Q4 2022 Prothena Corporation PLC Earnings Call

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Good afternoon. My name is Audra and I will be your conference operator today. At this time, I would like to welcome everyone to the Procena Corporation fourth quarter and full year 2022 Financial Results Conference call. There will be a question and answer session to follow. Please be advised that this call is being recorded at the company's request. I would now like to turn the call over to Mr. Eric Indicott, Procena Senior Vice President Corporate Affairs and Communications.

Please go ahead. Thank you, operator. Good afternoon, everyone, and welcome to Prothena's Investor Conference call to review our business progress, our fourth quarter and full year 2022 financial results, and our 2023 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. On today's call, Dr. Gene Kinney, our president and chief executive officer, will provide introductory remarks.

followed by an overview of Prothena's portfolio and development strategy as we continue advancing toward becoming a fully integrated commercial biotechnology company. Following Jean's opening remarks, Dr. Hideki Garan, our Chief Medical Officer, will provide an overview of the significant achievements and progress made in 2022 across our entire portfolio.

Tran Nguyen, our Chief Financial Officer and Chief Strategy Officer, will then review our financial results for the fourth quarter and full year of 2022, and will discuss our 2023 financial guidance. Jean will then provide closing remarks, and then we will open the call up for a Q&A session for Dr. Wagner Zago, our Chief Scientific Officer.

and Susana Mesa, our Senior Vice President, Strategy and Operations, will also be participants. 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 forward-looking statements. For 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, Eric, and thank you all for joining us today to review our 2022 financial results and business highlights. We're excited today to share with you this major achievement in 2022 and how we are advancing a portfolio of drug candidates targeting both neurodegenerative and rare peripheral amyloid diseases.

At Prothena, we are driven by our mission to create impactful treatments for the millions of patients that are affected by diseases caused by protein dysregulation. That mission is enabled by our deep scientific expertise, which serves as a unifying thread between our business strategy, our portfolio development, and our

the dedication that propels prothineans every day. Turning now to slide 5. Today Prothena is a late-stage clinical biotechnology company with a robust pipeline.

which includes four wholly owned programs and five partner programs. This intentional mix allows us to build a diverse portfolio by leveraging partner payments while still maintaining full upside potential for all wholly owned assets.

For our Alzheimer's programs in 2022, we advance both PRX-12 and PRX-5 into the clinic and expect to report top-line phase 1 multiple ascending dose data from both programs this year.

For Peer X 1-2-3, we have completed several IND-enabling studies and look forward to submitting an IND by year-end.

For our Parkinson's disease program, presenizumab is being evaluated by Roche in both the phase 2b-PDOVA and open-label extension portion of the phase 2 Pasadena study. We also have two rare peripheral amyloid disease programs. First, for tamamab, a holion program which is being evaluated in a confirmatory phase 3 setting.

and NMC6019, formerly PRX4, which is being evaluated by Novo Nordisk in a phase 2 study. Collectively, these achievements position us well for a transformational period over the next 24 months. And finally,

I will highlight that we remain well-funded to execute on our strategic objectives. We ended 2022 with a strong cash position of $713 million, which included $40 million received for a clinical milestone from NovoNerdi. Our partnership with Novo, together with our Bristol-Myers Squibb and Rose collaboration and our wholly owned programs, allows us to advance our robust pipeline with blockbuster potential.

for the supporting our goal to address the unmet medical needs of millions of patients affected by diseases caused by protein dysregulation. We believe that our focus on treating and preventing neurodegenerative and rare peripheral amyloid diseases addresses significant unmet medical needs. Our clinical expertise and differentiated approach enables us to advance best-in-class therapies that have the potential to transform the treatment landscape for protein dysregulation diseases. Our focus on developing treatments for neurodegenerative disorders includes therapeutic approaches for alveolar dysfunction.

are being developed in targeted patient populations at high risk for early mortality, which underscores our commitment to develop therapy as for patients with an urgent need for improved survival. Before I turn the call over to Hedeke, I would like to highlight several breakthroughs that occurred in 2022, that have meaningfully advanced the overall treatment landscape for Alzheimer's disease. Over the past several months, multiple milestones have been achieved in the Alzheimer's community.

that targets the immunoterminous of A-beta in patients with Alzheimer's disease.

the immunoterminous of A-beta in patients with Alzheimer's disease to both clear plaques and neutralize soluble protofibrils.

In early January , Lecanumab received accelerated approval from the FDA for the treatment of early Alzheimer's disease. Notably, the approval was based on Phase II data that demonstrated that Lecanumab reduced the accumulation of A-data plaque in the brain, which was noted by the agency as a surrogate endpoint reasonably likely to predict positive clinical outcomes.

The results from Clarity AD plus the accelerated approval of lecanimab continues to support the A-beta treatment pathway in Alzheimer's disease, and we believe paved the path for the next generation of plaque-clearing anti-A-beta antibodies, including PRX12, a potential best-in-class subcutaneous treatment for Alzheimer's disease. Another notable development at the CTED conference was the many scientific advancements in the area of biomarkers. This included research from Dr. Randy Bateman's team at Washington University in St. Louis, which showed that cerebral spinal fluid levels of MTBR tau 243 closely tracked with tau PET, distinguishing amyloid positive individuals with tau tangles from amyloid positive individuals without tau tangles. Hadecki will cover this exciting data in more detail shortly. At Prosthena, we celebrate these advancements and also strive to create novel treatments that further improve efficacy and quality of life for patients.

Finding solutions to treat and prevent this disease is crucial. This is why we are advancing one of the most robust Alzheimer's disease portfolios in the industry, guided by our comprehensive therapeutic strategy to address the unmet needs in Alzheimer's. Our portfolio is well positioned in light of these recent scientific advances in the field and positions Pratina as a leader in the transformation of Alzheimer's therapeutic approaches. We are currently advancing three product candidates, PRX12, PRX5, and PRX123, targeting key pathological pathways of the disease cascade, which have the potential to expand from next generation disease modifying treatments to combination and prevention paradigms. With that, I'll now turn the call over to Hideki to highlight the progress made across our robust R&D portfolio in 2022. Thank you, Gene. With PRX12, our next generation, patient-centric, subcutaneously delivered investigational treatment for Alzheimer's disease.

which targets a key epitope at the immuno terminus of amyloid beta with high binding potency. Preclinical data have shown that PRX12 binds to amyloid plaques with very high humidity, consistent with the potential for more effective A-beta plaque clearance at lower doses than currently approved anti-A-beta therapies, allowing for subcutaneous delivery in our clinical trials. PRX12 is designed with a patient in mind, and we believe it has the potential to be best-in-class, transforming the treatment of Alzheimer's disease. In 2022, the FDA cleared the IND for this program and granted PRX12's fast-track designation for the treatment of Alzheimer's disease. We then successfully initiated a randomized, double-blind, placebo-controlled, phase 1, single-setting dose study, a series of advocates to thwart access to label-based powerfully- correcting Sunnyborn TITA, and published theADE Honey Foundations and

evaluating the safety, tolerability, immunogenicity, and pharmacokinetics of PRX-12, in healthy volunteers, and in patients with Alzheimer's disease. The multiple-ascending dose portion of this study has commenced, and we expect to report top-line data from the initial dose level cohort by year-end 2023. We look forward to having a significant presence at the upcoming 2023 International Conference on Alzheimer's and Parkinson's Diseases, or ADPD, which begins in late March. Among the planned events are an oral presentation featuring preclinical data showing the superior binding characteristics of PRX-12, and a Prostino-sponsored symposium featuring key thought leaders.

antibody concentrations in the brain. I would like to turn now to PRX5, our NTPR tile targeting monoclonal antibodies. PRX5 is designed to be a best in class, and TBR specific anti-tile antibody.

Tau tangles, along with amyloid beta plaques, are pathological hallmarks of Alzheimer's disease, and research indicates that tau pathology correlates with the clinical and cognitive decline associated with this disease. Early research conducted by Christina found that targeting specific regions within the MHRP results in a more consistent and robust production in the pathogenic uptake of tau into neurons and the downstream neurotoxic effects. As Gene mentioned in his earlier remarks, Dr. Randy Bateman's presentation of CTAD 2022.

of drug concentration from plasma with robust central nervous system penetration.

Single doses from three dose double cohorts were generally safe and well tolerated, meeting the primary objective of the study. Exposure in cerebral spinal fluid was measured in high dose cohorts and based on the robust exposure of PRX5 in the CSF.

which is approximately 0.2% of peripheral levels, substantial target engagement is expected in the CMS. PRX5 had a reliable immunogenicity profile with no persistent PRX5-induced anti-drug antibodies observed. We plan to present these results from the Phase I single-sending dose study at an upcoming medical conference. The multiple-sending dose portion of the Phase I study is ongoing.

The purpose of the phase one multiple ascending dose trial is to evaluate the safety, solubility, pharmacokinetics, pharmacodynamics, and immunogenicity following the administration of multiple doses of PRX5 in healthy adults and patients with Alzheimer's disease. We anticipate that these results will help us determine the appropriate dose level for subsequent clinical studies. Hotline results are expected by year end 2023.

PRX5 is one of three programs being developed in partnership with our colleagues at Bristol-Myers-Squibb. For our third Alzheimer's program, PRX123, a dual A-beta-tau vaccine, we present the preclinical data at ADPD 2022 that demonstrated the generation of anti-A-beta and anti-MT-BR-tau antibodies that enable phagoplytosis of A-beta and neutralization of pathogenic tau. We look forward to filing an IMD for PRX123 by year-end 2023. This program is exciting because it combines the knowledge and mechanisms of both amyloid beta and tau targeting in a single construct, potentially aligning with the prevention as well as therapeutic strategy. Turning now to Prasumismat and Parkinson's disease. In 2022, Roche, our partner for Prasumismat, presented data from the phase two passogen study at ADPD 2022. These data are compelling because they support a potential effect of the virus.

on delaying motor progression in Parkinson's disease. In addition to the past student study, Roche is now conducting the ongoing phase IIB Padova study in patients with early Parkinson's disease. Roche expects to report top-line data from the Padova study in 2024. Now I'd like to discuss the Botanimat program for the treatment of NAIL stage IV, AL amyloidosis. Certain treatments for AL amyloidosis target the clonal plasma cells that overproduce light change. While these therapies can reduce new light change production, they fail to directly address the amyloid that has already been deposited and is causing organ toxicity and organ failure. Botanimat is refrigerated and that is designed to deplete the amyloid and soluble aggregates most proximally associated with organ dysfunction. Patina has advanced Botanimat into the ongoing confirmatory phase III, a FIRM-AL study in patients with NAIL stage IV AL amyloidosis. Under a Special Protocol Assessment, or SPA, agreement with the US FDA that the primary endpoint of all-cause mortality is the

at a significant level of less than or equal to 0.10. Patient recruitment continues to be on track, and the confirmatory Phase III of FIRM-AL top-line data is expected in 2024. In December at the American Society of Hematology 2022 conference, we reported clinical data from the completed Phase III VITA study, which demonstrated in a post-doc analysis of patients with NAO Stage IV AL amyloidosis a statistically significant survival benefit of 74% in patients taking Britanumab versus 49% in patients on placebo at 9 months. This reflects a hazard ratio of 0.413 and a p-value of 0.021. Survival benefit of Britanumab is vital, and may consist across all key baseline variables in NAO Stage IV patients.

Reinforcement of strength of the survival data in these patients at a high risk of early mortality. For TEMAD, it was generally safe and well tolerated in the overall population and in Mayo Stage 4 patients. And moving now to events in the ATTR amyloidosis program, PRX4, which has been developed by Novo Nordisk and has been renamed NNC-6019, has now advanced into an ongoing phase 2 clinical study for the treatment of ATTR cardiomyopathy. Novo expects to report top-lying data from the phase 2 study in 2024. At this time, I'd like to turn the call over to Tran for discussion of our 2022 financial performance and our 2023 financial guidance. Tran? Thanks, Hideki. Today, we reported results that were either in line or favorable to our 2022 financial guidance. Please refer to our press release for a detailed breakdown of our financial results. As Gene mentioned during his opening remarks, last year we strengthened our capital position. First, with our strong partnership with Novo Nordisk, we have been working with the National Review of Foodventure Science Services and the four research-aram organizations around sustainable water these days, including the Families III Center, daily

net loss was 116.9 million dollars which was favorable to our guidance of 121 to 137 million dollars. As of December 31st, 2022, Prothena had 712.6 million dollars in cash, cash equivalents, and restricted cash.

which exceeded our guidance of $522 million. As of February 17, 2023, Prothena had approximately 52.6 million ordinary shares outstanding. Additionally, we continue to have a clean capital structure with zero debt. Turning to our 2023 financial guidance, we expect our full year 2023 net cash used in operating and investing activities to be between $213 and $229 million. We expect to end the year with approximately $512 million.

Thank you, John . Before we talk about our 2023 milestones, I want to first acknowledge and thank our talented Perthina employees for their ongoing commitment to advancing our protein dysregulation science to make a real impact for the patients and families we serve. Patients, families, physicians, and study site staff who participate in our studies.

Without their support, we could not elucidate the potential impact of the new medicines we're developing. Over the past year, our team has delivered on multiple milestones, further advancing Prothena as a leader in addressing devastating diseases caused by protein dysregulation. As you heard today, our dedication to our mission, combined with our diversified best-in-class portfolio, and our scientific heritage and human talents, have made possible multiple meaningful achievements in 2022 and have positioned Prothena well for a transformational period ahead. As new data becomes available on the clinical, regulatory, and commercial landscape in the Alzheimer's field, we will continue to work to ensure the success of the new medicines.

we believe our programs are well positioned to revolutionize the care of patients suffering from this devastating disease. To that end, we can expect the following key milestones in 2023 and 2024. First, preclinical data demonstrating the superior binding characteristics of PRX-12 at the upcoming ADPD 2023 annual meeting. Second, the multiple ascending dose portion of the phase 1 PRX-12 study has commenced and we are on track to report top-line data from the initial cohort by the end of 2023. Third, the phase 1 multiple ascending dose study for PRX-5 is ongoing with...

And finally, for NMC6019, we expect that our partner, Novo Nordisk, will report top-line phase 2 data in patients with ATTR cardiomyopathy in 2024. I am proud of the progress that Prosthena has made in 2022. We have a robust portfolio with multiple wholly-owned assets and strong collaborations.

for NNC 6019. We expect that our partner, Nova Nortis, will report top line phase 2 data in patients with ATTR Cardiomyopathy in 2024. I'm proud of the progress that Prasina has made in 2022. We have a robust portfolio with multiple wholly owned assets and strong collaboration. We are well capitalized.

have a robust cash position, and remain focused on executing during the next 24 months. We expect to make additional progress across our R&D pipeline this year, and we look forward to continuing to provide additional portfolio updates when appropriate. With that, we'll now open the call for questions. Operator? Thank you. At this time, I would like to remind everyone in order to ask a question press star then the number one on your telephone keypad. If you would like to remove yourself from the queue press star 1 again. We ask that you please limit yourselves to one question to allow everyone an opportunity to ask a question. We'll go first to Michael Yeh at Jefferies. Hey guys, good afternoon. Thanks for the update. I'll keep it to one question. As a PRX012, I think you've initiated the MAB portion in Alzheimer's patients at the first cohort. Later this year when you have data, can you just describe what you're looking for after treating patients for six months? Are you looking for a certain level of amyloid pet reduction on on pet, and how should we contextualize that data and try and compare it to other Alzheimer's antibodies like Likand. Thank you. Yeah, really important question Mike and thanks for asking. So let me just you know start...

We're looking for active data. And so we'll use the SAD data and also some from the MAD data to further elucidate doses behind the first dose.

Yeah, and I'll just add, remember, this is a phase one study, so the primary endpoint is safety. We'll, of course, look at pharmacokinetics and pharmacodynamics, as both Jean and Tran have alluded to, and importantly, we'll have additional dose cohorts to look at bracketing that dose.

We'll go next to Nina Vitrito-Garg at Citi. Hey, guys. Thanks for taking my question. Just to follow up on the question that was just asked, could you give us a little bit more detail on exactly how many patients we might expect to see data for, for PRX-012 later this year? And then also if you can provide any more specifics on exactly the metrics that you'll look at, whether you'll be able to provide us with metrics like the proportion of patients who are amyloid negative, or whether we should expect to see results on a centiloid scale, and how we should think about that. Thanks.

Yeah, thanks, Nina. Great questions. So, maybe I can hand it over to Hideki to talk a little bit about the multiple dose study design and some of the elements of that. And you can talk a little bit, maybe, Hideki, as well, about just some of the parameters that we're evaluating from a PET perspective. Yeah. So, we have, in this first cohort, we have enough patients in order to meet our endpoints, that being safety, pharmacokinetics, and pharmacokinetics as measured by amyloid PET. We will also have MRI to look for any safety issues, as well. And so, those are the main parameters. We have optional biomarkers, as well. So, we'll have a very robust dataset, remembering, again, that the primary endpoint is safety in this phase one MAD. And we'll also have enough patients in the cohorts, MAD cohorts, to make a statistical analysis as it pertains to the amyloid PET.

data from a pharmacodynamic perspective. And we'll be looking at, you know, the basically a various analysis of centaloids and SUVR reads. Yeah, I mean, the other thing I'll just point out, Nina, as a follow up to your question is, you know, I don't want to lose sight of the fact that the single dose data, you know, is something that we'll also be talking about this year. And we think that's of importance as well. You know, as you know, with PRX012, given its finding characteristics and its development as a subcutaneous approach with the target product profile once monthly sub-q delivery, you know, we think the single dose data could be quite informative as well just to tell us how closely we've come to our target product profile. So we think all that data.

will be important, you know, and again, the anticipation is we'll talk about that altogether. And next, we'll move to Charles Duncan at Cantor Fitzgerald. Yeah, hi, guys. Thanks for taking the question and congrats on a good year of progress. I also had a question on 012 and probably a two-part one, and that is that with regard to the single dose data, could you be presenting that at AAIC or CTAD? And then the second part is when you talk about sub-q and being patient-centric, best in class, what exactly are you going to be considering to evaluate whether or not you hit that target product profile? Yeah, thank you for the question. So, first, I think with respect to where the data will be discussed, obviously, we'll wait until we actually, you know, are able to speak to that. So, clearly, that requires not just us targeting a certain meeting but, you know, an abstract being submitted and being accepted. So, typically, we wouldn't talk about where we would talk about those data until such time as we announce that publicly.

I think for the single dose data, the current expectation should be that we'll speak about the single dose data along with that first cohort of multiple dose data. So that's the current communication around that. So that's, I think, the right expectation to have currently. I'll mention just from a sub-Q perspective, and maybe I can ask Wagner to talk about some of the characteristics of PRX-12, which we think enable this. It really is about a target product profile, and what we set out to do with PRX-12 was to develop an antibody that by design would lend itself to subcutaneous administration. And that, of course, requires a number of key characteristics being met. It was an intensive screening campaign to develop antibodies with the right characteristics. And what we're looking for now in our clinical studies is obviously to understand if we've met that. And at the highest level, what I would say is we're most eager to have a once-monthly sub-Q delivery that provides the same level of occupancy of A-beta as some of these first-generation antibodies, which may require much more intensive delivery because of their less optimal profile and characteristics. And so if you think about once-monthly sub-Q single syringe, that's really what we're going for. That's the optimal target product profile for us. We think that that enables potentially patient access. So for patients that have a potential to advantage from these types of treatments, we want to make sure that the patients can access this health tool yeah, that they want to be part

my concentration solution, but the stability in that same compartment where it's delivered. And all of that was part of this screening, in fact, that raised PRX to the top. This is different than a campaign where you normally start with an IV antibody and try to make it as soon as you mind.

encounter some challenges at that point. And we didn't want to because, as Gene said, X12 was born to be a subcutaneous antibody and we're deristed that pre-clinically. So as was said before, the importance of a phase one for us, sad to confirm that we, there are assumptions pre-clinically are reading in patients that by availability exposure all of that is read very early on. That's very important for us because we can tweak our models and ensure that the doses that we selected for the med, for example, are appropriate doses, that they are active and not only that, but they are leading for let's say all the patients

to a target engagement that will be meaningful for the target's product profile. We'll take our next question from Jay Olson at Oppenheimer. Oh, hey, guys. Congrats on the progress, and thank you for taking the question. Can you talk about how you see the reimbursement landscape evolving for Alzheimer's therapeutics, especially with yesterday's comments from CMS, and also since PRX012 is designed to be delivered as a sub-q, and then also maybe in the context of your broader Alzheimer's portfolio with PRX005, and also your dual tau amyloid vaccine. Thank you. Yeah, Jay, really good question. Thank you for with him. Maybe I'll ask Tron to...

that are the full NCD moving forward. That said, as you appropriately pointed out, the NCD is a subcutaneous approach.

You know, particularly those that may be envisioned to occur in the home could actually be in part D as opposed to part D in the Medicare scheme. And of course that has different consequences with respect to NCD, natural coverage determinations. And we think actually position Derek's 12 quite well.

for potential reimbursement in that context. I think the other question that you're kind of asking a little bit maybe around the accelerated approval pathway and what that continues to look like. And of course we were encouraged by the accelerated approval of the Canimab. In particular, the fact that the basis of approval there was based on the phase two data and the basis of that approval was really on amyloid plaque reduction as measured by PET. So we think that that accelerated pathway from our perspective provided that you can meet the key elements of the accelerated approval pathway, which is a serious disease and an unmet medical need. We think that that continues and remains open and is a potential path for PRX-12. But at the same time, we're looking at our program in a holistic way. We're thinking about it end to end. How do we move this molecule forward through the clinic in a way that's most appropriately ambitious, but at the same time provides us with the broadest data package.

on which to enter the commercial market. So we do think about that from an end to end perspective. But maybe Tron, I can ask you to comment a little bit further on the decision yesterday that CMS kind of published and how you see the field. Yeah, I know. I think just to build on what you said is, I mean, clearly the letter pointed to the fact that they understood that there is more data, meaning how we read it was the phase three data. I think during this review, they didn't look at that. What they said is in order to work expeditiously to get a broader coverage for patients, they wanted to work within the existing, you know, NCD and the CD that they put out there and they have brought that what they've basically communicated that they will broaden that upon full approval. They do mention a registry. There is a registry that, you know, the, the, the, the, the, the, Alzheimer's Association has. And so we'll see how, with the details of that are, but at this point, you know, they are broadening it. They're saying, hey, between review.

full approval, we'll review the data, at least in that period you'll get broader coverage potentially through a registry and then after real-world data is collected and then after review of the phase 3 data they would go back and take a look at potentially changing that to something even broader than that. And so I think what they were working with was do we start from you know kind of a zero which is okay it'll take 9 to 12 months for a new NCD process versus you know broadening through a registry. So we do see it as CMS working with you know working with FDA and and you know I think they understand that FDA's job is to approve you know or to make the decision on approval for Canemab and once that happens you know they can then review the data and then do what they need to do but again we see that as very encouraging and you know again we will work with regulators and to build again on what Gene was saying about our path to patients.

There are potential paths forward for us that Gene just covered, but also ultimately we need to talk to regulators about that. But again, we do feel that accelerated approval is based on unmet need. As you know, there's millions of patients in the prodromal, the mild stage of the disease. We think that even according to E-size, estimates of 100,000 patients in a year after three years of marketing, that's an under-penetrated market, so to speak. So there will be an unmet need and we'll work hard to figure out what our path to patients are and we'll come back and update you-all when that happens. Thank you.

We'll go next to Brian Abrahams at RBC Capital Markets. Hi there. Good afternoon. Thanks for taking my question and congrats on all the progress. I'm curious how are you guys envisioning the future dosing paradigm for Alzheimer's beta amyloid antibodies? Do you think this will be finite dosing with amyloid checks, chronic dosing or some sort of induction maintenance? I guess I'm curious how that might shape your 012 development strategy with regards to potentially enabling the most robust safety data set for potential accelerated approval. Thanks. Thanks, Brian . I think you're exactly right. There are a couple of different monoclonals out there that target slightly different species of amyloid beta and are talking about the dosing paradigm slightly differently. I think from our perspective, as we think about targeting the most pervasive form of amyloid in the brain.

found that target aid data in slightly different ways. Our current view of the data is the chronic treatment is likely needed. The AMOLED data is a key toxic insult in the CNS and the context of Alzheimer's disease. Not only does it cause problems on its own, but at least dysregulation of other key proteins such as PAL. One of the key reasons that we talked about PRX123 is the dual AMOLED data PAL targeting agents. The AMOLED data is a key toxic insult in the context of Alzheimer's disease.

is because we do believe that those biologies are on target pathways. So we do know, for example, that amyloid beta can lead to tautase regulation, which can lead directly to neuronal dysregulation. So we do think that ultimately, A beta will continue to provide a toxic insult if it's left unchecked, and therefore it needs to be part of a foundational treatment as we think about disease modification. So maybe, Yvago, do you want to expand on some of that science?

Just to echo what you just said, I think what determines the period of treatment is likely what the mechanism is. If you have an antibody that binds to a multitude of toxic forms from all the very small solid aggregates of the H-dominoides, you likely need that antibody to be delivered chronically because those small toxic forms can be formed very quickly in the brain of patients. You need to remove completely the most compact forms of the plaque and that's what we visualize when we do a PET scan. It doesn't mean that you don't have amorphous material around.

that can accelerate the position of more amyloid and make even more soluble aggregates. If your antibody binds to all those forms, all the pathogenic forms, we see that as a chronic treatment. Now, if the antibody is binding to a post-translation modification that requires time to happen once you got rid of the initial material, then there is, of course, a lag between that and the formation of a new pathogenic form. So it probably wouldn't make sense to have an antibody around if you don't have a target. So again, it all depends on the mechanism of action of the antibody and an interminal antibody that binds to all pathogenic forms like lecanumab, like PRX12, we think that it makes perfect sense to position as a chronic treatment.

Just to build on what Gene and Wagner were saying is, and clearly we're going to follow the data here. I think the phase three data from Clarity AD, given what Wagner just said about hitting all the species that could be pathogenic, not just maybe the post-translational modification, you know, pyroglutamate A beta. We know what that results in, in terms of the phase three clarity. We're excited to see the phase three trailblazer two trial from Denonimab, and we'll look at that data in terms of the trial design that they have where they dose to amyloid negative and stop. So we'll see how that all affects clinical endpoints, because I think that'll be a great learning, and it'll tell us how to design our registrational trials going forward. And we'll move to our next question from Jason Butler at JMP Securities. Hi. Thanks for taking the question. Just had one on PRX5. Just wondering if you could give some comments about what you're looking to take away from the MAD results later this year, I guess what you've taken from the SAD results in terms of target engagement and how you're thinking about it going forward and how you think about biomarkers specifically, as you mentioned, how 243 CSF and how you could include that in the program. Thanks. Yeah, thanks, Jason. Good question. So, I mean, first, you know, just a little bit about how we got to the MTBR region. You know, we were, you know, TAL is a complex protein, right? It has six splice variants over 440 amino acids and some of those variants. And so understanding how to target that protein in order to ameliorate some of the negative biology.

associated with it when it becomes dysregulated. It was quite important. I think the team under Wagner's direction did a great job and really looking at how you target that protein, you know, really exploring immunoterminous targeting antibodies, carboxytherminous targeting antibodies. And really it was this key region within the MTBR region that ended up being something that gave us very consistent and robust biological effect. And so we were encouraged then when we started to see some really compelling work in the field. Start to focus in on these MTBR region and the MTBR containing fragments. So for example, Mark Diamond's work suggesting that these MTBR fragments are critically important in the self-self transmission of dysregulated towel. You know, and also as we mentioned in the call Randy Bateman's work at WashU, really suggesting that when you evaluate these MTBR containing fragments in the CSF, they much better track with with not only towel pet, but also with potential level of dimension patients with Alzheimer's disease. So we were encouraged by that. To your question specifically in the multiple dose study, again, I'd be remiss. And Hadekki would definitely correct me if I didn't say that, you know, the primary objective of that study is safety tolerability. But as you say, we are interested in looking at CSF target engagements were interested in particular in these MTBR fragments. And I don't know Hadekki or Warrant. Or Wagner, if you want to speak to kind of the nature of the fragments that will be evaluating in the context of potential pharmacogenomic effect in the central nervous system, prepartments here like the CSF. Yeah, I'll just go ahead Wagner. You go first. Maybe on the identity. So we will provide the full detail.

of what fragments we are looking for, but certainly they are not different from the fragments reported as fragments that track well with the digit progression by Wash U, for example. And it's a great opportunity for us. We have a very good understanding of what is the engagement of the target that we want to reach full potential for this antibody. So we'll use that as a confirmation of our assumptions for those selection and activity in the brain as well. And the details about the assays that we're gonna be using, we will review that once we have the data and the full data set. I just want to mention that we are extremely lucky that we found the MTBR domain of TAL is being impactful via screening. It was an empirical determination, but at the same time, the field developed to a point that today we can measure MTBR in the CSF. Not long ago, it was a mystery why MTBR is not present in the CSF, why all the other fragments are. And it was a question of sensitivity. So now we are in a position where we have what we believe is one of, or if not the best anti-MTBR antibody that binds to multiple sites in the MTBR-containing fragments. But also the assay that allows us to confirm that it has the activity that we designed and invited you to have in the CNS. And with all of that, basically you can make your recommendations for a phase two readout. And I'm just gonna add one more element as these studies become bigger. There is another element that also helps us in decision making with...

which is the availability of PET ligands for tau that we can use to track directly intracellular pathology. So all of that is part of the plan, but I would like to hear Daky talk about it. Yeah, I just wanted to reiterate that we're very pleased with the sad results that we announced earlier. It's very safe, tolerable, and in particular, the CSF data show we have 0.2% penetration, which we're extremely pleased with, but that really indicates a substantial target engagement. And as far as the MAD data, as Wagner mentioned, we will have not only safety, but we'll have the CSF data in terms of MTBR engagement from the CSF and Alzheimer's patients. So that's all data we expect by end of the year. And at this time, there are no further questions. I will turn the call back over to Gene Kenney for closing remarks. Well, thanks, operator. I want to thank you all for joining us on the call today. We appreciate your interest in PRFINA, and over the coming months, we look forward to sharing further updates on our program. Thank you all. That does conclude today's conference call. Thank you for your participation. You may now disconnect. body.