Good day, ladies and gentlemen, and welcome to the Procena Biosciences 4th Quarter and Full Year 2025 Financial Results Conference Call. My name is Jeannie, and I will be your coordinator for today. At this time, all participants are in listen-only mode. We will be facilitating a question and answer session at the end of today's call. If at any time during the call you require assistance, please press star, followed by zero, and a coordinator will be happy to assist you. I would now like to turn the presentation over to Mark Johnson, Vice President and Head of Investor Relations at Prothena. Please proceed.

Thank you, Operator. Good afternoon, everyone, and welcome to today's call to review Prothena's business progress, fourth quarter and full year 2025 financial results, and 2026 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 8K filed today with the SEC. In addition, we are using supplemental slides, which are available on our investors' website, events, and presentation section. On today's call, Dr. Gene Kinney, our President and Executive Officer, will provide opening remarks, including an overview on Prothena's corporate strategy. Chad Swanson, our Chief Development Officer, will provide an update on our ongoing partnered clinical program. Then, Phil Dolan, our Vice President and Head of Discovery Research, will provide an update on our active preclinical program. Tron Nguyen, our Chief Strategy Officer and Chief Financial Officer, will then discuss our 2025 financial results and 2026 financial guidance before turning it back to Gene's closing remarks, at which point we will open up the call for a Q&A session. Brandon Smith, our Chief Operating Officer, will also be available during the Q&A session. Before we begin, I would like to remind you that during 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 reported to in any of the forward-looking statements. For discussion of these 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 and our annual report on Form 10-K to be filed with the SEC for our fiscal year 2025. We disclaim any obligation to update our portal link statement. With that, I'd like to turn the call over to Gene.

Thank you, Mark, and thank you all for joining us today. Let's begin on slide five. In 2025, we saw significant progress with our clinical pipeline where two of our partner programs, Pracinizumab and Gramatog, advanced into phase three clinical trials. Roche advanced plasinizumab into the Phase III CARECO trial, evaluating 900 participants with early Parkinson's disease. This decision was informed by results from two Phase II clinical trials that both demonstrated consistent slowing of disease progression. Novo Nordisk advanced Caramitug into the Phase III Cleopatra trial, evaluating 1,280 patients with amyloid transliuretin cardiomyopathy, or ATTRCM. This decision was informed by results from their Phase II trial demonstrating positive NT-ProBNP and echocardiogram changes, as well as directional observation of benefit in the six-minute walk test. Our collaborations with Bristol-Myers-Swim also progressed in 2025 with several important advancements, including the Phase II Target-Tal-1 clinical trial, evaluating BMS 986446 in early Alzheimer's disease, which was fully enrolled in 2025 with completion expected in the first half of 2027. Crystal Myers, we have also completed a Phase I study evaluating a subcutaneous formulation of BMS 986446 in 2025. And BMS 986446 obtained fast-track designation from the US FDA for the treatment of Alzheimer's disease. And finally, we are conducting a Phase I trial for PRX19, which is on track for completion in 2026. We also shared important updates from our wholly-owned preclinical portfolio in 2025. In the fourth quarter, we introduced our Cytope technology with presentations of our TDP-43 Cytope program for ALS at two scientific congresses. At a high level, these data demonstrated that our cytotechnology has the potential to enable precise targeting of intracellular disease pathways. We also reported results from our Phase I Ascent clinical program evaluating PRX-12 in patients with early Alzheimer's disease. The results helped to elucidate the profile of this once-monthly subcutaneous anti-A beta antibody. Based on significant scientific advances over the last several years, we believe we can further improve this profile with the addition of transparent receptor technology and are actively advancing a PRX-12 transparent program in preclinical development. Turning to slide 6, we have several key 2026 priorities that we believe meaningfully contribute to long-term value creation. The first is to ensure we are best positioned to capture value embedded in our clinical partnerships. As a reminder, all of our partnerships with large pharma companies are programs that originated from Prathena's R&D engine. This year, we have the potential to earn up to $105 million in aggregate clinical milestone payments if Karamatug achieves a pre-specified enrollment target in its ongoing Phase 3 trial and if BMS decides to advance PRX-19 into Phase 2 clinical development. In addition, we have now received all the necessary approvals from our Extraordinary General Meeting of Shareholders and confirmed by the Irish High Court to support a share redemption program in 2026. Finally, we continue to advance our knowledge and understanding of our preclinical portfolio to support our business development team as they explore research collaborations and licensing agreements. For example, we are engaged in a research collaboration with a large pharmaceutical company that explores multiple approaches for applying our Cytope technology to advance and elucidate intracellular targeting. We look forward to establishing additional research collaborations which may lead to future licensing deals. Our strategic priorities are supported by our $308.4 million cash and restricted cash balance as of year-end 2025 and our prudent capital utilization to ensure that we are well positioned to receive future potential economics from our partner programs. Let's move to slide seven to review our upcoming catalysts from our partner portfolio. Looking ahead, we have two potential milestones in 2026 from Karamatug and PRX19, which could be worth up to $105 million. In the first half of 2027, we expect Bristol-Myers Squibb to complete their Phase II Target TAL-1 trial for BMS 986446. And in 2029, we expect primary completions from the two Phase III trials evaluating Roche's Pracinizumab and Novanordis Gramatoc. In total, when you look at our four partner clinical programs, they have the potential in aggregate to deliver up to approximately $3 billion in future milestone payments, which is in addition to any royalties. With that, I'll now turn the call over to Chad to discuss our partner programs in more

Thanks, Gene. Let's start on slide nine. Presonuzumab is a humanized IgG1 monoclonal antibody designed to selectively bind aggregated forms of alpha-synuclein to reduce neuronal toxicity and slow disease progression of Parkinson's disease by blocking further accumulation and propagation of these toxic aggregates. Based on the consistent results from two phase two clinical trials, ADOVA and Pasadena, and their open label extensions, our partner Roche made the decision to advance presenism back to phase three, bringing this potential first disease-modifying therapy one step closer to patients. In fact, Roche made this decision based on a number of important questions. First, is there an unmet need? Yes. There are over 10 million patients globally, and it is the fastest-growing neurodegenerative disease with no approved disease-modifying therapies to slow progression. Second, does it address the foundational target? Yes. Alpha-synutinine is a known biological driver of PD progression, and the clinical evidence today demonstrates efficacy potential and supports a favorable safety and tolerability profiled. Third, is there a meaningful therapeutic differentiation? Yes. The totality of data suggests clear evidence delayed motor progression, even on top of the standard symptomatic treatment levodilva. And finally, is there a strong commercial rationale? Yes. Roche believes Preston is a member who sends a global peak sales opportunity greater than $3.5 million. For Prothena, our deal includes up to $620 million in potential future milestone payments and sales royalties tiered to high teen percentages. In the fourth quarter of 2025, Roche initiated the Phase III Paradeso clinical trial, which will enroll approximately 900 participants with early Parkinson's disease with primary completion expected. Moving on to slide 10, this is an important data set from the Phase IIb PEDOVA trial, which Roche presented at ADPD 2025. Here they show progression on the MDS-UPDRS Part III scale from baseline, which is used to measure disease progression on motor symptoms. This figure shows the results for an exploratory endpoint looking at the subset of participants, approximately 75% of the trial population, for unstable levodopa treatment, comparing 24 months of prexenuzumab treatment versus placebo. What we see is a 40% relative reduction in progression with a nominal p-value of 0.0177. These were very important results as they were used to further optimize aspects of the Phase III peri-ESO trial design. On slide 11, let's review key aspects of the Phase III protocol that were optimized to increase the relative probability of successful outcomes. First, increased patient population. The Phase III trial is evaluating 900 patients, whereas the Phase IIb Fidova trial enrolls 586 patients. Second, all patients in the Phase III trial are required to be on stable symptomatic treatment with levodopa. In the prior Phase IIb Fidova trial, the approximately 75% of patients on levodopa treatment were nominally statistically significant on the primary outcome and exploratory endpoints shown on the previous slide. The duration of the Phase III trial is a minimum of 24 months versus 18 months in the prior Phase II B Vidova trial. In the Vidova trial, the patients who are on treatment for at least 24 months did greater separation from placebo on the exploratory endpoints shown on the previous slide. We believe Roche will continue to communicate clinical results from its completed Phase II trials and ongoing open-label extensions at upcoming medical conferences. We look forward to the primary completion of the Phase III paraesop trial expected in 2029. Moving to Paranatog on slide 12, potential first-in-class amyloid depleter antibody for the treatment of ATTR cardiomyopathy being developed by Novo Nordis. ATTR-CM is a rare, progressive, and potentially fatal disease characterized by deposition of abnormal non-native forms of transbibritin amyloid in the vital organs. Parametog is thought to deplete both a positive amyloid and circulating non-native TTR to prevent further deposition and to improve organ function. This mechanism of action has the potential to provide benefit for all ATTR-CM patients, even those patients currently receiving treatment with a stabilizer or silencer. Novo Nordis completed its Phase II clinical trial evaluating Parametog and ATTR-CM in 2025 and presented those positive results in a late-breaking session at the American and Heart Association's 2025 Scientific Sessions, with a simultaneous publication in the journal Circulation. The results demonstrated reductions in NTPRO-BMP and echocardiogram improvements suggested of cardiac remodeling, all with a favorable safety profile. It's important to note that these results were demonstrated on top of standard of care, with over 80% of patients across keranatum and placebo control arms receiving concomitant TTR stabilizers. Based on these results, Novo Nordis initiated a Phase III Cleopatra trial, which is intended to enroll approximately 1,280 ATTR-CM patients, primary completion expected in 2029. Based on peak sales estimates for the currently approved ATTR-CM drug, we believe that Karamitub represents a multi-billion-dollar market opportunity, allowing for FINA to potentially capture future milestone payments as up to an additional $1.13 billion. Let's review the Phase II results in Slide 13. This was a 12-month, 105-patient phase-to-trial randomized to placebo, 10 mg per kilogram parametog, or 60 mg per kg parametog. The co-primary endpoints were change from baseline versus placebo in NT-pro-VMP in the six-minute walk test. The 60 mg per kg dose of parametog resulted in a statistically significant reduction in NT-pro-VMP versus placebo with a 48% difference and a p-value equal to 0.0017. In addition, parametog actually reduced anti-pro BMP below baseline values in the 16 mg per kilogram group. For the six-minute walk test, the 16 mg per kg parametog group demonstrated an encouraging numerical improvement that was not statistically significant, likely due to small sample size and short study duration. Additional analyses included a wide range of equicardiogram parameters, including measure of left and right ventricular systolic function, diastolic function, and estimated pulmonary arterial pressures. Across these measures, kramatog at 60 mg per K was associated with improvement compared to placebo suggested of cardiac remodeling. These results were the basis for advancing kramatog phase. As we see in slide 14, the phase 3 Cleopatra trial is anticipated to enroll approximately 1,280 ATTRCM patients, randomized one-to-one to kramatog-plus-standard of care, placebo-plus-standard of care. The trial is available to New York Heart Association class 1 through 4 patients with some additional inclusion-exclusion criteria. The primary endpoint is a positive endpoint of either the number of cardiovascular deaths or recurrent cardiovascular events, such as hospitalization or an urgent... We look forward to the primary completion of the phase 3 Cleopatra trial expected in 2029. Moving on, let's now discuss BMS 986446 on flight 15. This is our potential first-in-class anti-tow antibody being developed by Crystal Meyer-Swift. VMS-986446 was specifically designed to target key epitopes within the microtubule binding region, or MTBR, of tau, protein implicated in the causal pathophysiology of Alzheimer's. Contangles, along with amyloid beta-plats, are core hallmarks of Alzheimer's pathology, and tau is strongly linked to clinical and cognitive decline. To date, VMS-986446 has completed its Phase I MAD and FED, as well as an open-label single-dose trial to assess the subcutaneous formulation. In addition, BMS 986446 was granted fast-track designation by the U.S. FDA for the treatment of Alzheimer's disease. Crystal Meyer-Squibb completed enrollment in the ongoing phase two target TATO I clinical trial in approximately 310 patients with early Alzheimer's in 2025, and we expect study completion in the first half of 2027. Alzheimer's disease represents a multibillion-dollar market opportunity, and in our partnership with BMS, we have the potential to earn up to an additional $562.5 million future milestones as well as tiered sales royalties up to high T16 illustrates the various areas where antibodies have been developed to target tau. Tau is a large protein comprised of approximately 440 amino acids in some forms with multiple phosphorylation sites, truncation sites, and multiple slice variants. One of the longstanding challenges in the field has been how to best target the tau protein in order to provide functional benefits in the context of disease. We took an approach called empirical episode mapping in order to identify an antibody that delivered consistent robust effects. This work led us to target the MTBR domain, which was the only area that satisfied our internal requirements. The field has since clarified that MTBR domain is central to fibroflammation, seeding, and cell-to-cell transmission of talpothal. MTBR-TAU-243 has been shown using highly correlated TALPET and disease progression. In preclinical studies, MTBR-targeting antibodies demonstrated blocking of internalization and spread of TAU, leading to the reduction of TAU pathology. Ongoing phase 2 clinical trials, including the phase 2 target TAU-1 trial for our partner BMS, are underway. A different anti-MTBR-TAU antibody recently demonstrated positive trends on biomarkers including MTBR TAU-243 and TALPAD and a small number of patients. Slide 17 highlights the Phase II target TAU-1 trial design, which enrolled approximately 310 patients with early Alzheimer's disease. Randomized 4-3-3 in placebo, low-dose BMS 986446 and high-dose BMS 986446. The primary endpoint is change from baseline and brain-tow deposition, measured by TALPAD at 76 weeks. The secondary endpoint is measuring functional and cognitive changes, including CDRs, some of boxes, and IDRIS. We are excited to learn the results from this Phase II trial with primary completion expected in the first half. And finally, I'll briefly review PRX 19 on slide 18. For our agreement with Bristol-Myers Squibb, we are conducting the Phase I trial, both single and sending in multiple doses, evaluating safety, colorability, immunogenicity, TK, and pharmacodynamic effects. We expect to complete the trial in 2026 and are eligible for a potential milestone in your BMS society to further develop PRX-19. In total, we have the potential to earn up to $617.5 million in future milestones, tiered sales royalties, up to high-end percentages. With that, I'll now turn the call over to Phil Dolan to discuss our wholly-owned preclinical portfolio.

Thanks, Chad. Please turn to slide 20 for an overview of our exciting new Cytop technology. Our Cytop technology is an innovative targeting technology invented by Prasena to reach virtually any cell type, and enable precise targeting of intracellular disease pathways in the brain and periphery through an endosomal uptake and escape mechanism that preserves membrane and vesicle integrity following systemic administration. This technology potentially allows for targeting of previously undruggable intracellular disease targets. Each CYSO program is uniquely tailored to target a specific intracellular disease pathway. It is comprised of a cell-internalizing technology, a targeting element derived from a macromolecule, such as an antibody, and may include optional elements, such as the addition of receptor-mediated technology to enable delivery to specific cells or tissues. Our first proposed program to utilize this technology is our TDP43 CYSO program for amyoscopic lateral sclerosis for ALS. Let's discuss further on slide 21. ALS is a progressive, fatal neurodegenerative disease characterized by the selective loss of upper and lower motor neurons, and in the majority of cases by cytoplasmic aggregation and nuclear depletion of the RNA-binding protein TDP43. Current-approved therapies used to treat ALS seek to affect disease progression by targeting broad mechanisms, such as excitotoxicity and oxidative stress, rather than the core molecular pathology. These treatments do not stop reverse motor neuron degeneration and, to date, provide limited clinical benefits. Consequently, there remains a major unmanned need for disease-modifying therapies that directly address TDP-43-driven mechanisms. Using our internally discovered cytokine technology, we have developed an antiphosphorylated TDP-43 cytokine that is designed to address the core molecular pathology associated with approximately 97% of ALS cases. This regulation of TDP-43 triggers both toxic gain-of-function and loss-of-function deficits in the context of disease. A key challenge in the field has been how to effectively target intracellular phosphorylated TDP43 aggregates which are broadly deposited in the CNS and periphery while preserving normal TDP43 functions. As shown in the slide, neither conventional antibodies, small molecules, or oligonucleotides have all of the components needed to effectively target and eliminate intracellular phosphorylated TDP43 aggregates. Enter TDP43 Cytope on slide 22. TDP-43-SYTOP was designed to specifically bind to and degrade intracellular phosphorylated TDP-43 aggregates that are central to ALS pathology. In preclinical studies, our unique TDP-43-SYTOP has been demonstrated to degrade phosphorylated TDP-43-associated aggregates located in the cytoplasm, addressing the toxic gain of function pathology. In addition, we have demonstrated that administration of our TDP-43-SYTOP addresses related loss of function of biology, potentially through restoration of TDP-43 trafficking and the function of normal TDP-43 in the nucleus. Importantly, the unmatched targeting specificity suggests that we may effectively reduce the pathogenic phosphorylated TDP-43 aggregates while preserving normal TDP-43 activity throughout the body. Moving to slide 23, which highlights some of the key data presented at the Society for Neuroscience Congress in November of last year. On the left, we show supportive data on how TDP-43 Cytope addresses toxic gain of function by significantly reducing brain and muscle pathology in a highly aggressive ALS mouse model following systemic administration. These findings are particularly compelling given rapid, persistent, and aggressive accumulation of pathogenic aggregates in the RNLSA transgenic mouse model of ALS. On the right, we show supportive data demonstrating the TDP43 CYTOP also addresses the loss of function biology. Here, TDP43 CYTOP attenuated RNA misflicing caused by cytoplasmic TDP43 aggregation in both human neuronal cells and mice. This is exciting data from our TDP43 CYTOP program and supports the potential of our CYTOP technology more broadly. We look forward to continuing to elucidate the potential of this program and the technology. Let's move to slide 24 to provide an update on our PRX-12 Transferring Receptor Preclinical Program, or PRX-12 TFR. Frontinimab is an anti-A beta antibody developed from gantinarumab to also include transferrin receptor binding technology. So far, reported data indicate the addition of transferrin targeting in frontinimab as resulted in improvements over gantinarumab, including significantly decrease the time required to achieve meaningful amyloid reduction and substantially lower risk of REI-E associated with amyloid-targeting antibodies. Given the potential of our PRX-12 antibody, which is based, in part, on our demonstration of the activity of this antibody in the clinical setting, we believe the combination of transfer and receptor binding technology could be very exciting. Let's move to slide 25. Last year, we reported interim results from the PRX-12 phase I clinical program, including a mean reduction in amyloid debt to approximately 27.5 centiloids at month 12 for patients that received a monthly subcutaneous dose of 400 milligrams of PRX12 from the start of the Preliminary results for patients reaching 18 months of treatment with a 400 milligram dose showed a mean reduction in amyloid debt to approximately 16 centiloids, and nine of the 12 patients achieved amyloid negativity defined as having a centiloid value less than 24.1. But as we reported in August, the ARIA-E rates for PRX-12 were noncompetitive relative to FDA-approved anti-AVETA antibodies. Based on these collective results, we believe a PRX-12 TFR approach is appropriate for further developments. It is our desire to improve over PRX-12 while maintaining a convenient once-monthly subcutaneous administration. Currently, we are exploring partnership interests for PRX-12 TFR while advancing the program preclinically. With that, I'll turn it over to Tron to review our financial results.

Thanks, Phil. Please turn to slide 27. Today, we reported financial results that were in line or favorable to our 2025 financial guidance. Please refer to our press release for a detailed breakdown of our financial results. In terms of our 2025 financial performance relative to guidance, we had net cash used in operating and investing activities of $163.7 million, which was favorable to our guidance range of $170 to $178 million. Net loss was $244.1 million, which was in line with our guidance range of $240 to $248 million. As of December 31, 2025, Christina had $308.4 million in cash, cash equivalents, and restricted cash, which was favorable to our guidance of $298 million. As of February 12, 2026, Christina had $53.8 million ordinary shares outstanding. Additionally, we continue to have a simple capital structure with zero debt. Turning to our 2026 financial guidance on slide 28, we expect our full year 2026 net cash used in operating and investing activities to be between $50 and $55 million. We expect to end the year with approximately $255 million in cash, cash equivalents, and restricted cash. which represents the midpoint of the range. The estimated full year 2026 net cash use in operating and investing activities is primarily driven by an estimated net loss of $67 to $72 million, which includes an estimated $24 million of non-cash share-based compensation expense. And as a reminder, our 2026 financial guidance does not include the up to $105 million of potential aggregate clinical milestone payments from strategic partners in 2026 related to the advancement of both Karamatug or ATTR amyloidosis with cardiomyopathy by Novo Nordisk and PRX19 for Neurodegenerative Diseases by Bristol Myers-Swiss. With that, I'll turn the call back to Gene for closing in, Mark. Thank you, Tron.

Moving to slide 30. As we've shared today, we have a robust pipeline of programs that address significant unmet needs for potentially millions of patients, caregivers, and their families. It is our mission to continue to further develop our programs and elucidate the potential of our technology to address these needs. Let me end by recapping our 2026 strategic priorities, which are to capture the value embedded in our clinical partnerships, including up to $105 million in clinical milestones in 2026, to implement a share redemption program, and invest in our preclinical portfolio to support our ongoing partnering efforts in the form of research collaboration, especially on our CYTO technology, and drive future partnerships for our unpartnered programs. I'm proud of Prathina's execution and resilience in 2025, setting us up for an exciting future. They're well-capitalized with a robust cash position and remain focused on delivering long-term shareholder value by delivering on our mission to patients. With that, we will now open

the call to Q&A. Operator? Ladies and gentlemen, if you wish to ask a question, please press star followed by one on your touchtone telephone. If your question has been answered, press star one again. Please limit yourself to one question. I repeat, please limit yourself to one question. Please stand by for your first question. Your first question comes from the line of Yasmin

Rahimi with Piper Sandler. Please go ahead. Hi, this is Shannon on for Yaz Rahimi. Congrats on the great progress, guys, and thank you so much for taking our question. We just wanted to know, with the primary completion dates for the partnered program trials for ESO and Cleopatra, not expected until 2029, could you maybe walk us through some of the key milestones to look out for in 2026 and 2027 and what those milestones might be contingent on? Yeah, thanks for the question,

Shannon. So as we kind of laid out, we have a lot of things happening this year into next year and for the next several years. So I think as we look to some of our emerging technologies, some of the CITESOPE activities that we talked about on the call, we certainly expect to share more of that information this year through scientific presentations, in particular around our TDP-43 CITESOPE program and obviously the progress we're making there. We talked about in in the first half of 2027, starting to see the data coming from our partner TAL program with Bristol-Myers Squibb, so we think that phase two program would be very interesting as it was outlined by Chad on the call. Clearly the primary outcome measure there is TAL-PET, so we think this is going to be a very interesting evaluation of our MTBR targeting TAL approach, and then obviously We're very much looking forward to the two phase three readouts with primary expected completion dates in 2029, as you outlined, for both Karamatug and Prasenuzumab. And clearly, as we indicated, not only do we think that those are well positioned based on the phase two results to be, you know, tested in an adequate way in the phase three studies, but also represents the potential for significant medical advance in areas with a pretty high unmet need, and also, I think, very interesting economic opportunities with respect to the commercial opportunity there. But so, yeah, so I think it's actually going to be a very busy time for us. And the only other thing I would mention here, and maybe, Tron, if you want to speak to it further, is we look forward to instituting our share redemption program this year as So that's something that we needed to get approval for in an EGM, which took place in last year, needed Irish High Court approval for that, and, you know, I think this year we expect to implement that.

Yeah, and we'll make further announcements with that closer to the filing of our 10K. But that also being said to repeat that this year we'll also have, you know, potentially up to $105 million worth of clinical milestones gene covered in our prepared remarks from Karamatug and X19. So, exciting 2026, and Jill.

Great. Thank you so much.

Your next question comes from the line of Michael DiFiore with Evercore ISI. Please go ahead.

Hey, guys. Thanks so much for taking my question.

One on PRX012, if you could just elaborate how you try to keep the AMO1 data story alive versus much larger, more advanced. As a relative follow-up, there are many transfer receptor technologies. Maybe you could describe.

So thank you for the question. You broke up a little bit, but I think I got most of it. And maybe I'll ask Brandon to jump in just with respect to the BD space a little bit here. But just to answer the question first, in terms of why we're excited about our PRX-12 transparent-based approach, you know, look, there are two elements to these types of molecules, And I think, you know, a lot of what we've learned about this space and potential of adding transparent technology or receptor technology to anti-beta antibodies comes from the Gantanirumab slash Trontinimab approach. You know, and there, I think we had a good understanding of what the activity rate on both, you know, the amyloid removal side as well as the ARIA-E side for Gantanirumab was, and then adding a transparent-based approach that, you know, had certain characteristics to it. This is the Roche approach, I think, you know, gave us the results in Trontinimab that we can directly compare to Gantanirumab. You know, what we think we have here with PRX-12 is we've described now data for the parent molecule PRX-12 and with a once-monthly subcutaneous presentation, you know, showing what we think are very interesting and impressive results in terms of amyloid removal. So, you know, at a flat dose, at once a month subcutaneous administration, seeing the majority of patients be amyloid negative, seeing the average centeloid value being quite low, you know, we think positions us in a way that we can say this is a very convenient and very robust antibody with respect to amyloid removal. You know, what we thought was a little less competitive in those results were some of the REAE rates. And so here, with this technology provided that, you know, we follow the path with respect to TransPharin that, you know, that others have seen success with, a la Gantnerimab and Trontinimab, that we have the opportunity to take advantage of that emerging biology and, you know, potentially see an improvement in the overall profile of CRX-12 with the CRX-12 TransPharin program. So we're excited about that. We think that's something that we can move forward relatively quickly and get a pretty definitive answer, you know, very early in that we know that there's been a lot of interest in this space. You know, we're certainly happy to see that the momentum is not only continuing, but I think continuing to build around these types of approaches, which have the potential to decrease some of the AE profile limitations of the anti-beta antibodies and potentially increase the primary mechanism of action, which is removal of amyloids. But maybe, Brandon, you can speak a little bit more to just, and appreciate the question.

So from his perspective, there is clearly a high level building off of, relative to what cancer neuromath saw with trontinamath, we think we're uniquely suited to build upon that story. And the market has begun to recognize that. What's really interesting about the space, though, is also the opportunity potentially to grow. And what we're following very closely is that profile that Gene described, which is once a month sub-Q, leveraging a better ARIA profile that we expect the market is headed, not just early Alzheimer's disease, which we're looking forward to what the field is seeing in the pre-symptomatic. And that opens up a unique opportunity for us because we are a much less frequent, something that is uniquely recognized in the field and something that is very interesting. I think, obviously, we're also very interested in the data that we're generating internally.

Your next question comes from the line of Eric Schmidt with Cancer Fitzgerald. Please go ahead.

Hi, guys. This is Alexa Diemer on for Eric. Congrats on a great year. So, for the Phase I study of 019, which is expected to complete this year, do you plan to share data from the study this year, and what do you want to see for this program to advance?

Yeah, it's a great question. Thank you for the question. So with PRX-19, that is a program that we have a partnership with Bristol-Myers Squibb on. We have not, for strategic reasons, talked about the target of that yet, except to say that it's broadly applicable to neurodegeneration. I think as Chad mentioned in his comments, that Phase I study is being conducted by us. We expect that to complete this year. And what we would then do is share that information with our partners at Prista-Meyer Squibb. And I think you heard both Tron earlier say, and I said in my remarks as well, that the potential to achieve up to $105 million this year through partnership progress, some of that is tied to decisions made around PRX-19. So what we expect is that we'll share that information with Prista-Meyer Squibb. At the end of the day, it will be up to them to decide what and how much of that information to share publicly, but obviously we'll be talking about that a little bit later this And with that said, maybe, Charm, you can ask...

Yeah, just a reminder, they have global rights to this program. They exercised it. They paid us $80 million for it. Got it.

Thanks so much. Your next question comes from the line of Jason Butler with Citizens. Please go ahead.

Thanks for taking the question. Can you maybe just from a broader level speak to how you would think about the amount of data necessary to secure a partnership for the CITO platform, or ultimately, if you made the decision to advance a program into the clinic yourselves from the CITO platform, what data you'd want to see to de-risk the initial clinical development? Thank you.

Yeah, thanks for the question, Jason. So maybe I can start with a little bit of the biology here, and then Brandon can speak a little bit to just this development strategy. But I think from a TDP43 perspective, the data we shared last year, I think, was interesting, both with respect to the cytotechnology and also to the idea of targeting TDP43 in the context of ALS. And Phil covered this in some of his remarks, but I think for the cytotechnology, one of things you clearly saw, and particularly in those animal studies, the in vivo animal studies in the RNLS eight mice, is you saw that with systemic administration, you know, you were not only seeing active engagement with this intracellular target in a very disease or pathological specific way, but you were seeing actually removal of that target. And in the CNS, you were seeing that as well. So that's an important context here, which is systemic administration. You're seeing robust CNS activity. So not only does this platform appear to allow us to target things in the intracellular space, but also seems to allow us to do so in the central nervous system as well. And so I think that that's a really important lesson learned from the technology. And again, as was mentioned by Phil, we're not seeing any evidence that we're disrupting endosomes or... We know 97%, again, Phil covered, so that's 97% of patients have TDP-43 dysfunction as a core element of their pathology, and one of the challenges in targeting TDP-43 is to target the abnormal form of these proteins while leaving the normal form to do its day job, which is essential for targeting approach. You were able to see that specificity translate into not only the aggregates that you see in the cytosol, but also, interestingly, in an in vitro setting in human cell types, correcting the loss of function, which is really the mis-splicing variance or the mis-splicing dysfunction that you see in the level of the nucleus. And so that seemed to be corrected as well. So that's very exciting, targeting an abnormal form of TDP-43, which we know leads to both a loss of function and gain of function and seeing indications that you can address both. So we think the mouse model, which is an extraordinarily aggressive mouse model, in unchanged way if they don't change the mouse model in some way really struggle to see any effect here um we saw some very robust clearing of the intracellular uh in terms of what we need to see we think we're very excited by what these data are telling us to date um and obviously we are interested in continuing to move that program forward in terms of just the strategy around this program and potentially other programs within our site technology platform maybe brandon you

you can speak a little bit to that. Yeah, maybe the easiest thing to do is just to note that the technology itself didn't become publicly known until November of last year, right? And so we are, you know, with that, that was the impetus for, and what we've been finding is that there really is, and what's unique is that set of applications goes well beyond neuroscience, which is our area of expertise, and it's a very wide net from a BD standpoint, and solve problems that some of our potential partners are looking to solve by utilizing this. And I think we alluded to this, and we're already, you know, even in the three, four months timeframe that we're talking about, to establish resources, to have others focused on learning what we've learned from our, and applying it in many ways. So that application, much more broadly, is uniquely suited, and we're excited about the project. What happens when you have those discussions is those potential partners are actually spending their time and resources to get this in their own hands. And they want to make sure that what we see is what they'll also see as a target. We're very excited about where we are and a lot more to go.

Your next question comes from the line of Brian Abrams with RBC Capital Markets. Please go ahead.

Hi, everyone. This is Nevin on for Brian. Thank you so much for taking your questions. Just a couple from us. So I guess I'm curious to know, based on some of the preclinical experiments that you've done in-house, what you think might be maybe some of the mechanistic hypothesis for why the transferrin modification ends up reducing the ARIA risk? And I guess along with that, do you expect potential lower heme toxicities with this? And then an additional clarification question on my end. Just wanted to see if the transferrin modification to O112 would still enable O112 to be subcutaneously delivered or if this would be ID administered. Thanks so much.

Yeah, so good questions around X12. So let me start, and maybe, Phil, if you have anything to add, you can do so. I think first, in terms of transferrin and how that actually sorts out some of the ARIA events, you know, there are a lot of hypotheses out there. I think the one that both Roche and Eli Lilly have put forward as a more likely mechanism is really the location of transparent and, you know, where that is in the vasculature, in the cerebral vasculature. So this idea that potentially starting to get more penetration into the brain through capillary structures relative to arterial structures may be providing some benefit. And it has some face validity in as much as we know that when amyloid deposits in the cerebral vasculature tends to do so in the larger arterial structure, particularly in the perivascular space. And so obviously, you know, moving the route of entry into the capillary system could have some advantages in that respect. And so that's one possibility. Another possibility that I think, you know, folks talk about and feel sometimes time is an idea of the amount of time that the antibody may sit on amyloid in the vasculature and potentially with the transparent based approach, you get a transcytosis across the blood-brain barrier, which minimizes that dwell time, if you will. And of course, it could be a combination of things as well. But I think what it points to, and it's a good question, is that, you know, we need to make sure that the transferrin-based approach, and obviously we're taking steps to do this with X12, trontinimab, down the fairway, whatever that mechanism is. I think in terms of, you had some other parts of that question there, the sub-Q part of that question. We have no reason to believe that the addition of transparent at this point would cause us to change our route of entry. We think subcutaneous is for PRX-12 transparent-based PRX-12 that provides us the ability to actually have a biological effect at a lower dose level setting, which obviously gives us the opportunity to have both the pharmacokinetic as well as potency advantage. And I think that's something that you can evidence and how that would prepare that back to some of the earlier Gantt-Nuromab data, you know, which maybe was less robust by making sure to believe that to be true.

I might just say one thing, Gene. So, you actually touched on the potency, right, comparable in robust levels of reduction at 18 months with an antibody that is a flat dose of 400, which is significantly less, I would say, than the 10 mg per kg that's in the clinic now. Now, I don't know the answer to this, but I know you had a question about heme toxicity. And because of the potency, it's possible that we could dose at lower levels and see similar effects to what Trontinimab saw, for instance. If that's the case, there is potential, perhaps, to minimize risk in terms of these non-ARIA anemia or others. So I think there's potential there, and we just, you know, we have to do this. That's very helpful.

Thank you, everyone. That completes our question and answer session. I'll now turn it over to Gene Kinney, CEO, for closing remarks.

Thank you, Operator, and I want to thank you all for joining us on the call today. We appreciate your interest in Prathena and look forward to sharing further updates on our program.

Thank you for your participation in today's conference call. This concludes the presentation. You may now disconnect. Good day.