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 8-K filed today with the SEC. In addition, we are using supplemental slides, which are available on our investors' website, Events and Presentations 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 programs. Phil Dolan, our Vice President and Head of Discovery Research, will provide an update on our active preclinical programs.

Tran 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 for 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 referred to in any of the forward-looking statements. For a 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 forward-looking statements. 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, prasinezumab and crinetide, advanced into Phase 3 clinical trials. Roche advanced prasinezumab into the Phase 3 PADRE-CO trial, evaluating 900 participants with early Parkinson's disease.

This decision was informed by results from two Phase 2 clinical trials that both demonstrated consistent slowing of disease progression. Novo Nordisk advanced crinetide into the Phase 3 CLEAR-PATH trial, evaluating 1,280 patients with amyloid transthyretin cardiomyopathy, or ATTR-CM.

This decision was informed by results from their Phase 2 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 Squibb also progressed in 2025, with several important advancements, including the Phase 2 TARGET-Tau1 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.

Bristol Myers Squibb also completed a Phase 1 study evaluating a subcutaneous formulation of BMS-986446 in 2025, and BMS-986446 obtained Fast Track designation from the U.S. FDA for the treatment of Alzheimer's disease.

Finally, we are conducting a Phase 1 trial for PRX-19, 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 CYTOPE technology has the potential to enable precise targeting of intracellular disease pathways.

We also reported results from our Phase 1 ASCENT clinical program evaluating PRX-12 in patients with early Alzheimer's disease. The results help to elucidate the profile of this once-monthly subcutaneous anti-Aβ antibody.

Based on significant scientific advances over the last several years, we believe we can further improve this profile with the addition of transferrin receptor technology and are actively advancing a PRX-12 transferrin program in preclinical development. Turning to slide six, 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 Prothena's R&D engine.

This year, we have the potential to earn up to $105 million in aggregate clinical milestone payments if crinetug 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 cyto 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 crinetug and PRX-19, which could be worth up to $105 million.

In the first half of 2027, we expect Bristol Myers Squibb to complete their Phase II TargetTau-1 trial for BMS-986446. In 2029, we expect primary completions from the two Phase 3 trials evaluating Roche's prasinezumab and Novo Nordisk's coramitug.

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 detail.

Thanks, Gene. Let's start on slide nine.

Prasinezumab 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 2 clinical trials, the PADOVA and their open-label extensions, our partner Roche made the decision to advance prasinezumab to Phase 3, 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 a foundational target? Yes.

alpha-synuclein is a known biological driver of PD progression, and the clinical evidence to date demonstrates evidence potential and supports a favorable safety and tolerability profile. 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 treatments available.

Finally, is there a strong commercial rationale? Yes.

Roche believes prasinezumab represents a global peak sales opportunity greater than $3.5 billion. For Prothena, our deal includes up to $620 million in potential future milestone payments and sales royalties tiered to high teens percentages.

In the fourth quarter of 2025, Roche initiated the Phase 3 PARADISO clinical trial, which will enroll approximately 900 participants with early Parkinson's disease, with primary completion expected in 2029. Moving on to slide 10, this is an important dataset from the Phase 2b PADOVA trial, which Roche presented at ADPD 2025.

Here they show progression on the MDS-UPDRS Part 3 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, who are on stable levodopa treatment, comparing 24 months of prasinezumab treatment versus placebo.

What we see is a 40% relative reduction in progression with a nominal p-value of 0.0177 on this exploratory endpoint. These were very important results as they were used to further optimize aspects of the Phase 3 PARADISO trial design.

On slide 11, let's review key aspects of the Phase 3 protocol that were optimized to increase the relative probability of successful outcome. First, increased patient population.

The Phase 3 trial is evaluating 900 patients, whereas the Phase 2b PADOVA trial enrolled 586 patients. Second, all patients in the Phase 3 trial are required to be on stable symptomatic treatment with levodopa.

In the prior Phase 2b PADOVA trial, approximately 75% of patients on levodopa treatment were nominally statistically significant on the primary outcome and exploratory endpoint shown on the previous slide. Third, the duration of the Phase 3 trial is a minimum of 24 months versus 18 months in the prior Phase 2b PADOVA trial.

In the PADOVA trial, the patients who were on treatment for at least 24 months showed greater separation from placebo on the exploratory endpoint shown on the previous slide. We believe Roche will continue to communicate clinical results from its completed Phase 2 trials and ongoing open-label extensions at upcoming medical conferences.

We look forward to the primary completion of the Phase 3 PARADISO trial, expected in 2029. Moving to crinetug on slide 12, potential first-in-class amyloid depleter antibody for the treatment of ATTR cardiomyopathy, being developed by Novo Nordisk.

ATTR-CM is a rare, progressive, and potentially fatal disease characterized by deposition of abnormal non-native forms of transthyretin amyloid in vital organs. Coramitug is thought to deplete both the 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 Nordisk completed its Phase 2 clinical trial evaluating crinetug in ATTR-CM in 2025 and presented those positive results in a late-breaking session at the American Heart Association's 2025 Scientific Sessions with a simultaneous publication in the journal Circulation.

The results demonstrated reductions in NT-proBNP and echocardiogram improvements suggestive 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 crinetug and placebo control arms receiving concomitant TTR stabilizers.

Based on these results, Novo Nordisk initiated a Phase 3 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 drugs, we believe that crinetug represents a multi-billion-dollar market opportunity, allowing Prothena to potentially capture future milestone payments of up to an additional $1.13 billion.

Let's review the Phase 2 results in slide 13. This was a 12-month, 105-patient Phase 2 trial randomized to placebo, 10 milligrams per kilogram cramatug, or 60 micrograms per kilogram cramatug.

The co-primary endpoints were change from baseline versus placebo in NT-proBNP and the six-minute walk test. The 60 microgram per kilogram dose of cramatug resulted in a statistically significant reduction in NT-proBNP versus placebo, with a 48 percent difference and a p-value equal to 0.0017.

In addition, cramatug actually reduced NT-proBNP below baseline values in the 60 milligram per kilogram dose. For the six-minute walk test, the 60 microgram per kilogram cramatug group demonstrated an encouraging numerical improvement, but it was not statistically significant, likely due to small sample size and short study duration.

Additional analyses included a wide range of echocardiogram parameters, including measures of left and right ventricular systolic function, diastolic function, and estimated pulmonary arterial pressures. Across these measures, cramatug at 60 microgram per kilogram was associated with improvement compared to placebo, suggested a cardiac remodeling.

These results were the basis for advancing cramatug to Phase 3. As we see in slide 14, the Phase III CLEOPATTRA trial is anticipated to enroll approximately 1,280 ATTR-CM patients, randomized 1 to 1 to cramatug 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 and 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 heart failure visit.

We look forward to the primary completion of the Phase III CLEOPATTRA trial expected in 2029. Moving on, let's now discuss BMS-986446 on slide 15.

This is our potential first-in-class anti-Tau antibody being developed by Bristol Myers Squibb. BMS-986446 was specifically designed to target a key epitope within the microtubule binding region, or MTBR, of tau, a protein implicated in the causal pathophysiology of Alzheimer's.

Tau tangles, along with amyloid beta plaques, are core hallmarks of Alzheimer's pathology, and tau is strongly linked to clinical and cognitive decline. To date, BMS-986446 has completed its Phase 1 MAD and SAD, 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.

Bristol Myers Squibb completed enrollment in the ongoing Phase 2 TARGET-TAU-1 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 multi-billion-dollar market opportunity, and in our partnership with BMS, we have the potential to earn up to an additional 562.5 million dollars in future milestones, as well as tiered sales royalties of up to high teens percentages on a weighted average basis.

Slide 16 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 splice variants.

One of the longstanding challenges in the field has been how to effectively target the tau protein in order to provide functional benefits in the context of disease. We took an approach called empirical epitope 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 fibril formation, seeding and cell-to-cell transmission of tau pathology.

MTBR tau 243 has been shown to be highly correlated with tau PET 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 tau PET in a small number of patients.

Slide 17 highlights the Phase 2 TARGET-TAU-1 trial design, which enrolled approximately 310 patients with early Alzheimer's disease, randomized 4 to 3 in placebo, low-dose BMS-986446, and high-dose BMS-986446 respectively. The primary endpoint is change from baseline in brain tau deposition measured by tau PET at 76 weeks.

The secondary endpoints measure functional and cognitive changes including CDR-sum of boxes and IADRS. We are excited to learn the results from this Phase 2 trial with primary completion expected in the first half of 2027.

Finally, I'll briefly review PRX-19 on slide 18. Per our agreement with Bristol Myers Squibb, we are conducting this Phase 1 trial, both single ascending and multiple doses, evaluating safety, tolerability, immunogenicity, PK, and pharmacodynamic effects.

We expect to complete the trial in 2026 and are eligible for a potential milestone from BMS to further develop PRX-19. In total, we have the potential to earn up to 617.5 million dollars in future milestones, tiered sales royalties up to high teens 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 CYTOPE technology.

Our CYTOPE is an innovative targeting technology invented by Prothena 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 CYTOPE program is uniquely tailored to target a specific intracellular disease pathway and 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 disclosed program to utilize this technology is our TDP43 CYTOPE amyotrophic lateral sclerosis, or 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 or reverse motor neuron degeneration and to date provide limited clinical benefit.

Consequently, there remains a major unmet need for disease-modifying therapies that directly address TDP43-driven mechanisms. Using our internally discovered CYTOPE technology, we have developed an anti-phosphorylated TDP43 CYTOPE that is designed to address the core molecular pathology associated with approximately 97 percent of ALS cases.

Dysregulation of TDP43 triggers both toxic gain-of-function and loss-of-function deficits in the context of disease. The 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 function.

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.

TDP43 CYTOPE was designed to specifically bind to and degrade intracellular phosphorylated TDP43 aggregates that are central to ALS pathology. In preclinical studies, our unique TDP43 cytope has been demonstrated to degrade phosphorylated TDP43-associated aggregates located in the cytoplasm, addressing the toxic gain-of-function pathology.

In addition, we have demonstrated that administration of our TDP43 CYTOPE addresses loss-of-function pathology, potentially through restoration of TDP43 trafficking and the function of normal TDP43 in the nucleus. Importantly, the unmatched targeting specificity suggests that we may effectively reduce the pathogenic phosphorylated TDP43 aggregates while preserving normal TDP43 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 TDP43 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 CYTOPE also addresses loss-of-function biology.

Here, TDP43 CYTOPE attenuated RNA missplicing caused by cytoplasmic TDP43 aggregation in both human neuronal cells and mice. This is exciting data from our TDP43 CYTOPE program and supports the potential of our CYTOPE 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 PRX12 transferrin receptor preclinical program, or PRX12 TFR.

Trontinemab is an anti-Aβ antibody developed from gantenerumab to also include transferrin receptor binding technology. Far, reported data indicate the addition of transferrin targeting in frontenumab has resulted in improvements over gantenerumab, including significantly decreased the time required to achieve meaningful amyloid reduction and substantially lower risk of ARIA-E associated with amyloid-targeting antibodies.

Given the potential of our PRX12 antibody, which is based in part on our demonstration of the activity of this antibody in the clinical setting, we believe the combination of transferrin receptor binding technology could be very exciting. Let's move to slide 25.

Last year, we reported interim results from the PRX12-A Phase 1 clinical program, including a mean reduction in amyloid PET to approximately 27.5 centiloids at month 12 for patients that received a monthly subcutaneous dose of 400 milligrams PRX12 from the start of the study. Preliminary results for patients reaching 18 months of treatment with the 400 milligram dose showed a mean reduction in amyloid PET to approximately 16 centiloids, and nine of the 12 patients achieved amyloid negativity, defined as having a centiloid value less than 24.1.

As we reported in August, the ARIA-E rates for PRX12 were non-competitive relative to FDA-approved anti-Aβ antibodies. Based on these selective results, we believe a PRX12 TFR approach is appropriate for further development.

It is our desire to improve over PRX12 while maintaining a convenient once-monthly subcutaneous administration. Currently, we are exploring partnership interests for PRX12 TFR while advancing the program preclinically.

With that, I'll turn it over to Tran 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, Prothena 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, Prothena 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 used 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.

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 crenigacestat, or ATTR amyloidosis with cardiomyopathy, by Novo Nordisk, and PRX19 for neurodegenerative diseases by Bristol Myers Squibb. With that, I'll turn the call back to Gene for closing remarks.

Thank you, Tran. 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 reduction program and invest in our preclinical portfolio to support our ongoing partnering efforts in the form of research collaboration, especially on our CYTOPE technology, and drive future partnerships for our unpartnered programs.

I'm proud of Prothena's execution and resilience in 2025, setting us up for an exciting future. We'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 touch-tone 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.

this is Shannon on for Yasmin 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, PARAISO and CLEOPATTRA, 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?

Thanks for the question, Shannon. As we kind of laid out, we have a lot of things happening this year into next year and for the next several years.

I think as we look to some of our emerging technology, some of the site-ops 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 TDP43 site-ops program, and obviously the progress we're making there. We talked about in 2027, the first half of 2027, starting to see the data coming from our partner Tau program with Bristol Myers Squibb.

We think that Phase 2 program would be interesting, as was outlined by Chad on the call. Clearly, the primary outcome measure there is tau PET.

We think this is going to be a very interesting evaluation of our MTBR-targeting tau approach, and then obviously very much looking forward to the two Phase 3 readouts with primary expected completion dates in 2029, as you outlined, for both cramatug and prasinezumab. Clearly, as we indicated, not only do we think that those are well positioned, based on the Phase 2 results, to be tested in an adequate way in the Phase 3 studies, but also represent the potential for significant medical advance in areas with pretty high unmet need, and also, I think, very interesting economic opportunities with respect to the commercial opportunity there.

I think it's actually going to be a very busy time for us. The only other thing I would mention here, and maybe Tran, if you want to speak to it further, as we look forward to instituting our share redemption program this year as well.

That's something that we needed to get approval for in an EGM, which took place in the last year, needed Irish High Court approval for that, and I think this year we expect to implement that.

We'll make further announcements with that closer to the filing of our 10-K. That also being said, to repeat that this year we'll also have potentially up to $105 million worth of clinical milestones from our partners, which Gene covered in our prepared remarks, from cramatug and X19.

An exciting 2026 indeed. Great.

Thank you so much.

One on PRX012, if you can just elaborate how you try to keep the amyloid data story alive versus much larger, more advanced competitors. As a relative follow-up, there are many transferin receptor tech platforms out there.

Maybe you could describe what the ideal transferrin platform would offer that would make you want to

partner. Thank you.

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.

Just to answer the question first in terms of why we're excited about our PRX12 transferrin-based approach, look, there are two elements to these types of molecules, right? I think a lot of what we've learned about this space and potential of adding transferrin technology or receptor technology to anti-Aβ antibodies comes from the gantenerumab slash trontinemab approach, and there I think we had a good understanding of what the activity rate on both the amyloid removal side as well as the ARIA-E side for gantenerumab was, and then adding a transferrin-based approach that had certain characteristics to it — this is the Roche approach — I think gave us the results in trontinemab that we can directly compare to gantenerumab.

What we think we have here with PRX12 is we've described now data for the parent molecule PRX12, and with a once-monthly subcutaneous presentation, showing what we think are very interesting and impressive results in terms of amyloid removal. At a flat dose at once a month subcutaneous administration, seeing the majority of patients be amyloid negative, seeing the average centiloid value being quite low, 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.

What we thought was a little less competitive in those results were some of the ARIA-E rates. Here, with this technology, provided that we follow the path with respect to transferrin that others have seen success with, a la gantenerumab and trontinemab, that we have the opportunity to take advantage of that emerging biology and potentially see an improvement in the overall profile of PRX12 with the PRX12 transferrin program.

We're excited about that. We think that's something that we can move forward relatively quickly and get a pretty definitive answer very early in Phase 1 clinical testing, given that we know the characteristics of the parent PRX12 so well.

As you say, there's been a lot of interest in this space with respect to licensing, and we think that's a good thing. 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-Aβ antibodies and potentially increase the primary mechanism of action, which is removal of amyloid.

Maybe, Brandon, you can speak a little bit more to just some of the dynamics of what's happening in the business development space, particularly in this. Yeah,

appreciate that, Gene, and appreciate the question. From the market perspective, there is clearly a high level of interest for the approach that we're taking.

What we're building off of relative to what gantenerumab saw when they added transferrin and turned it into trontinemab, we think we're uniquely suited to build upon that story. The market has begun to recognize that in our dialogues, probably the best I can say about the BD dialogues.

What's really interesting about the space, though, is also the opportunity potentially to grow. 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 to see and hope to see coming with the addition of transferrin, is uniquely suited for where the market is heading, not just for Alzheimer's disease, which we think we have a unique capability there, but really around the pre-symptomatic space.

We're looking forward to what the field is seeing in the pre-symptomatic space. We expect readouts this year, and that opens up a unique opportunity for us because we are a paradigm that is much less frequent, much less cumbersome, and when you're talking about those pre-symptomatic patients, that's exactly what they need: something that is uniquely set up for them, something that is not cumbersome and that potentially helps prevent progression.

That's recognized in the field and something that is very interesting. Obviously, we're also very interested in the data that we're generating internally to help build upon that program.

We hope to talk about that over the course of this year in terms with you and with our potential partner.

this is Alexa Deemer on for Eric. Congrats on the great year.

For the Phase 1 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?

Thank you. It's a great question.

Thank you for the question. With PRX19, 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 one 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 Bristol Myers Squibb. I think you heard both Tran 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.

What we expect is that we'll share that information with Bristol-Myers 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.

Obviously we'll be talking about that a little bit later this year. With that said, maybe Tran, you can add some comments.

Just a reminder, they have global rights to this program. They exercise it.

They paid us $80 million for it. Hence the data is theirs, and it's theirs to decide on how to disseminate that.

That being said, what we would do is, of course, announce if we've earned, and they've taken that molecule forward into further clinical development, and that's when we'll earn the clinical milestone associated with X-19. Got it.

Thanks so much.

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 CYTOPE platform, or ultimately, if you made the decision to advance a program into the clinic yourselves from the CYTOPE platform, what data you'd want to see to de-risk the initial clinical development?

Thank you. Thanks for the question, Jason.

Maybe I can start with a little bit of the biology here, and then Brandon can speak a little bit to just the development strategy. I think from a TDP-43 perspective, the data we shared last year I think was interesting both with respect to the CYTOPE technology and also to the idea of targeting TDP-43 in the context of ALS.

Phil covered this in some of his remarks, but I think for the CYTOPE technology, one of the things you clearly saw, particularly in those animal studies, the in vivo animal studies in the RNLS8 mice, is you saw that with systemic administration, you were not only seeing activity with this intracellular target in a very disease- or pathological-specific way, but you were seeing actually removal of that target. In the CNS, you were seeing that as well.

That's an important context here, which is systemic administration, you're seeing robust CNS activity. 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.

We think that that's a really important lesson learned from the technology. Again, as was mentioned by Phil, we're not seeing any evidence that we're disrupting endosomes or causing problems that other forms of technology that have attempted to do these sorts of things have suffered from.

I think in terms of ALS, it's particularly interesting. We know 97%, again Phil covered, so that 97% of patients have TDP-43 dysfunction as a core element of their pathology.

One of the challenges in targeting TDP-43 intracellularly directly is how to target the abnormal form of these proteins while leaving the normal forms to do its day job, which is essential for cells to function properly. By having a very specific targeting approach, you were able to see that specificity translate into not only kind of sorting out the toxic gain-of-function, which is 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 missplicing variant or the missplicing dysfunction that you see in the level of the nucleus.

That seemed to be corrected as well. 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.

We're excited by those data. We think the mouse model, which is an extraordinarily aggressive mouse model, most folks in an unchanged way, if they don't change the mouse model in some way, really struggle to see any effect here.

We saw some very robust clearing of the intracellular aggregates of TDP-43. That said, in terms of what we need to see, we think we're very excited by what these data are telling us to date.

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 CYTOPE technology platform, maybe Brandon, you can speak a little bit to that.

Maybe the easiest thing to do is just to note that the technology itself didn't become publicly known until November of last year. We are, with that, that was the impetus for many subsequent conversations.

What we've been finding is that there really is a very broad set of applications for this technology. What's unique is that set of applications goes well beyond neuroscience, which is our area of expertise, and it's essentially therapeutic area agnostic.

We can cast a very wide net from a BD standpoint and solve problems that some of our potential partners are looking to solve utilizing this technology. One of those specifics is that, and I think we alluded to this in our call, is that we're already, even in the three-, four-month time frame that we're talking about, we've established specific research collaborations but have others in process that are very focused on learning what we've learned from our TDP-43 program and applying it to a specific target and area of their interest, and applying it in many ways.

That application breadth broadly is uniquely suited for this technology, and we're excited about the progress we've made. In parallel, 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.

This is new. This is new and very exciting to them, and they want to make sure that what we see is what they'll also see when they apply to their targets of interest.

Doing that allows us to then see for the next step, which is a partnership around a target, around a set of targets, or maybe even more broad than that. We're very excited about where we are, and a lot more to go.

this is Nevin on for Brian. Thank you so much for taking our questions.

Just a couple from us. 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?

I guess along with that, do you expect potential lower heme toxicities with this? Then an additional clarification question on my end, just wanted to see if the transferrin modification to 012 would still enable 012 to be subcutaneously delivered, or if this would be IV-administered.

Thanks

so much. Yeah.

Good questions around X12. Let me start, and then 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, 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 transferrin and where that is in the vasculature, the cerebrovascular.

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, it tends to do so in the larger arterial structures, particularly in the perivascular space. Obviously, moving the route of entry into the capillary system could have some advantages in that respect.

That's one possibility. Another possibility that I think folks talk about in the field from time to time is an idea of the amount of time that the antibody may sit on amyloid in the vasculature, and potentially with the transferrin-based approach, you get a transcytosis across the blood-brain barrier, which minimizes that dwell time, if you will.

Of course, it could be a combination of things as well. I think what it points to, and it's a good question, is that we need to make sure that the transferrin-based approach, and obviously we're taking steps to do this with X12, is something that has similar characteristics to those things that we know already work.

Again, I think that is a pretty small sample set to date. That's the gantenerumab, crenezumab story that we've been talking about a little bit.

Clearly we're trying to stay as close to that down the fairway approach so that we can be sure that whatever that mechanism is, that we're taking advantage of that as well. I think in terms of some other parts of that question there.

Some of the sub-Q part of that question, we have no reason to believe that the addition of transferrin at this point would cause us to change our route of entry. We think subcutaneous is still a viable approach for PRX12 transferrin-based amyloids.

We think that, in fact, it's the potency of PRX12 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 a pharmacokinetic as well as potency advantage. I think that's something that you can evidence, for example, in the dataset.

We talked about the impact of PRX12, parent PRX12, on amyloid reduction and how that was quite robust, particularly at the 400 milligram dose level. I think you can compare that back to some of the earlier gantenerumab data, which may be less robust by comparison.

That really speaks to the potency of PRX12, which we have always felt was a key element in terms of making sure that that is available to a subcutaneous route of administration, and obviously we continue to believe that to be true. I don't know, Phil or Chad, if you have a comment that you'd like to make?

I might just say one thing. You actually touched on the potency, right?

Clearly we see pretty comparable and robust levels of reduction at 18 months with an antibody that is dosed flat dose of 400, which is significantly less, I would say, than the 10 milligram per kilogram that's in the clinic now. Because of that, and obviously we don't know the answer to this, but I know you had a question about gene toxicity, and because of the potency, it's possible that we could dose at lower levels and see similar effects to what trantenumab saw, for instance.

If that's the case, there is potential perhaps to minimize risk in terms of these non-ARIA AEs, i.e., anemia or others. I think there's potential there, and we just have to do the study.

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