASADENA study of prasinezumab in patients with early Parkinson's disease. Prasinezumab specifically targets the C-terminus of alpha-synuclein and is the first anti-alpha-synuclein antibody to demonstrate significant slowing of motor progression and improvements on imaging biomarkers consistent with disease modification. Based on these results, we announced that with our partners at Roche, we are advancing prasinezumab into a late-stage phase IIb study with further details expected in the second quarter. As someone who has devoted the better part of my career focused on advancing medicines for progressive neurodegenerative diseases, I was particularly encouraged by the consistent signals of efficacy observed in this proof of concept study. This is an exciting time for our company. I'd like to start by highlighting what differentiates Prothena's proven approach, how it positions us as a leader in developing therapies for diseases caused by protein dysregulation, and how we are well-positioned for an extraordinarily productive future. Our unique approach starts with science, specifically our deep scientific understanding of how protein dysregulation contributes to the cause and progression of devastating rare peripheral amyloid and neurodegenerative diseases. This stems from our decades of foundational work in protein biology and an understanding of the dynamic aspects of protein dysregulation, which subsequently informs our selection of targets. We apply our proven protein dysregulation platform to specifically target the pathogenic forms of the proteins that cause disease. We can simplify this process into the saying, epitope matters. It certainly starts with selecting the right epitopes to target on a pathogenic protein. Beyond identifying the optimal epitope, we also engineer a molecule to interact with that epitope in a way that is most likely to intercept or halt the underlying disease process. We do this by designing molecules with a bias toward the pathogenic forms of the protein. Specifically or selectively targeting the toxic protein species in order to alleviate their detrimental effects, while leaving the native or healthy form of the protein unaffected, is important in order to maintain normal, healthy biological function. This unbiased and empirical methodology is highly customized for each target. In some cases, we may target a cryptic epitope. In others, we may select antibodies with hyperavidity, and yet in other cases, we may select a neoepitope. This customized approach depends on the unique characteristics of each target and underlying disease pathology. After a thorough evaluation of a target, we advance discovery candidates after we have demonstrated consistent and robust biological outcomes in preclinical development. An optimized molecule is only useful if you can influence the biology in a way that results in meaningful clinical benefit for patients. We've now achieved this across multiple programs in our pipeline. Our ability to consistently translate our science into clinical proof of concept is an important distinguishing feature of Prothena today. Key to this consistency is knowing how to design a comprehensive clinical program that tests a biological hypothesis in the right patient populations with the right outcome measures. Our growing pipeline includes therapies with blockbuster potential for diseases with enormous unmet medical needs that lack disease-modifying approaches. Importantly, we enjoy a strong capital position that provides a foundation to fund our growing pipeline. With this slide, I want to further illustrate the concept of epitope matters and how targeting a protein at different regions or epitopes results in very different biological outcomes. Here we highlight five protein targets in our portfolio, which are ordered by their length. We have found that targeting epitopes represented by the green areas along the protein results in observations of biological activity in preclinical studies and/or on clinical efficacy measures. We discovered the benefit of targeting these epitopes by first systematically mapping the length of the protein to assess how targeting different epitopes impacts multiple disease-relevant biological outcomes. This approach is absolutely central to our platform and is what enables the design of novel molecules that aim to alleviate the detrimental effects of pathogenic proteins in multiple dysregulated states. Let's start with Alzheimer's disease. Our experience in this space dates back to the development of both AN1792 and bapineuzumab. Our preclinical and clinical research has consistently indicated that potentially disease-modifying antibodies that target the N-terminus of the Aβ protein, shown here in green, could more effectively block toxic effects of both soluble and insoluble forms of beta amyloid than antibodies that target other areas of the protein, which are exemplified in red. Recent clinical results are consistent with this view. Data not only from the aducanumab program but also from recent clinical studies evaluating Eli Lilly's donanemab demonstrate that targeting this region consistently results in clinical benefit. Targeting other regions of the protein have not shown similar clinical benefit. It is our confidence in this approach that led us to develop PRX012. We are advancing this molecule as a next-generation N-terminally directed anti-Aβ antibody for subcutaneous administration in order to improve access to this class of potentially disease-modifying treatments for patients with Alzheimer's disease. This concept has been further illustrated recently in Parkinson's disease, where prasinezumab, our anti-alpha-synuclein antibody in development with Roche, is the first potentially disease-modifying therapeutic to demonstrate signals of efficacy in the phase II PASADENA study on multiple pre-specified secondary and exploratory clinical endpoints, including measures of motor function in patients with early Parkinson's disease. Prasinezumab targets the C-terminus of alpha-synuclein. In contrast, a different anti-alpha-synuclein antibody, Biogen's cinpanemab, which targets the N-terminus of the protein, was recently discontinued from development due to lack of efficacy in a phase II proof of concept study. This finding was consistent with our own preclinical experience, which found that targeting the N-terminus was suboptimal. We adopted a different approach for the development of birtamimab and PRX004, both of which target a cryptic epitope on their respective proteins. With birtamimab, this led to findings of improved survival in a mouse efficacy model, which subsequently translated to an observed significant survival benefit in Mayo Stage IV patients with AL amyloidosis in our phase III VITAL study. PRX004, our antibody that was shown preclinically to specifically bind to pathogenic forms of the TTR protein, translated into positive clinical observations on neuropathy and cardiac function in patients with ATTR amyloidosis in our phase I study. We think this story will play out again with tau, another protein implicated in Alzheimer's disease. Specifically, we believe that targeting the microtubule binding region will be key to intercepting the pathological progression of tau that underlies Alzheimer's pathology. Understanding where and how to target these pathogenic proteins was also critical in the design of our multi-immunogen active vaccine, which has demonstrated robust and balanced immune responses to both tau and Aβ in preclinical studies. Importantly, these immune responses were targeted to the key epitopes that we have identified as relevant for both of these proteins. We recently presented preclinical data on this program at CTAD. As you can see from this slide, disease-related proteins vary widely in terms of their length and their potential conformations of dysregulated forms. This inherent complexity suggests that our approach is one that cannot be easily replicated. One of the key distinguishing features of Prothena today is that we have translated science from our internal discovery engine into positive clinical outcomes for patients, as measured by objective clinical endpoints across multiple programs. Across several indications, we've seen that targeting the appropriate epitope with the optimal binding strength and in the context of the right study design and the right patient population can result in meaningful clinical benefit. Our rare peripheral amyloid portfolio includes birtamimab for AL amyloidosis and PRX004 for ATTR amyloidosis. These molecules have differentiated mechanisms of action from the standard of care therapies, which have not demonstrated an improved survival benefit for patients with advanced cardiac disease at high risk for early mortality due to amyloid deposition. The depleter mechanism of birtamimab and PRX004 directly target and clear the toxic amyloid that deposits in the heart and other vital organs. Earlier this month, we announced our plan to initiate the confirmatory phase III AFFIRM-AL study of birtamimab in AL amyloidosis. AFFIRM-AL is being conducted under a SPA agreement with FDA to enable registration at an unprecedented P value of less than or equal to 0.10 on the primary endpoint of all-cause mortality in Mayo Stage IV patients. We were able to reach agreement with the FDA on this SPA because of the significant survival benefit observed in our previous VITAL study, where we demonstrated a 59% relative risk reduction on all-cause mortality in Mayo Stage IV patients over nine months. In December, we reported results from our phase I study of PRX004 in ATTR amyloidosis. In this study, after only nine months of treatment with PRX004, in eligible patients, we observed less progression on neuropathy than expected, and in several patients, we observed improvement. We also observed important improvement on global longitudinal strain, a key measure of cardiac systolic function in all eligible patients. Turning to the neurodegenerative disease programs in our Alzheimer's disease portfolio, we believe that interventions that target both tau and Aβ have the potential to reduce the clinical decline in or prevent the onset of Alzheimer's disease. As such, our pipeline is advancing programs for both antibodies and vaccines. Our two most advanced preclinical programs are our anti-tau antibody, PRX005, and our anti-A-beta antibody, PRX012. We look forward to sharing preclinical data on PRX005 at an oral presentation at ADPD in March. We've tested a large number of antibodies to epitopes along the tau protein and found that those that target the microtubule binding region more effectively block the binding of tau to neurons and prevent downstream neurotoxic effects. Understanding this biology increases our confidence in selecting and evaluating PRX005 as a clinical candidate, and we look forward to sharing our preclinical data at ADPD. Last year at CTAD, we presented data on PRX012, our next-generation high-potency anti-Aβ antibody. PRX012 has a higher binding strength to amyloid than aducanumab, with as much as an 11-fold greater affinity, and also recognizes Aβ pathology to a greater extent, demonstrating more extensive plaque area binding at lower antibody concentrations. We are developing PRX012 for subcutaneous administration to improve access to this class of treatment for patients with Alzheimer's disease. I'll conclude by highlighting the results from the phase II PASADENA study of prasinezumab in patients with early Parkinson's disease that we announced last September. In Parkinson's, existing treatments are symptomatic and only address a subset of symptoms. There are currently no treatments available that target the underlying cause of the disease to slow its progression. Prasinezumab is designed to block the cell-to-cell transmission of the aggregated pathogenic forms of alpha-synuclein that are the hallmark of Parkinson's disease, thereby slowing clinical decline. In PASADENA, treatment with prasinezumab resulted in significantly reduced decline in motor function of 35% versus placebo at one year and delayed time to clinically meaningful worsening of motor progression. This 35% reduction of clinical decline over just 12 months is particularly noteworthy relative to Alzheimer's disease, where aducanumab has demonstrated reduced cognitive decline of approximately 22% over 18 months. In PASADENA, we also observed improvements on imaging biomarkers and signals of efficacy consistent with disease modification across multiple pre-specified secondary endpoints. Our programs that I've just described address diseases where there are no approved disease-modifying treatments. Each of these programs have the potential to become blockbuster therapies in areas of extraordinarily high unmet need. Our rare peripheral amyloid disease portfolio addresses two orphan disease market opportunities. We are developing birtamimab and PRX004 in targeted patient populations at high risk for early mortality with a particularly urgent unmet medical need for improved survival. Our neurodegeneration portfolio addresses Parkinson's and Alzheimer's, which are the two most common neurodegenerative diseases. Since the occurrence of many neurological disorders, including both Parkinson's disease and Alzheimer's disease, increases with advancing age and the worldwide population is aging at a rate never before observed, the magnitude and impact of the pending healthcare crisis in the absence of better therapies is both predictable and alarming. As we've discussed, our proven protein dysregulation platform is our engine for sustainable growth. This year, we expect three programs to initiate late-stage clinical studies for birtamimab in AL amyloidosis, prasinezumab in Parkinson's disease, and PRX004 in ATTR amyloidosis. Beyond these programs, we expect internal R&D to deliver as many as six INDs for new molecules over the next three years. A combination of potential payments resulting from our collaborations with Roche and Bristol Myers Squibb, as well as our existing robust cash position, give us the ability to fund our programs through key milestones. We expect our growing pipeline with programs at every stage of development to facilitate our transition to a fully integrated research, development, and commercial biotechnology company. At this time, I'd like to turn the call over to Tran for a discussion of our 2020 financial performance and our 2021 guidance. Tran? Thanks, Gene. Today, we reported results that were in line with our 2020 financial guidance. Net cash used in operating and investing activities was $81 million compared to our guidance of $75 million-$85 million. Net loss was $111 million compared to our guidance of $101 million-$118 million. As of December 31st, 2020, Prothena had $298 million in cash equivalents, and restricted cash compared to our guidance of $294 million-$304 million. We continue to have no debt. Please refer to the press release issued today for further details regarding our fourth quarter and year-end 2020 financial results. Turning to our 2021 financial guidance, we expect our full year 2021 net cash used in operating investing activities to be $51 million-$74 million, which includes an expected $60 million milestone payment from Roche upon first patient dosed in the previously announced late-stage phase IIb study of prasinezumab. We expect to end the year with approximately $235 million in cash, which represents the midpoint of the range. The estimated full-year 2021 net cash used in operating and investing activities is primarily driven by an estimated net loss of $79 million-$111 million, which includes an estimated $20 million of non-cash share-based compensation expense. With that, I'll turn the call back over to Gene to summarize our upcoming milestones. Thanks, Tran. Before we talk about our near-term milestones, I want to first acknowledge and thank our extraordinarily talented employees for their ongoing commitment to advancing our science to help patients. We continue to operate in challenging times. I could not be more proud to work alongside my colleagues at Prothena. I'd also like to thank the patients, their families, clinicians, and study site staff who participate in our studies. Without their support, we could not elucidate the potential value of the new medicines we're developing. Over the past year, our team has delivered multiple clinical milestones, further positioning Prothena as a leader in protein dysregulation. We look forward to communicating multiple R&D milestones over the next 12 to 18 months. Our AFFIRM-AL study for birtamimab, our most advanced program, is expected to initiate in mid-2021. We also expect to report the nine-month study results from the previous VITAL study at a future medical conference. We anticipate that Roche will initiate the late-stage phase II-B study of prasinezumab in patients with early Parkinson's disease in the second quarter of this year. Prothena will earn a $60 million clinical milestone payment upon first patient dosed in this study. At the upcoming ADPD conference, new pre-specified exploratory subgroup analyses from part one of the phase II PASADENA study of prasinezumab will be highlighted in an oral presentation. We further expect Roche to present results from part two of the PASADENA study at a future medical conference. For PRX004, we expect to initiate the phase II/III study in patients with ATTR cardiomyopathy in the fourth quarter of this year and also plan to present results from our phase I study at a future medical conference. Our portfolio of Alzheimer's disease programs has also advanced. Building on our foundational science and the discovery and development of anti-Aβ antibodies and vaccines, we continue to be highly active in this space with four programs in Alzheimer's disease, including antibody, vaccine, and small molecule approaches. One of these programs, PRX005, is under our global neuroscience collaboration with Bristol Myers Squibb. We expect to file an IND for PRX005 in the third quarter of 2021, triggering a possible U.S. option payment of $80 million. Preclinical data for this anti-tau antibody will be presented in an oral presentation at ADPD in March. Finally, we expect to file an IND in the first quarter of 2022 for our anti-Aβ antibody, PRX012. We're excited about the year ahead. Our team has the capabilities to drive transformational innovation for some of the most devastating diseases affecting society today, and we look forward to providing updates on our programs as they progress. At this time, we'll open the call for questions. Michelle? Thank you. Ladies and gentlemen, if you have a question at this time, please press star then one on your touch-tone telephone. If your question has been answered or you wish to remove yourself from the queue, please press the pound key. To prevent any background noise, we ask that you please place your line on mute once your question has been stated. Our first question comes from the line of Jay Olson with Oppenheimer. Your line is open. Please go ahead. Hey, congrats on all the progress, and thank you for the clear explanation of your strategy and vision for Prothena. The importance of the epitope is really appreciated. Since you've mentioned the differences between prasinezumab and cinpanemab, are there other differences between those two molecules besides the epitope? Also, any feedback on PASADENA Part One that you've gotten from the medical community? Then I had a follow-up question, if I could. Yeah, thanks for the question, Jay Olson. Very important question. Obviously what we're highlighting in today's discussion is that clearly where you target these proteins imparts very different biological outcomes. We spend a lot of time in the preclinical space really exploring these proteins to understand the optimal way of targeting them. Not only where to target them, what the appropriate epitope is, where in the sequence, but also, are there post-translationally modified forms of the protein? Are there phosphorylated forms, for example, versus different misfolded conformations that we want to think about? Ultimately, we impart an approach where we bias our molecule in a manner that tries as best we can to spare the normal form and function of the protein and specifically go after the more pathological forms. In the case of prasinezumab, that was done by using a technique where we really looked for an antibody that had a high preference for the aggregated forms of the protein over the non-aggregated forms of the protein. Using very specific kinetic and quantitative analyses, have been able to show that selectivity or preference is over 400-fold. We think that's a key component as well. Maybe the thing, I can ask Wagner to speak on this, because as we were doing our characterization of antibodies against different parts of the protein, of course, we had our own antibodies that targeted the N-terminus. Maybe, Wagner, I can ask you to speak a little bit about just our experience in that space. Yes. It's a little challenging to make a direct comparison between cinpanemab and prasinezumab other than the epitope. Simply because the data around cinpanemab is so sparse, at least the published data, that it's really hard for us to make that direct comparison. What we can say is that we spent many years screening the entire alpha-synuclein protein. What we found very early in the program is that there was a consistency for antibodies that target the C-terminal portion of alpha-synuclein around where prasinezumab binds. There is a consistency in terms of efficacy for those antibodies. The other antibodies that target the N-terminal portion of alpha-synuclein did not show that consistency. We consider it suboptimal, in fact, efficacy, when we did see efficacy. We focused on the C-terminal portion, and as Gene indicated, one step is to define the right epitope, but the qualities of the antibody that target that epitope is also very important. Binding with the highest binding strength possible that region and be as selective or as specific as possible to the pathogenic forms and sparing what we consider normal biological forms, it was part of the selection of prasinezumab. Prasinezumab has a picomolar, we are talking about 40 picomolar affinity to aggregated alpha-synuclein. That's very important when you consider the blood-brain barrier penetrance of antibodies. We selected prasinezumab based on that affinity, the epitope. We confirmed in multiple animal models the efficacy, but also the dose response of the antibody. Interesting enough, in the clinic with prasinezumab, we confirmed that the occupancy that we expected for the target in the CNS translated in the two doses that we selected a priori as being saturating of that target, showing equivalent efficacy in our phase II. We are very happy. It was a very successful transition or translation of a preclinical, very rigorous preclinical exploration into a clinical evidence of change in the disease progression. Thank you for those details. That's super helpful. As a follow-on, since you have two super high-quality partnerships and now a growing number of wholly owned assets in the clinic or about to enter the clinic, would you consider partnering birtamimab or any of your other wholly owned assets? Our plans with birtamimab are to pursue a commercialization approach with that, particularly, obviously in the major markets in particular, Jay. We think that it's a very focused call point from a commercial perspective. We are addressing what we think is the major unmet medical need in that space, which is to improve survival for patients that are at high risk of early mortality due to the amyloid deposition in the heart in particular. That would be our current plans. Maybe I'll just ask Tran if you want to speak to that further. Yeah, no, I think based on our past experience, we do believe that there is interest, clearly from strategics, on birtamimab, given its concentrated hematology call point. To what Gene just said, given that based on our market research, we are planning to commercialize birtamimab. Basically, as we stated before, it shows that approximately 75% of the Mayo Stage IV patients are treated at about 500 amyloidosis centers of excellence and specialty centers in the U.S. and Europe, which makes for a very efficient hematology sales force footprint. Given the known diagnosed prevalence in regions such as Japan and China, we may explore some regional partnerships. Great. Thanks for taking the questions. Thanks, Jay. Thank you. Our next question comes from the line of Michael Yee with Jefferies. Your line is open. Please go ahead. Hey, guys. Good morning. Congrats on all the progress and thanks for this nice pipeline update. I had two quick questions. They both relate to early-stage compounds. One is on the Bristol Celgene collaboration. You talked about how you do expect a potential milestone there. Maybe just talk about how that dialogue and ongoing conversations have been with that on that program, the progress, and how confident you are that that milestone will come. Maybe just talk a little bit about that target program and conversation. The second question is, obviously, there's a lot more industry interest in Aβ, of course, and we're awaiting a big decision by the FDA. You made some nice comments about your epitope. Can you clarify, is your compound actually more similar to donanemab rather than aducanumab? Maybe just talk about your epitope just a little bit more and the comparison between those programs. Thanks. Yeah. Great questions, Mike. First, let's start with why don't I go backwards order here. let's start with Aβ. Sure. The PRX012 molecule does target the amino terminus of Aβ. Our own research, which Wagner has authored quite a bit of, indicates that targeting that region gives you the optimal ability to interact with both the deposited forms that are the forms that you can actually see on PET imaging and what have you, but also the aggregated soluble forms, which some, I think, feel contribute to disease. The idea there is that you want to hit both of those species, and the way you hit both of those species is by targeting the amino terminus of the protein. aducanumab targets the amino terminus of the protein as well, as does donanemab. Donanemab sees specifically a post-translationally modified version of the amino terminus, particularly the pyroglutamated forms, but it is still targeting that same region. We think there's consistency here in terms of what we're seeing. Importantly, elements of clinical design that one needs to look at as well, and that is when you go to treating prodromal to mild patients and you specifically using endpoints, as was the case with aducanumab using their endpoint CDR Sum of Boxes and also even with BAN2401 using ADCOMS and the most recent donanemab studies, those endpoints tend to be more sensitive and more geared towards those prodromal to mild patient populations. Selecting the right patients and using the right clinical assessment scales are equally important to being able to demonstrate clinical efficacy in our estimation. What do you see? What you tend to see is what has been found now across those studies, which is with aducanumab. In the EMERGE study, you saw a 22% slowing of cognitive decline over the 18-month period. Something in that neighborhood with donanemab as well, again, across 18 months, which we think is good consistency with respect to how we view the biology playing out here. Finally with PRX005, coming back to that, I think there's good dialogue with Bristol Myers Squibb and Celgene. We enjoy the collaboration. It's additive in terms of the value it brings to the program. Obviously the milestone there is an option, which is their option. They'll have to make that decision at the right time. It is connected with the IND filing. We're looking forward to that. I think I'll add something there, Gene. I mean, yes, our teams have been working together. There's a governance committee from a joint steering committee. In order to file an IND, you have to have a plan for a phase I, and so we've been working with their team in that design, because as you know, there's an ex-U.S. global right that they have at the end of phase I to exercise. That's $55 million. Clearly we've been focused on not just the $80 million, but on the $55 million, too. We have been working with them on that phase I design and ultimately the IND package. As Gene just stated, we'll file the IND, and they have a certain time period to make that U.S. option decision, and we look forward to it later this year. Great. Got it. There's a joint steering and there's ongoing communication on that. That adds some color. Lilly is a pGlu targeted specifically on the epitope, too. Thank you for clarifying that. Thank you. Correct. Yep. Mm-hmm. Yep. Thank you. Our next question comes from the line of Charles Duncan with Cantor Fitzgerald. Your line is open. Please go ahead. Good morning, Gene and Tran. Thank you for taking the question and I also appreciate all the platform information that you provided. I'll come back to that. I have a couple of questions on the platform. First, before I do, with regard to near-term clinicals, I guess I'm wondering generally about rate limiting steps, both for AFFIRM as well as the prasinezumab phase II-B. I'm wondering if you could provide us a little bit more color on the operationalization for AFFIRM and when you would anticipate that, and then if you have further information on its size. Similarly with prasinezumab in phase II-B, I'm wondering if you anticipate being able to provide periodic updates beyond just the initial dosing of the first patient. Yeah. Why don't we start with AFFIRM-AL, and maybe Radhika, I can ask you to speak to where operationally what's happening en route to our opening of that study. Sure, Gene. Thanks for the question. It's a really exciting time for Prothena as we embark on getting the AFFIRM-AL study up and running. I think given our history in the space and our past relationship as well as our ongoing program in the ATTR space, we're quite poised to ultimately get this study up and running. The standard activities, as you would assume, as we engage for a Phase III study in terms of site contracts and so forth, are really the main dynamic that we're working through, and we're looking forward to getting that study up and running and initiating it ultimately in mid-2021, so in the very near future. The other dynamic to think about is, we've got a longstanding relationship, and when you consider the study itself and birtamimab, it's an agent in which there's a significant amount of data that's already out there in addition to the post-hoc analysis. I think it really gives us a fair amount of information to communicate and engage the clinical community with, and we've seen that come through with regards to excitement as we get this study started. Yeah. I think, Charles, you also asked about the size of that study. Yeah. It's a 2:1 random. We anticipate enrolling up to 150 patients in total. As Radhika says, we're excited to see that get started. On the prasinezumab side, I think your question was just about news flow. I think what we can say at this point is that we anticipate Roche getting the Phase IIb study up and running. We've talked about the idea that with that study and first patient dose, that avails us of a $60 million clinical milestone in the partnership. I think, we do expect at ADPD that there will be additional analyses of the PASADENA Part 1 study. These are based on pre-specified subgroups. We further expect that at a future conference, TBD, Roche will be talking about the Part 2 PASADENA study as well. I think those are things we can look forward to just from additional information around prasinezumab. Okay. That's helpful. Thank you, Gene. I do have a couple of questions on the platform, but just one more that I was thinking about with regard to the firm. You mentioned the all-cause mortality and the P value 0.1 as being unprecedented, and I guess, when I think about that, it's almost a challenge to think about because it's so low. I guess, is there any other color that you can provide with regard to the discussions that you had with the agency around that? Any perspectives on that P value for AFFIRM? Well, I think as we looked at our data from the VITAL study, and noted what we considered certainly to be a robust survival benefit in Mayo Stage IV patients with a hazard ratio that basically translates to a 59% relative risk reduction of all-cause mortality. That's meaningful. It shouldn't go unsaid that every one of those events is just really beyond quantification, right? These are individuals, families, friends. You look at that, and you don't just turn your head from that sort of data. We spent a long time ourselves really digging into that data. We brought external statisticians in to the team to help challenge us around that data. We looked for ways to try and explain that data away. Failing to do so, we engaged not only with KOLs but also with the regulators. Really the goal there was both to understand the data, but also then to find a feasible path forward in this population. I have to say, it was really a good collaboration with the FDA. It encompassed multiple formal and informal meetings. It was really aligned around understanding both the strength and relevance of the VITAL data and what would be required then to move this forward from a registration perspective. We were very happy that we came to an accord with the agency in the form of this Special Protocol Assessment that underlies what the AFFIRM-AL study is, right? A study that's a 2:1 randomization, up to 150 patients enrolled. As you say, with all-cause mortality at a P value significance of.10, which would enable a registration path when combined with our other datasets. Maybe I'll just add one thing, Gene Kinney. This is Tran Nguyen. In that, simply put, Charles Duncan, if we didn't have this significant survival benefit. In these patients that are at high risk for early mortality, we would not have gotten that, like what you just said, the unprecedented P value of 0.1. We don't believe our other competitors who don't have double-blind placebo-controlled trial data can go to the FDA and have this amazing outcome. We're very excited to be initiating AFFIRM-AL later this year, as Radhika Tripuraneni said, mid 2021. We really do, excited for the VITAL data where, again, you see significant survival benefit. Good deal. We're looking forward to that start and believe that perhaps that setup may drive enrollment faster than are anticipated. One platform question, and that is on PRX012. Follow kind of to Michael's questions regarding how the profile looks relative to, say, aducanumab and donanemab. I guess I'm wondering beyond what you mentioned in that answer, what do you think about the implications of the design of the molecule for, say, CNS penetration and then the potential for ARIA? Since you are gonna have, better targeting, and therefore perhaps even better CNS penetration, but any implications in terms ARIA? Yeah. Since Wagner is an author on a paper that basically described what ARIA is from the biological perspective, I'll let him answer this question. Okay. Let me start by talking about the mechanism behind ARIA. Two things we think is contributing to these vascular observations. One is certainly the removal of Aβ from the vasculature itself. We think that that contributes. Also what we've seen is that during the process of plaque clearance from the parenchyma, not from the vasculature, during that process of clearance by antibodies, there is a mobilization of Aβ from the plaques to perivascular spaces. That process of mobilization, which we believe is an important clearance mechanism in addition to the phagocytosis, that process can alter vascular permeability by changing the interaction of vascular elements with, for example, astrocytes. All of that is to say that we believe that in order to seek to reach clearance of plaques from the brain, you will see ARIA happening at a certain point. We think that that incidence of ARIAs, more specifically the symptomatic ARIA, will very much depend on the Cmax, the maximum concentration of the antibody that's reached in the brain. That is normally a peak. If you do intravenous, you see a maximum Cmax, and the antibody goes down. From our program, what we are positioning PRX012 is to deliver subcutaneously. With a subcutaneous delivery, you will reduce that Cmax but maintain the AUC over the course of one month. You potentially could have even better efficacy, which is underlined, which is driven by the AUC. Potentially the same or even lower ARIA than other antibodies. What we do believe is that if you don't see ARIA, you are not seeing clearance of the meaningful pathogenic forms of Aβ in the brain. We are not surprised that donanemab and aducanumab and BAN2401 all show ARIA. We are also not surprised that the antibodies that did not show efficacy did not show ARIA. Again, because clearance of plaques and that perivascular clearance process is an important component. Yeah. When we think about the blood-brain barrier technologies, and we've looked at many of these very closely. I think what's key is what Wagner is just talking about. This issue of Cmax versus AUC. What you need to be very careful of course, is that you're not increasing in a very transient way concentrations in the brain. That at the end of the day, that compromises the total exposure. One of the techniques that we subscribe to, and I think is built into PRX012, if you will, is this idea of interacting more specifically with aggregated forms of the protein, which would be more exclusively found in the brain, and thereby providing the antibodies over time with better access to that compartment. We think that that's an appropriate approach. It's the approach that we've taken with prasinezumab as well. We think, for some of these types of diseases, particularly where pathology is a little bit more focused in the central compartment, that these types of approaches make sense. Thank you. Our next question comes from the line of Bert Hazlett with BTIG. Your line is open. Please go ahead. Thank you. Thank you for taking the question. Great discussion this morning. I just have a couple of granular ones on the tau program with regard to Bristol. Just with regard to the ADPD data, what are the expectations for data for the upcoming program? I have a couple of follow-ons for the Bristol collaboration more generally. Yeah. Wagner, maybe you can address some of the types of preclinical data that would be expected to be discussed at ADPD. Yeah. We'll be very consistent with what we did in the past with the other programs that we have in the pipeline. We like to publish first. We like to show our data out there and deliver it timely as well. What you're going to see in ADPD is the first round of preclinical data that really guided us to target the MTBR portion of tau, and some in vitro data suggesting that is the most impactful portion of tau that can block the binding to neurons and also neurotoxic effects downstream to that binding to neurons as well. It's the first round. We're going to continue releasing data as we move forward. It's for the first time that we're putting those data as well out there. Also, certainly the superiority of the clinical candidate versus all the antibodies, even within a pool of antibodies that targets the MTBR region, the superiority of PRX005 versus others. That's helpful to frame it. Thank you. Just because these collaborations are so material, could you remind us of the deliverables to gain the $80 million and then the $55 million? As you talk about the collaborative effort, are the principals that were at Celgene still involved in these discussions at Bristol Myers? I think some are, but a little bit more color on that aspect of it would be helpful. Thank you. Yeah. Maybe, Tran, you could address just the structure of the collaboration milestones and then maybe also just a comment on how we've dealt with that in our forecast. Yeah. More importantly to what you're saying, Bert, is that the delivery of the IND, when we file that, we deliver it to them, too. There's some other documents that we send to them, but in a timely manner. They have a certain time period after that to make their decision on their exercising of their U.S. rights. We believe we are on path to deliver all of those necessary documents for them to make their decision. In terms of your question around the players involved, as you know, Bristol had a CNS group back in the day, and they don't anymore in a sense, in terms of Bristol proper. When they acquired Celgene, that CNS team came from Celgene. The team that did the deal with us at Celgene are for the most part there at Bristol, and key relationships still exist that Gene has and that Wagner has up and down from a joint steering committee perspective. We still have daily to weekly conversations with that team, and we've been planning with that team in terms of our ability to be able to say we're on track to deliver the IND, both submission to regulatory authorities and also delivery to that team to make their decision. Yeah. Radhika, maybe you would want to comment on this as well, given that you're driving that towards the clinic. No, of course. I think it's an exceptional relationship that we've had in the beginning with Celgene and now with Bristol. We're really thrilled to continue that collaboration, not just from the business dynamics, but of course the scientific aspects are heavily involved in every aspect of our PRX005 program and have been engaged at all levels, both the formal governance meetings and honestly, there's also over the last couple of years, we've built a very close personal relationship with a number of individuals. We have a number of informal conversations as well in the interim. They're very well versed in the progress and opportunities as we think about getting ready for the IND and launching our first human study. It's been a great relationship. Thanks. Look forward to the catalyst. Appreciate it. Thanks, Bert. Thank you. Our next question comes from the line of Kennen MacKay with RBC Capital Markets. Your line is open. Please go ahead. Hi. Thanks for taking the question here. A question on birtamimab development and, again, how you're thinking about AL amyloidosis in that market moving forward. Obviously in Mayo Stage IV patients, incredible unmet medical need. Just wondering, as you're thinking about the future, whether you think Darzalex will be playing a part in the treatment of those specific patients or whether really thinking about the future beyond birtamimab that is, whether there's anything else in development that might offer any benefit to those patients. Thank you. Yeah. Great questions, Kennen MacKay. Maybe Radhika, do you want to start with those? Yeah. No, thanks for the question. It's great to see, as a clinician, any therapy that's created and ultimately approved for patients, regardless of competition per se by any means. I think when you look at the Darzalex data in closer detail, I think it will still be used for hematological response, but they clearly have not shown any survival benefit that we think is meaningful. Obviously, hematological response is a component of the ultimate management and progress of these patients. At the end of the day, you want to actually maintain survival in these patients. I think the role for birtamimab is clear. I think the opportunity is very clear as we think about the patient population. Maybe Radhika, I'll add a little bit there. I think as we developed in this space, as you see, Ken, and we have a lot of experience in it, and we've learned a lot in terms of our own data and, of course, Dara and others' data. I think the role that our molecule plays in terms of birtamimab is that we're starting to really learn that the advanced patients, especially these Mayo Stage IV patients, they need an antibody that depletes the toxic forms out of tissue, especially the heart. When you look at the great Dara data from the six months, they've got great hematologic response. Six months, they got great organ response. Again, at six months, it didn't translate into better survival. Matter of fact, they had 25 deaths on the Dara arm plus CyBorD versus 20 deaths on the CyBorD arm at six months. Again, those patients at high risk for early mortality, they need an anti-amyloid immunotherapy like birtamimab. That's what our data was showing out, that if you look at our Kaplan-Meier curves, the median OS for the control arm was about eight months. You saw, again, a 59% relative risk reduction in all-cause mortality that was significant in- Yeah Mayo Stage IV patients. Just a reminder on that control arm, that was with standard of care, addressing the hematologic burden. The 59% number that Tran spoke of was on top of standard of care. We think, obviously, that's important. Thank you. Our next question comes from the line of Tazeen Ahmad with Bank of America. Your line is open. Please go ahead. Hi, guys. Good morning, and thanks for taking my question. As all of our companies have been reporting, we've been getting guidance for both sales as well as trial enrollment, with the caveat that people think that COVID could have an impact and the rate of vaccinations might have an impact. As it relates to your particular study with AL amyloidosis, given that it is a serious patient population, how are you thinking about any impact from the pandemic at all, and how important will be the rate of vaccination to your internal view on rate of enrollment in this study? Thank you. Thanks, Tazeen, for the question. Well, I'll ask Radhika to speak on it, but maybe just a quick comment, which is that when we had our webcast on birtamimab, we were fortunate to have Dr. Morie Gertz from Mayo Clinic on the phone with us. Dr. Gertz, of course, treats patients with AL amyloidosis, he was asked the similar question. I think just to reiterate what he said was there were really two mitigating factors there. The first is that patients with AL amyloidosis, particularly Mayo Stage IV patients, because they are at such extreme risk of early mortality that it is not considered optional. It's considered a medical emergency that those patients be seen, diagnosed, and treated as rapidly as possible. The importance of those patients coming into study sites, I think really can't go understated. Then, of course, the second piece that I think he talked about a little bit was just the idea that those patients, because of that very fact, would be expected to be prioritized for COVID vaccination. We think both of those things are mitigating factors, but maybe Radhika, do you want to add? Yeah, no, of course. Thanks, Tazeen. Thanks for the question. I think as Gene noted and as Dr. Morie Gertz noted, it's very much true. These are incredibly ill patients who ultimately come to the front of the line with regards to seeking and ultimately needing to go into these clinics or centers of excellence for care. It's not by any means that it's a slow disease that you simply wait and watch. The reality, too, is when you think about COVID and the general healthcare system, unfortunately, this is not the beginning of the pandemic from a public health dynamic. For the sake of these patients, it's actually quite helpful because a lot of these institutions, particularly the centers of excellence, have instituted protocols, know now after nine, eight months, if not even a year, and in certain cases around the world, more than a year of learning how to manage this condition and really have optimized their protocols to ensure the safety not only of the patients, but also of the caregivers that accompany them, along with the clinical staff that obviously is responsible to provide that care. The reality here is we're really talking about a holistic healthcare system that I think is going to be best suited to optimize the care for these critically ill patients. The other dynamic that we're trying to instill within our study is creating as much flexibility to make it as easy for these patients. Obviously, it's already a stressful time being diagnosed with AL amyloidosis and trying to comprehend all the information that comes with that. The dynamic, I think between the protocol benefits that we've implemented, along with the key centers of excellence and experience of those centers, I think really give us a fair amount of comfort that we'll be able to move forward with this study easily. Thank you. I'm showing no further questions at this time, and I would like to turn the conference back over to Gene Kinney for any further remarks. Great. Thank you, Michelle. Thank you all for joining us. We appreciate your interest in Prothena, and over the coming months, we look forward to sharing further updates on our programs. Thank you. Ladies and gentlemen, thank you for participating in today's conference. This does conclude the program, and you may all disconnect. Everyone, have a great day.