Prothena Corporation plc Price & Performance (PRTA)

In addition, we are using supplemental slides which are available on the Events and Presentations section of our Investor Relations website. On today's call, Doctor. Gene Kenny, our President and Chief Executive Officer will provide opening remarks including an overview of Protheonix Prothena and development strategy. Chad Swanson, our Chief Development Officer will provide an update on our ongoing wholly owned clinical program. And Brandon Smith, our Chief Operating Officer, will provide commercial insights on those programs. [indiscernible] our Chief Financial Officer and Chief Strategy Officer, will then discuss our 2024 financial results and 2025 financial guidance before turning it back to Gene for closing remarks at which point we will open up the call for a Q and 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 forward looking statements. For a discussion of the risks and uncertainties associated with our forward looking statements, please see our press release issued today 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, Mark, and thank you all for joining us today. Let's begin on Slide five. Our mission at Prithina is to create transformational therapy addressing significant unmet medical needs for the millions of patients and their loved ones that are affected by devastating life threatening diseases caused by protein dysregulation, That mission is enabled by our deep scientific expertise which serves as a unifying thread connecting our corporate strategy our portfolio development, and the dedication that propels Protheneans every day. As a result of our commitment to our mission, we have created a robust portfolio of therapeutic drug candidates targeting both neurodegenerative and rare peripheral amyloid diseases as shown on Slide six. Our portfolio has four wholly owned and four partnered programs across late to mid to early stages of clinical development. This intentional mix allows us to leverage the benefits of working with key strategic partners to rapidly advance these treatments to patients while maintaining financial upside for Foresina, These partnerships further allow us to invest in the full upside potential of our wholly owned programs Advancing them further in development, to potential commercialization. Moving to Slide seven, Our wholly owned clinical programs are nearing significant inflection points in 2025.

Setting up its transformational year for Prothena Prothena. Protamimab is currently the only potential treatment for AL amyloidosis that has demonstrated an early survival benefit in a randomized clinical trial.

The survival data from our prior Phase III VITAL trial enabled us to receive a special protocol assessment or a SPA agreement with the FDA confirm these results in our ongoing Phase three AFFIRM AL trial at an unprecedented statistical significance level of 0.1. The primary endpoint in Affirm AL is time to all cause mortality and we expect to announce top line results in the second quarter of this year. If positive at a P value equal to or less than 0.1, we would expect to submit a BLA to the FDA for potential U. S. Launch by the second half of twenty twenty six. Protanumab represents a very attractive potential multibillion dollar global commercial opportunity. This is a rare disease patient population primarily treated by hematologists and amyloidosis specialty centers for which the ongoing britamimab program is designed to address the significant unmet need of early mortality In addition, our Alzheimer's disease portfolio, PRX-twelve and PRX-one hundred and twenty three, includes unique programs designed to address the unmet need of the millions of pre symptomatic and early symptomatic AD patients and their families. TRX12 is our anti abata program designed to be a single injection once monthly subcutaneous treatment to alleviate treatment burden and improve access with an easy to use at home administration.

Around mid year twenty twenty five, we expect to announce initial results from our ongoing Phase one Ascent clinical trial evaluating PRX-twelve in early Alzheimer's patients with additional data updates throughout the year. Chad will describe the trial and readouts in more detail later in his presentation. In addition, our PRX-one hundred and two three dual anti abeta and anti cal vaccine has been granted Fast Track designation has an IND cleared by the FDA. That will describe our confidence in this program and potential next steps as well. Moving on to Slide eight. We have four ongoing clinical partnerships with large pharmaceutical companies enabling us to leverage external resources and expertise to further advance potentially transformative medicines patients and create long term value for Prothena Prothena, Pratinezumab is being investigated as a potential treatment for early Parkinson's disease. And our partner Roche announced top line results from the Phase 2b PDOVA study in December of twenty twenty four. The PDOVA Phase 2b trial evaluated five eighty six people with early Parkinson's for a minimum eighteen months while on stable symptomatic treatment. In the study, parenzumab showed a potential clinical effect in the primary endpoint of time to confirmed mode of progression with a hazard ratio of 0.8 and narrowly missed statistical significance with a P value of 0.0657.

The effect of prasinezumab was more pronounced in a pre specified analysis and the approximately seventy five percent of participants treated with Levodopa, with a hazard ratio of 0.79 and a nominal P value of 0.0431. In pre specified supplementary covariate adjusted analyses of these endpoints, the effects were even more pronounced and all nominally statistically significant. Consistent positive trends across multiple secondary and exploratory endpoints were also observed that prestinezumab continued to be well tolerated. The Phase 2b PDOVO results along with prior clinical study results before further clinical development of prasinezumab, as a potential first in class disease modifying treatment for patients with Parkinson's disease. Roche is continuing to evaluate the effects of prasinezumab in open label extension studies from both the Phase two Pasadena and the Phase 2b PDOVA trial. Roche will continue to evaluate the data and work together with health authorities to determine next steps. Moving on to Koramitab, an anti amyloid antibody for the potential treatment of ATTR amyloid doses, with cardiomyopathy or ATTRCM Novo Nordisk is currently conducting a Phase II signal detection trial in approximately ninety nine patients with ATTRCN. The trial should complete in the first half of twenty twenty five.

And we expect Novo to announce results and potential next steps in the second half of twenty twenty five. We look forward to future updates from Novo including potential further clinical development of moving this important new treatment closer to patients. We made significant progress in 2024 with our two partner clinical programs with Bristol Myers Squibb. BMS-nine hundred and eighty six thousand four hundred and forty six formerly PRX-five, is a potential best in class antibody for the treatment of Alzheimer's disease that specifically targets a key epitope within the microtubule binding region or MTBR of TAO, In 2024, BMS initiated four seventy five patient target TAU-one Phase two trial The trial is evaluating placebo versus low and high doses of BMS-nine hundred and eighty six thousand four hundred and forty six in patients with early Alzheimer's The primary endpoint has changed from baseline in the clinical dementia rating scale from a BOXES score at eighteen months. Enrollment is ongoing and the trial is expected to complete in 2027. Also in 2024, BMS opted into a global license agreement for PRX19 which included a payment of $80,000,000 As part of the agreement, Prothena has initiated a Phase one first in human clinical trial to evaluate the safety tolerability, immunogenicity and pharmacokinetics of single ascending and multiple doses in healthy adults.

The trial is enrolling and expected to complete in 2026. This is an exciting year for PRATINA. And our strategic partners To discuss our wholly owned clinical programs in further detail, I will now turn the call over to Chad. Thanks, Gene. I'd like to start my discussion with a review of vitamina, our anti amyloid treatment for AL amyloidosis We are nearing the completion of our confirmatory Phase three AfirmaL clinical trial.

The trial is being conducted with a primary endpoint of time to all cause mortality for statistical significance and success is defined at a P value equal to or less than 0.1 under a SPAA agreement with the FDA. Let's start by discussing the disease biologies of AL amyloidosis and where the unmet need is with the current standard of care. There are three hallmarks of ALM ludosis. The first is production of misfolded light chain Prothena. The second is formation of toxic soluble aggregates and the third is accumulation of insoluble amyloid deposits Current standard of care consists of plasma cell directed therapies which may decrease the production of misfolded light chains that do not address the toxic soluble light chain aggregates and insoluble analyte deposits which cause organ damage, dysfunction and failure and can lead to early mortality. Ritamab is specifically designed to directly target misfolded light chains both neutralized toxic soluble light chain aggregates and clear insoluble amyloid deposits in vital organs. As the heart. For tadalamab, with its differentiated anti amyloid mechanism, seeks to address the urgent unmet medical need for AL amyloidosis patients at high risk of early mortality. Moving on to Slide 11. Let's review the results of our previous Vital trial which supported our SPA agreement with the FDA where statistical significance and success is defined at P value equal to or less than 0.1 for our ongoing confirmatory Phase three of firm AL trial.

In the approximately thirty percent of the AL amyloidosis patients who are categorized [indiscernible] observed the impressive survival benefit shown on this slide. The Kaplan Meier curve shows early separation resulting a fifty nine percent risk reduction of all cause mortality at month nine with a nominal P value of 0.021. This was further supported by clinically meaningful and nominally on function is measured by the six minute walk test distance and SF36 physical component summary score. And britainolumab has been well tolerated with a favorable safety profile across multiple clinical trials. In VITAL and in the ongoing AFRAM AL trial, we compared vitamimab in combination with current standard of care versus placebo with current standard of care. Moving on to Slide 12.

Recently presented data from the ENDRAOMEDA study demonstrates a significant need for a therapy that clears amyloid and addresses early mortality.

For the VITAL and AFRM ALS trial, standard of care comprised of bortezimab, and often include cyclophosphamide and dexamethasone the combination referred to as Cyber D or BCD, Recently daratumumab has emerged as a standard treatment in clinical practice and is allowed to be used as standard of care at randomization in our AFRM AL trial. This slide, which was adapted from a presentation at ASH in December 2024 on the Phase three ANDROMADA study, clearly shows that the survival curves comparing the addition of daratumumab with BCD the VCD alone did not separate until after approximately fifteen months This suggests that the addition of daratumumab to this regimen in AL amyloidosis patients does not have an impact on early mortality. However, for Tamimann's differentiated mechanism is specifically designed to address directly the disease pathology potentially reduced the risk of early mortality as we observed in the vital results. And are looking to confirm in Affirm AL. Please turn to Slide 13.

Based on our extensive analysis of the vital data, as well as further confirmation of the data with external statistical experts and leading physicians in the field, we actively engaged with the FDA to align on a path towards regulatory success for bertamimab. The prior survival data from our Phase III VITAL trial enabled us to receive a SPA agreement with the FDA to confirm these results in our ongoing Phase three OFIRMAIL trial again with statistical significance and success is defined at a p value equal to or less than 0.1.

This is a time to event trial and patients are randomized two:one on betamimab plus standard of care versus placebo plus standard of care. We expect to announce results in the second quarter of twenty twenty five. Now let's review our Alzheimer's portfolio starting with PRX-twelve on Slide 14.

TRX12 is our anti amyloid beta antibody specifically designed with the patient in mind. We believe that a treatment with similar efficacy and safety to currently approved anti A beta therapies but delivered with less burden in the home represents significant value for people living with Alzheimer's disease. PRX-twelve is a human eye IgG1 monoclonal antibody designed to have highly potent binding with high affinity and affinity, and a slow off rate allowing for consistent target engagement, all of which are optimal for a once monthly subcutaneous treatment We look forward to further confirming the potential of PRX-twelve. In the clinic and now let's turn to Slide 15, Ascent-two is our double blind placebo controlled multiple clinical trial evaluating pure in people with early Alzheimer's disease. Each cohort is randomized three to one to receive PRS PRS-twelve or placebo once monthly for six months.

The objectives of the trial are twofold. First is to evaluate the safety, tolerability and immunogenicity of PRX-twelve in patients with early Alzheimer's disease. And the second is to characterize the pharmacokinetics and the pharmacodynamics of PRX-twelve twelve. To find the optimal dose regimen for a registration enabling clinical trial. Starting around mid year, our initial data share will include results from the five eight cohorts shown here. This represents approximately two twenty five participants that are all either APOE4 non carriers or APOE4 heterozygous carriers with early Alzheimer's disease. Additional data readouts and presentations may include any of the following. Data from the 3b cohorts which enrolled approximately 36 participants and who are all APOE homozygous carriers and longitudinal data for some patients who have been on treatment for upwards of twelve and eighteen months at various dose levels three open label extension study, Let's move to Slide 16 to review our PRX PRX-one 23 program.

PRX-one 23 targets key epitopes within the N terminus of abeta and the MTBR region of tau designed to promote amyloid clearance and block the cell to cell transmission of pathogenic tau. New data was presented at CPAD in 2024 on potential treatment targeting the mid region of tau which showed some early signals of activity. In particular, a very small number of participants, AZE2814 antibody which also targets areas within the MTVR region, [indiscernible] including NTBR Tau-two 43, [indiscernible] TCAL-two 17, which has been associated with clinical efficacy.

In addition, our partner Bristol Myers Squibb, has advanced DMS nine hundred and eighty six thousand four hundred and forty six formerly known as PRX-five, an anti MTBR tau antibody into a robust Phase two trial signaling their confidence in the target.

These data points give us further confidence in our PRX123 program and we look forward to providing further updates on its development path this year. I'll now turn it over to Brandon to discuss the commercial potential for a wholly owned program. Thanks, Chad. Moving to Slide 18, we are focused on building out our commercial capabilities to support bertamab as our first potential commercial product. While the standard of care has evolved, there continues to be significant unmet need in the treatment of ALM ligosis for patients at risk of early mortality. Providers and patients are waiting for an anti amyloid treatment that directly clears amyloid from the heart and other vital organs. Leading to early survival benefit. With positive Phase three results for britamab, we expect to launch in The U. S. By the second half of twenty twenty six. This has the promise to make a significant impact on patient outcomes and will be a very attractive commercial opportunity. There are several factors which support our enthusiasm. First, this is an established market. Our claims data and market research indicate that as of 2024, there were approximately sixteen thousand diagnosed and treated AL Amvidosis patients in The United States.

With the vast majority, approximately thirteen thousand, having cardiac involvement, segment with the highest risk for early mortality Market size is similar across the five major European markets, at approximately fifteen thousand patients with ALM Lytosis with cardiac involvement. Given upwards of thirty percent of all ALM Lytosis patients are Mayo Stage IV, we believe the diagnosed and treated population of Mayo Stage four patients is close to five thousand patients in The U. S. And over five thousand patients in the major European markets. Globally, we estimate there are over twenty thousand diagnosed patients with Mayo Stage four ALM Lycosylaxis across the major market including The United States, Europe, China, Brazil and Japan. Second, with a significant unmet need for treatment options, that address early mortality and the observed favorable safety profile to date, we expect very high peak penetration in MayoStage four patients if approved. And third, this is a rare disease patient population with a targeted call point for hematologists with support from specialized cardiologists are the primary treating specialists. We are prepared to build out our sales force to call on this relatively consolidated And most patients in The U. S. And Europe are treated at Hemalodosis Centers of Excellence Hemolydoses Specialty Centers and academic medical centers.

We will ensure our sales force is able to cover these centers as well as high prescribing community practices in hospitals. As a reminder, with britamab, we have a spa agreement with the FDA Fast Track designation from the FDA and orphan drug designation from both FDA and EMA. With regulatory and IP positioning, we expect twelve years or more of market exclusive in The United States and ten years or more of market exclusive in Europe. Moving to Slide 19. Market dynamics for bertamivab as our first potential commercial products are quite compelling. Our plan is to independently commercialize britamivab in The U. S. And continue to evaluate launch timing in the European markets. Given the consolidated prescriber base, we believe we will be able to efficiently reach prescribers with a focused commercial presence. Our team continues to build upon the existing relationships we've established with KOLs and the experts in the field through our extensive clinical programs for ritamab.

We will continue to collaborate with these KOLs and the broader ALMIDOS community to ensure they are fully aware of and informed on the unique role of the anti amyloid [indiscernible] This includes continuing to present our data at top medical congress These ongoing educational efforts are important to further solidify Protemme's position as a potential new standard of care and to appropriately incorporate bertamab into treatment guidelines. Let's wrap up on bratama by reiterating a few key points.

First, with positive confirmatory Phase three results, ritamab has the potential to be the first anti amyloid therapy for AL amyloidosis and rupetamimab based regimen will be positioned as first line therapy. Becoming the new standard of care for patients at risk of mortality. Second, britamab would be the only AL amyloidosis therapy to demonstrate early survival benefit in double blind placebo controlled clinical And third, we expect bertemvab to be a multibillion dollar global market opportunity at peak. Moving to Slide 20.

As we've discussed, Protamiv is the perfect opportunity for Prothena to transition to a fully integrated commercial biotechnology company. We will look forward to continuing to build on this commercial capability in the future with the rest of our portfolio. Looking ahead, the future market opportunity for our two wholly owned Alzheimer's disease programs PRX-twelve and PRX-one 23 is very compelling. These programs may enable us to address some very large and underserved market, comprised of the millions of pre symptomatic and early symptomatic Alzheimer's disease patients and their families whose needs are not fully met or addressed with today's treatment options. PRX-twelve has a potential once monthly subcutaneous anti abatas treatment option would be well positioned for the early AD market and some portions of the presymptomatic market population if approved. PRX123 is designed as both a potential prevention and treatment option with a vaccine approach.

This opens up the full presymptomatic Alzheimer's market as well as some of the early symptomatic And now, I'd like to turn the call over to Tron for a discussion on our 2024 financial and our 2025 financial guidance. Thanks, Brendan.

Please turn to Slide 22.

Today, we reported financial results that were in line with our 2024 financial guidance. Please refer to our press release for a detailed breakdown of our financial results. In addition, in 2024, we received an $80,000,000 payment from BMS where they obtained the exclusive global license for PRX19.

In terms of our twenty twenty four financial performance, relative to guidance, we had net cash used in operating and investing activities of $150,300,000 which is at the low end of our guidance range of $148,000,000 to $160,000,000 Net loss was $122,300,000 which is at the low end of our guidance range of $120 As of December 31, 2024, Christina had $472,200,000 in cash cash equivalents and restricted cash which is in line with our guidance of $468,000,000 As of 02/20/2025, Christina had approximately 53,800,000.0 ordinary shares outstanding. Additionally, we continue to have a simple capital structure with zero debt. Turning to our 2025 financial guidance, on Slide 23, we expect our full year 2025 net cash used in operating and investing activities to be between 168 and $175,000,000 We expect to end the year with approximately $3.00 $1,000,000 in cash cash equivalents and restricted cash. Which represents the midpoint of the range. The estimated full year 2025 net cash used in operating and investing activities is primarily driven by an estimated net loss of $197 to $2.00 $5,000,000 which includes an estimated $41,000,000 of non cash share based compensation expense With that, I'll turn the call back over to Gene to discuss our upcoming milestones.

Thanks, John. Moving to Slide 25.

I'd like to acknowledge and thank the patients, their families, physicians and study site staff who participate in all of our clinical trials. Without their support, we could not elucidate potential impact of the new we're developing. I'd also like to thank our talented Fresenius for their ongoing commitment to advancing protein dysregulation science to make a real impact for the patients and families we serve. As we've discussed today, 2025 has the potential to be a transformational year for Prothena with significant clinical readouts from our wholly owned program as well as continued clinical readouts and development from our strategically partnered programs. Looking ahead, we are excited to announce top line results from our [indiscernible] evaluating bertamimab in patients with Mayo Stage four AL amyloid doses.

Clinical results from our Phase one ASCENT trials evaluating PRX twelve. As a potential best in class treatment in early Alzheimer's disease. Completion and results from Novo's Phase II signal detection trial evaluating Koramatug for the treatment of ATTRCM.

In addition, we look forward to sharing further clinical development updates for PRX123 prastinezumab, CMS-nine hundred and eighty six thousand four hundred and forty six and PRX19. I'm proud of Prothena's execution in 2024 setting us up for an exciting year ahead we're well capitalized with a robust cash position and remain focused on advancing our clinical programs as we strive to become a fully integrated commercial biotechnology company.

With that, we'll now open the call for Q and A. Operator?

Thank you. We will now begin the question and answer session. And your first question comes from Yashneen Rahimi with Piper Sandler. Please go ahead.

Hi, this is Emma on for Yas. I have two from us. On brotamumab. Firstly, what is considered the best the base and best case scenario into the Phase three of firm AL both on the primary endpoint as well as key secondaries. And then with that, how are you thinking about more in detail about the market opportunity in AL amyloidosis? Like digging into the commercialization about about. So any additional color on that would be super helpful. Thank you.

Great. Hi, Emma. Thanks for the question. So first, just in terms of expectations around the primary endpoint, Let me start again by reiterating this significant unmet need here. So as I'm sure you know, all of the current treatments used in ALMolydoses today target plasma cells.

Obviously, britamimab is fundamentally different in that regard in that it targets the amyloid directly And of course, what is lacking in the current treatments and Chad exemplified this in his discussions around bertumumab with the ANDREMA study, is an impact on survival in patients at risk of early mortality. So obviously, that's a significant unmet medical need with the current class treatments available to these patients. And really represents the opportunity for birtamimab as a differentiated mechanism and as a differentiated product We did show in our prior study that in particular in our vital trial in the Mayo stage four patients that there was a meaningful impact on survival. Particularly amongst those that had risk of early mortality. So we think that that really is the opportunity and with the spa agreement that we have with the FDA, that ascribes success at a P value of 0.1 We really think being able to demonstrate that kind of survival benefit would represent a best case for us. And so that said, maybe I can ask Brandon to talk a little bit more about the market and how that potential to address that unmet medical need then translates into the excitement that we have around the market opportunities.

Thank you. And maybe just to orient you to our earnings presentation on Slide eight. I think we laid out some of the ways to help you dimensionalize the opportunity, but a few key points to reiterate. First off, it's established. This is an established market. These are patients who are needed immediately treated upon diagnosis. It's a rare disease with a consolidated Callpoint Importantly, what we've learned in our conversations with OLs and Intermarket Research is an anti amyloid therapy designed to directly clear amyloid from the heart and other vital organs and that demonstrates that early survival benefit. With a favorable safety profile, a very strong update. Especially in the STEM patients at high risk of early mortality. So as I said in the [indiscernible] at peak, the Potamil opportunity is well over a blockbuster opportunity in The U. S. [indiscernible] Honestly, really looking forward to planning for and executing on the launch in the second half of twenty twenty Your next question comes from the line of Jay Olson for Oppenheimer. And also please be reminded that each analyst is only allowed one question.

Congrats on all the progress and thanks for taking the question.

Can you talk about the baseline characteristics of the patients enrolled in Affirm AL, especially with regards to the utilization of daratumumab? And then also, what would be a clinically meaningful OS benefit for [indiscernible] Thank you.

Yes. Thanks for the question, Jay. And I'll let Chad speak to some of the baseline characteristics One of the obvious things that I can point to as we think about the former Vital trial and now the Apermael trial is the focus on patients in Mayo Stage four Obviously, those are the patients at highest risk of early mortality. And given that significant unmet medical need in that patient [indiscernible] to focus the AFRAM AL trial. That in addition to the two to one randomization that we're using in the AFFIRM AL trial. And I think Chad spoke about that in his remarks as well. I'll just mention one thing about the use of DERA, which obviously has become much more widely used in terms of the plasma cell targeting agents in this space And that is just a reminder of what was shown in the deck. Which is that even with the hematologic control that DARTUMA brings along with it, What we're finding is probably not all that surprising is as a plasma cell targeting agent, there's still a relative lack of impact and in fact no impact on [indiscernible] across the first fifteen months of that ANDREWADA trial and of course that's those would be the patients at highest risk of early mortality and where that unmet medical needs continues to live.

So we're excited about the opportunity for britamimab in that space, but let me pass it over to Chad here and maybe he can talk a little bit more about the baseline characteristics. Yes. Thanks, Pete. Thanks for the question. So the baseline characteristics in Affirm are actually quite similar to those that we saw in the Vital Stage four [indiscernible] tying the study to results we saw in that Stage IV population in Vital. With respect to daratumumab, you may know, daratumumab is able to be used in this study in the firm At randomization, And in fact, it turns out that about eighty percent or so of the subjects who are participating in the study are on DARTUMAN. And I think I'll just maybe end by echoing respect to success again, to us success really means a fee value of 0.1 Well, that's per the agreement with FDA in this month. Your next question comes from Umer Rasat with Evercore.

Please go ahead. Hi guys. Thanks for taking my question. A couple if I may. First, could you speak to whether you have any visibility on long term randomized phase of the trials, both for your Phase two pronto and previously treated as well as for Phase three vital. And I understand there's no active arm going on, but I just curious about mortality trends.

Second, for the Stage four analysis from Vital, there were a lot of treatment emergent deaths treatment emergent, a TA that's on the standard of care arm. Could you just elaborate on what drove that? And finally, what's your expectation on medium DFLC in Phase three at baseline? Thank you very much.

Yes. Thanks, Umer, for the questions. Let me just start with the Pronto and Vital question. And then I can ask Chad to comment on the other parts of your question. So first, in terms of visibility on long term mortality, of course, those trials have are no longer ongoing. What we do know from the PRONTO trial is that there were nine total deaths six of those were from the placebo group and three on active treatment with bertamimab. Of course, Pronto was a patient population that had previously received chemotherapy or plasma directed therapy and those patients were considered mesologically stable coming into the study but still had ongoing organ dysfunction In Vital, of course, the results are as we've described them in the past. So the Mayo Stage four patients in particular, you have a hazard ratio of zero point four one first nine months representing just something just shy of a sixty percent relative risk benefit Again, because that trial is no longer ongoing, there's no long term follow-up in terms of mortality that we can point to. That said, let me see if Chad has to comment on some of the other parts of the question that you asked.

Yes. Thanks, Gene. So with respect to the community origin Yes. So essentially, we were looking at all cause mortality in that study. So essentially, all deaths are counted. They all matter in the analysis. [indiscernible] Your next question comes from the line of Charles C. Duncan with Cantor Fitzgerald.

Gerald, please go ahead.

Thank you. Jean and team, congrats on a good year progress. Looking forward to a lot of news flow coming up here. I had a question that kind of goes back to the difference between statistical significance and declaring success for the trial and clinical meaningfulness. And I I assume that any stats are different difference is important to patients, but I'm kind of wondering if Brandon has any thoughts with regard to demand for the drug going forward. If there was call it, a minimum effect size in terms of time to get, but statistically significant versus a much larger Has there been any work that has gone to KOLs that suggest that there might be difference in interest in using the drug?

Yes. Thank you, Charles, for the question. I'll let Brandon can comment a little bit on some of the market research maybe. But just to kind of reiterate our view on this, which is there's nothing that addresses this early mortality in terms of the currently available plasma directed therapies. And so, this is a significant need for which there are is really no opportunity for meaningful benefit with any of the current approaches that we have for these patients. And so we do believe that anything that meets the statistical agreement that we have with the regulatory authority under our SPAA agreement where the P value would be less than 0.1 would be very meaningful for this patient population and very meaningful in the treatment armamentarium. And let me hand it to Brandon to talk to you a little bit about how that translates to commercial.

Yes.

Thank you for the question. Yes, our market research specifically our conversation with payers and with [indiscernible] really points to the fact that the unmet need is very widely known. And the Andromeda data that just came out in December confirms this.

Early on in this disease course, there is nothing that impacts all cause mortality, nothing that impacts mortality.

And because that unmet need is so well known, anything that shows a separation early as idle did and as we're trying to confirm to our firm, we'll be very meaningful to physicians, their patients, and even to payers, because they do fully realize that there is nothing that cost these patients. [indiscernible] honestly, the all cause mortality gold standard endpoint against standard of care is really what's driving a lot of their very strong interest in the therapy. Your next question comes from Jason Butler with Citizens JMP.

Please go ahead.

Thanks for taking the question. About the data that you'll have in hand by the end of the year. And what information you're looking for to design a late stage development program for the program? Thanks. Yes. Jason, thanks for the question. Maybe I can start and maybe ask Mark to talk a little bit about the data that we expect to have as we begin looking at this and talking about it probably So just a reminder, I mean, in this space, particularly as we talk about the anti data class, I think there's two kind of broad categories of how this field is evolving. On one hand, very much around risk benefits thinking about the ARIA relationship to in the first instance amyloid reduction and ultimately how both from a temporal perspective as well as a maximum amyloid reduction perspective how that's translating through to clinical benefit I think the other very important part here as well is treatment burden, something that we talked a little bit about in the remarks. I think Chad was talking about this a fair bit. We think treatment burden is is pretty significantly important with respect commercial uptake of these approaches. Obviously, very important as patients are diagnosed with a [indiscernible] devastating disease, a devastating diagnosis, then we're not adding to the treatment burden in the near term and really thinking about a profile that is amenable to the long term treatment throughout the disease course.

And that's why CRX-twelve is designed with the idea of a once monthly subcu home administration. So we think that's incredibly important But maybe, Mark, if you want to talk a little bit about just kind of what data we expect and how we think that's going to roll out?

Yes. Thank you, Gene. So just kind of building on what Chad presented earlier, looking at Slide 15, far as the data that's going to be shared, So starting around mid year, our initial data share is going to really be from those first 5A cohorts in the ascent to multiple dose trial represents about two twenty five participants all that are either AFOE4 non barriers or AFOE4 heterozygous Additional data readouts throughout the year could include data from the 3b cohorts that have the ApoE4 homozygous carriers. As well as longitudinal data for some patients who have been on treatment for as long as twelve or eighteen months at various dose levels from the ongoing ATTENT three and really just building on what we're looking for the objectives evaluating the safety, tolerability, immunogenicity, of PAR12 in patients with early Alzheimer's. And second, to evaluate the pharmacokinetics and pharmacodynamics really define that optimal dose regimen for registration enabling trial And I think overall what we're really looking for here is we believe that a treatment with similar efficacy and safety to currently approved anti beta therapies, but delivered with less burden in the home represents and addresses a significant unmet need for people living with Alzheimer's in their family.

Your next question comes from Michael Lee with Jefferies. Please go ahead. A question on the Phase three ALM LADOCA study, When you comment around your view that DERA is not impacting the study. Are you implying that the control arm is looking more like the control arm from Andromeda Or are you saying that it does look like [indiscernible] there. And so I just wanted to understand your expectations as it relates to how you powered the study. And what you assumed your control arm did given the fact that it's setting it's been going on for a few years now.

And show the curves do sort of separate over that period of time and maybe that's an explanation for why the study has been going on for so long. The second question, if I may just sneak in one on 2020. When you do read out the data, has your expectations for what is successful changed over time in terms of what you would expect on ARIA and AML reduction? And how should we think about what is good? That result that comes out.

Yes. Thanks, Mike. Some good questions there. Let me start with Your question about Andromeda and Cara, and the control arm. And I'll ask Chad to speak about the as well because I think it also fits into just our expected timing around the study. And how that's enrolling how we're accruing events from timing perspective. So to be to be clear, we do expect the control arm to behave in a somewhat similar manner. To what we observed in the VITAL trial. VITAL trial, if you look at the control arm, the median survival in that arm was around eight point three months. That's just a little bit longer than the literature would have expected, which would have been about six months at that time. But obviously, having monthly access to the world's expert treaters in this space We think it's very reasonable to see a control median survival of approximately eight months. And of course, you can then contrast that against the effect size that we saw across the first nine months there, which is 0.413 hazard ratio, on all cause mortality. So if we kind of look to that, we've done some external benchmarking. We've done, for example, patient matched studies with external databases and find mortality event rates in a very similar time form to what we observed in Vital.

So we do think that that's well founded. I think the point with daratumumab and the ANDREWMA study is that the inclusion of daratumumab does not seem to have an impact on early mortality events, particularly those occurring across first fifteen months. And that's certainly evidenced by the Andromeda data that was presented at ASH last year. So So we look at that and we feel like we're well aligned with what we've seen previously [indiscernible] also true from what we can see both with respect to the events that are occurring whether it be from a timing perspective or quality perspective. But maybe let me hand it over to Chad, he can speak a little more about this and maybe a little bit about just the overall timing of the study and how that's within our expectation.

Yes.

Thank you, Gene.

So I think Gene actually summarized that well, right. So as you know, we've designed a firm based upon the results that we saw in Vital. In the Stage IV patients in VITAL.

And what I can maybe add here is that and actually not so much, Ed, I think Jean alluded to this is that when we look at the timing events in Affirm so far, obviously in a blinded way, but the timing of events and the nature of those events, they're actually quite similar to what we observed in the Vital study. So The timing of these looks to be aligned and suggesting our desire to sort of replicate that study is on par.

Again, with the Dara piece of things as Gene mentioned, Slide 12 clearly shows that the introduction of Dara with standard of care does not seem to have any impact on early events and again, Gene had mentioned our median survival [indiscernible] was eight point three months. And so There are two of that certainly over the first fifteen months or so did not have an impact on survival. So we feel that again those things combined sort of suggest that there are control arms should be should be behaving similarly in the firm as it was in Your next question comes from Roodu Li from Chardan. Please go ahead.

Hi. Thanks for taking my question. So for bertamimab, just a quick follow-up on treatment landscape. How many patients are active treating these current stand up carers?

And did you notice any changes in the market dynamics since GENZ's data was approved in 2021? And secondly, for PI-twelve being sent to maybe talk about the rationale for the two hundred milligram expansion cohort roughly 100 patients any color will be helpful.

Thanks. Okay, great. So yes, let's talk and it's a great question because actually as we talk about some of these numbers, we are talking about patient that are actively being treated today. So maybe Brandon, do you want to talk a little bit about the numbers and Chad, you can address the XOL question. Sure. Happy to. And so what we always Well, I mean, our figure is it diagnosed and treated. Great. So the the patients that we described in our presentation was sixteen thousand patients in The U. S. Your question on whether or not that has increased as DARRA was approved back in 2021. Answer is yes. I think the number we used then was fifty thousand. So it has increased, but this is a disease once identified, the graphic and they rapidly move them into trying to make sure that whatever they can to affect the user logic response, which as Gene and Chad described, [indiscernible] [indiscernible] Our figure that we're quoting are the figures that we can identify from [indiscernible] Right. So I'll address the second part of your question, which was about the expansion cohort. So Quite frankly, we were able to be a bit opportunistic here, in using that expansion cohort given patient demand for the study.

So what I mean by that is in order for us to enroll our B cohorts now recall that our B cohorts are those that are APOE homozygous carriers.

It takes quite a large number of patients to screen in order to obtain the numbers that we were looking for.

In those B cohorts. And that's really because these ethically homozygous carriers make up about fifteen percent of the overall early AD population. So that gives us the ability to result in two ways.

Right? So the first is that One, we're able to use an expansion cohort to take those subjects who are screening that would otherwise not be able to go into the B cohort because they're not homozygous it also then allows for us to have a larger dataset actually to help better characterize PRX-twelve. So it kind of is not just opportunistic approach due to randomizing those people who are Your next question comes from Tazeen Ahmad with Bank of America. Please go ahead. I wanted to get a sense about how to think about commercial uptake. So you talked about these Mayo Stage four AL patients, about five thousand of them in The U. S. How easy are they to find, like if you had to find them tomorrow, could you And how long do you think it would take to really onboard patients from the time you get approved and the early launch phase. And then I also wanted to ask based on the study design, would it be limited to [indiscernible] to less severe patients. Thanks.

Yes. Thanks, Dadeem, for the questions. So I'm going to ask Brandon to comment on that. Obviously, right now, we're focused on the Mayo Stage IV patients. But, yes, maybe you can comment a little bit on just the identification of those patients. Yes.

So as I think I mentioned in my previous comments, these are the patients that we're quoting are diagnosed and treated. So the patients aren't that hard to find because they're diagnosed and treated. Over time, these patients do come in. It is a rare disease. So we fully expect that as you get newly diagnosed patients that those would then move into that [indiscernible] In terms of what it takes to initially launch and commercialize, [indiscernible] This will be our first entry in the marketplace and it does take time to get into the contract and get through and make physicians aware of new treatment options. So our launch of vision certainly is to get to a multibillion dollar opportunity. In the near term, it will take time in order to get that update.

And I think one of the Brandon has mentioned this to me, but I think one of the key things about this disease is that as these patients are diagnosed, they're treated. So this is a treated disease today and obviously, I think That's an awareness level that these physicians have as patients coming in and getting a [indiscernible] We only have time for one more question. And that is from Brian Abrams of RBC Capital Markets. Please go ahead.

Hey guys. Thanks for taking my question and congrats on the continued pipeline progress. Curious if you could talk about the cadence of commercial infrastructure build that you would expect both ahead of and after the Affirm AL readout. And then I'm curious also how you're thinking about the European path and plan, whether it's a far for your regulators Yes. Thanks, Brian. Great questions. Let me start with the latter part of your question. And I'll ask Brandon to talk a little bit about the build out.

So I think in terms of Europe or any other geography for that matter, Obviously, the medical need is to same. So I think what I can say is that from a risk benefit perspective, I think that conversation is very similar As in The U. S, it's also true in Europe and in other geographies, which is the current treatments, which are focused solely on the plasma cell targeting treatment do not have an impact on these patients early mortality events. So for those patients that are at high risk of early mortality, there is a significant palpable unmet medical need that is across all geographies and obviously we would expect productive dialogue with regulatory authorities across globe around that risk benefit profile of the molecule and of the program. So that said, maybe I can talk or maybe I can hand it over Brandon. He can talk a little bit about commercial build out, how we're thinking about Yes. Thank you for the question. And we are very excited to talk commercial build out. We probably won't go into too many details today, but what I can describe is the goals. Right? So the goal of our launch is a very positive first experience.

As I said, the first opportunity for Bettina to get her name out there commercially.

For Pritamidaz, a new mechanism of action to be available for aal hemaglutis patients But our goal is to ensure that [indiscernible] the patient the physician, the institution and the payer is seamless and provides the right services so that the patient can can get access to the treatment that they So that's really what our focus is. What that means is, as we move from top line data to launch, we'll be preparing for a lot of marked education, lot of ensuring that the mechanism is known in the marketplace then as we get our label and as we get approved, we'll move on into actually providing the brand identity for for our opportunity in this space. Really excited about building all that and really excited about that, getting more updates as we get past top line.

I now turn the call over to Gene Kinney for closing remarks.

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

Ladies and gentlemen, that concludes today's call. Thank you all for joining.