Good day, ladies and gentlemen, and welcome to the Proutina Biosciences 4th Quarter and Full Year 2024 Financial Results Conference Call. My name is Pam, and I will be your coordinator for today. At this time, all participants are in listen-only mode. We will be facilitating a question-and-answer session towards the end of today's call.

If at any time during the call you require assistance, please press star followed by zero and a coordinator will be happy to assist you i would now like to turn the call over to mark johnson vice president at prosina please proceed thank you good afternoon everyone and welcome to today's call to review prosina's business progress fourth quarter and full year 2024 financial results in 2025 financial guidance please review the press release we issued earlier today which is available on our website at prosina.com and is also attached to a form 8k file today with the SEC. In addition, we are using supplemental slides, which are available on the event and presentation section of our investor relations website. On today's call, Dr. Gene Kinney, our president and chief executive officer, will provide opening remarks, including an overview of Protena's corporate 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. Ron Nguyen, our Chief Financial Officer and Chief Strategy Officer, will then discuss our 2024 financial results and 2025 financial guidance before turning it back to Jean for closing remarks, at which point we will open up the call for a 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 forward-looking statements. For a discussion of the risks and uncertainties associated with our forward-looking statements, please see our press release issued today, as well as our most recent filings with the SEC. We disclaim any obligation to update our forward-looking statements. With that, I'd like to turn the call over to Gene.

Thank you, Mark, and thank you all for joining us today. Let's begin on slide five. Our mission at Prathina is to create transformational therapies 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 Prothenians every day. As a result of our commitment to our mission, we've created a robust portfolio of therapeutic drug candidates targeting both neurodegenerative and rare peripheral amyloid diseases, as shown on slide 5. 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 Prathena. 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 a transformational year for Prathena. Fertamumab 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 SPA agreement with the FDA to confirm these results in our ongoing Phase III AFIRM-AL trial at an unprecedented statistical significance level of 0.10. 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 2026. Patamumab represents a very attractive potential multibillion-dollar global commercial opportunity. This is a rare disease patient population primarily treated by hematologists in amyloidosis specialty centers for which the ongoing Bertamumab program is designed to address the significant unmet need of early mortality. In addition, our Alzheimer's disease portfolio, PRX-12 and PRX-123, includes unique programs designed to address the unmet need of the millions of pre-symptomatic and early symptomatic AD patients and their families. PRX-12 is our anti-A-beta 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 2025, we expect to announce initial results from our ongoing Phase I Ascent clinical trials evaluating PRX-12 in early Alzheimer's patients with additional data updates throughout the year. Chad will describe the trial and read out in more detail later in his presentation. In addition, our PRX-123 dual anti-A-beta and anti-cal vaccine has been granted fast-track designation and has an IND cleared by the FDA. Chad 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 to patients and create long-term value for Prathina. 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 2024. The PDOVA Phase 2B trial evaluated 586 people with early Parkinson's for a minimum of 18 months while on stable symptomatic treatment. In the study, presinezumab showed a potential clinical effect in the primary endpoint of time-to-confirmed mode of progression with a hazard ratio of 0.84 and narrowly missed statistical significance with a p-value of 0.0657. The effect of prasinezumab was more pronounced in a pre-specified analysis than the approximately 75% 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, and prastinezumab continued to be well tolerated. The Phase IIb Padova results, along with prior clinical study results, support further clinical development of pracinezumab as a potential first-in-class disease-modifying treatment for patients with Parkinson's disease. Roche is continuing to evaluate the effects of pracinezumab in open-label extension studies from both the Phase II Pasadena and the Phase IIb Padova trials. Roche will continue to evaluate the data and work together with health authorities to determine next steps. Moving on to keramatog, an anti-amyloid antibody for the potential treatment of ATTR amyloid doses with cardiomyopathy, or ATTR-CM. Novo Nordisk is currently conducting a Phase II signal detection trial in approximately 99 patients with ATTR-CM. The trial should complete in the first half of 2025, and we expect Novo to announce results and potential next steps in the second half of 2025. We look forward to future updates from Novo, including potential further clinical development of parambitone, 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 986446, formerly PRX005, is a potential best-in-class antibody for the treatment of Alzheimer's disease that specifically targets a key epitope. and within the microtubule binding region, or MTBR, of tau. In 2024, BMS initiated the 475-patient target tau 1 phase 2 trial. The trial is evaluating placebo versus low and high doses of BMS 986446 in patients with early Alzheimer's disease. The primary endpoint of change from baseline and the clinical dementia rating scales from a box score at 18 months. Enrollment is ongoing, and the trial is expected to complete in 2027. Also in 2024, BMS opted into a global license agreement for PRX-19, which included a payment of $80 million. As part of the agreement, Prithena has initiated a Phase I 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 Prathina 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 Batamib, our anti-amyloid treatment for AL amyloidosis. We are nearing the completion of our confirmatory Phase III Affirm AL clinical trial. The trial is being conducted with a primary endpoint of time to all-cause mortality, the statistical significance and success is defined at a p-value equal to or less than 0.1 under a SPA agreement with the FDA. Let's start by discussing the disease biology of AL amyloidosis and where the unmet need is with the current standard of care. There are three hallmarks of AL amyloidosis. The first is production of misfolded light chain proteins. The second is formation of toxic-soluble aggregates, and the third is accumulation of insoluble amyloid deposits in the organs. Current standard of care consists of plasma cell-directed therapies, which may decrease the production of misfolded light chains, but do not address the toxic, soluble light chain aggregates and insoluble amyloid deposits, which cause organ damage, dysfunction, and failure, and can lead to early mortality. Vitamumab is specifically designed to directly target misfolded light chains, both neutralized toxic-soluble light chain aggregates and clear insoluble amyloid deposits in vital organs, such as the heart. Vitamumab, with its differentiated anti-amyloid mechanism, takes to address the urgent unmet medical need for AL amyloidosis patients who are 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 a p-value equal to or less than 0.1 for our ongoing confirmatory Phase III Affirm AL trial. In the approximately 30% of the AL amyloidosis patients who were categorized as Mayo Stage IV at baseline in VITAL, we observed the impressive survival benefit shown on this slide. The Kaplan-Meier curve shows early separation, resulting in a 59% risk reduction of all-cause mortality at month 9 with a nominal p-value of 0.021. This was further supported by clinically meaningful and nominally significant effects on function as measured by the 6-minute walk test distance in SF36 physical component summary score. And bertamumab has been well-tolerated with a favorable safety profile across multiple clinical trials. In VITAL and in the ongoing AFIRM-AL trial, we compared bertamumab in combination with current standard of care versus placebo with current standard of care. Moving on to slide 12, recently presented data from the Andromeda study demonstrates a significant need for a therapy that clears amyloid and addresses early mortality. For the vital and affirmed AL trial, standard of care comprise of bortezomib and often include cyclophosphamide and dexamethasone, the combination referred to as CYBUR-D or VCD. 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 affirmed AL trial. This slide, which was adapted from a presentation at ASH in December 2024 on the Phase III Andromeda study clearly shows that the survival curves comparing the addition of daratumumab with VCD to VCD alone do not separate until after approximately 15 months. This suggests that the addition of daratumumab to this regimen in AL amyloidosis patients does not have an impact on early mortality. However, retamumab's differentiated mechanism is specifically designed to address directly the disease pathology to potentially reduce 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 Bertamomab. 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 III AffirmAL trial, again, where 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-to-one on botamumab plus standard of care versus placebo plus standard of care. We expect to announce results in the second quarter of 2025. Now, let's review our Alzheimer's portfolio, starting with PRX12 on slide 14. PRX12 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-12 is a humanized IgG1 monoclonal antibody designed to have highly potent bindings with high affinity and avidity and a slow off rate allowing for consistent target engagements, all of which are optimal for a once-monthly subcutaneous treatment. We look forward to further confirming the potential of PRX-12 in the clinic. And now let's turn to slide 15. Ascent 2 is our double-blind, placebo-controlled, multiple-dose clinical trial evaluating PRX-12 in people with early Alzheimer's disease. Each cohort is randomized three to one to receive PRX-12 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-12 in patients with early Alzheimer's disease. And the second is to characterize the pharmacokinetics and the pharmacodynamics of PRS-12 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 5A cohort shown here. This represents approximately 225 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 3D cohorts which enrolled approximately 36 participants and who are all APOE homozygous barriers, and longitudinal data for some patients who have been on treatment for upwards of 12 and 18 months at various dose levels from our ongoing ASCENT III open label extension studies. Let's move to slide 16 to review our PRX123 program. TRS-123 targets key epitopes within the end terminus of A-beta and the MCBR region of tau designed to promote abloid clearance and block the cell-to-cell transmission of pathogenic tau. New data was presented at CPAD in 2024 on potential treatments targeting the mid-region of tau, which showed some early signals of activity. In particular, in a very small number of participants, These IC2814 antibodies, which also targets areas within the MTBR region, should positive effects on biomarkers, including MTBR-TAU243, TALPET, and T-TAU217, which has been associated with clinical efficacy. In addition, our partner, Rysselmeyer-Squibb, has advanced BMS 986446, formerly known as PRX005, an anti-MTBR TAL antibody, into a robust phase 2 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 later this year. I'll now turn it over to Brandon to discuss the commercial potential for our wholly owned Thanks, Chad.

Moving to slide 18, we are focused on building out our commercial capabilities to support BRUTAMIMAB as our first potential commercial product. While the standard of care has evolved, there continues to be significant unmet need in the treatment of AL amyloidosis 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 BRUTAMIMAB, we expect to launch in the US by the second half of 2026. 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 16 000 diagnosed and treated alambidosis patients in the united states with the vast majority approximately 13 000 having cardiac involvement the segment with the highest risk for early mortality market size is similar across the five major European markets at approximately 15,000 patients with AL amyloidosis with cardiac involvement. Given upwards of 30% of all AL amyloidosis patients are Mayo Stage 4, we believe the diagnosed and treated population of Mayo Stage 4 patients is close to 5,000 patients in the U.S. and over 5,000 patients in the major European markets. Globally, we estimate there are over 20,000 diagnosed patients with Mayo Stage 4 AL amyloidosis across the major markets, including the united states europe china brazil and japan second with the significant unmet need for treatment options that address early mortality and the observed favorable safety profile today we expect very high peak penetration mayo stage 4 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 prescriber base. And most patients in the U.S. and Europe are treated at amyloidosis centers of excellence, amyloidosis 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 and hospitals. As a reminder, with pertamib, we have a SPA agreement with the FDA, fast-track designation from the FDA, and orphan drug designation from both the FDA and EMA. With regulatory and IP positioning, we expect 12 years or more of market-exclusivity in the United States and 10 years or more of market-exclusivity in Europe. Moving to slide 19. The market dynamics for Bertamumab as our first potential commercial products are quite compelling. Our plan is to independently commercialize Bertamumab in the U.S. and continue to evaluate launch time 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 experts in the field through our extensive clinical programs for pertamymeth. We will continue to collaborate with these KOLs and the broader AL amyloidosis community to ensure they are fully aware of and informed on the unique role of the anti-amyloid-like pertamymeth. This includes continuing to present our data at top medical congresses and publications in peer review journals. These ongoing educational efforts are important to further solidify bertamimab's position as a potential new standard of care and to appropriately incorporate bertamimab into treatment guidelines. Let's wrap up on bertamimab by reiterating a few key points. First, with positive confirmatory phase 3 results, bertamimab has the potential to be the first anti-amyloid therapy for AL amyloidosis, and a vertamimab-based regimen will be positioned as first-line therapy, becoming the new standard of care for patients at risk of mortality. Second, vertamimab would be the only AL amyloidosis therapy to demonstrate early survival benefit in double-blind, placebo-controlled clinical trials. And third, we expect vertamimab to be a multi-billion-dollar global market opportunity at peace. Moving to slide 20. As we've discussed, for TamMav is the perfect opportunity for Prathina to transition to a fully integrated commercial biotechnology company. We 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-12 and PRX-123, is very compelling. These programs may enable us to address a 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. PRX12 as a potential once-monthly subcutaneous anti-A beta treatment option would be well positioned for the early AD market and some portions of the pre-symptomatic market population if approved. PRX123 is designed as both a potential prevention and treatment option with a vaccine approach. This opens up the full pre-symptomatic Alzheimer's market, as well as some of the early symptomatic AD segments. And now, I'd like to turn the call over to Tron for discussion on our 2024 financial performance and our 2025 financial guidance.

Thanks, Brandon. 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 million payment from BMS where they obtained the exclusive global license for PRX-19. In terms of our 2024 financial performance relative to guidance, we had net cash used in operating and investing activities of $150.3 million, which is at the low end of our guidance range of $148 to $160 million. dollars. Net loss was $122.3 million, which is at the low end of our guidance range of $120 to $135 million. As of December 31st, 2024, Presena had $472.2 million in cash, cash equivalents, and restricted cash, which is in line with our guidance of $468 million. As of February 20, 2025, Presina had approximately 53.8 million 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 million. We expect to end the year with approximately $301 million in cash, cash equivalent, 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 $205 million, which includes an estimated $41 million 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 the potential impact of the new medicines we're developing. I'd also like to thank our talented proscenians 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 programs, as well as continued clinical readouts and development from our strategically partnered programs. Looking ahead, we're excited to announce top-line results from our confirmatory Phase III AFIRM-AL trial evaluating Birtamumab in patients with Mayo Stage IV AL amyloidosis. Clinical results from our Phase I ASCENT trials evaluating PRX-12 as a potential best-in-class treatment in early Alzheimer's disease. Completion and results from NOVO's Phase II signal detection trial evaluating Karamatag for the treatment of ATTR-CM. In addition, we look forward to sharing further clinical development updates for PRX-123 racinezumab, BMS 986446, and PRX19. I'm proud of Perthena'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&A. Operator?

Thank you. We will now begin the question and answer session. If you have dialed in and would like to ask a question, please press star 1 on your telephone keypad to raise your hand and join the queue. If you would like to withdraw your question, simply press star 1 again. If you are called upon to ask a question and are listening via loudspeaker on your device, please pick up your handset and ensure that your phone is not on mute when asking your question. And your first question comes from Yasmin Rahimi with Piper Sandler. please go ahead.

Hi, this is Emma on for Yaz. I have two from us on Bertanumab. Firstly, what is considered the best, the base and best case scenario into the phase three Affirm 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-MOA doses, like digging into the commercialization within the therapeutic landscape, especially given the concentrated prescriber base and all those things you talked about. So any additional color in that would be super helpful. Thank you.

Great. Hi, Emma. Thanks for the questions. So first, just in terms of expectations around the primary endpoint, let me start again by reiterating the significant unmet need here. So as I'm sure you know, all of the current treatments used in AL-enloidosis today target plasma cells. Obviously, brtamimab is fundamentally different in that regard, in that it targets the amyloid directly. And of course, what is lacking in the current treatment, and Chad exemplified this in his discussion around ferritumumab with the Andromeda 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 of treatments available to these patients, and, you know, really represents the opportunity for Birtamumab 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 MAAS-H4 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 0.10, we really think being able to demonstrate that kind of survival benefit would represent a best case for us. And so that said, you know, maybe I can ask Brandon to talk a little bit more about the market opportunity and how that potential to address that unmet medical need then translates into the excitement that we have around the market opportunities, Brandon.

Thanks, Gene. And maybe just to orient you to help you get an organization on slide 18. 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 immediately treated upon diagnosis. It's a rare disease with a consolidated call point. And importantly, what we've learned in our conversations with OLs and intermarket research is that an anti-amyloid therapy designed to directly clear amyloids from the heart and other vital organs and that demonstrates that early survival benefit with a favorable safety profile is a very strong update, especially in those patients at high risk of early mortality. So as I said in the presentation, at peak, the pertainment of opportunity is well over for a blockbuster opportunity in the U.S. and a multi-billion dollar opportunity. Honestly, really looking forward to planning for and executing on the launch in the second half of 2022.

Your next question comes from the line of Jay Olsen from Oppenheimer. And also, please be reminded that each analyst is only allowed one question. Thank you.

Oh, hey, congrats on all the progress and thanks for taking the question. Can you talk about the baseline characteristics of the patients enrolled in AFIRM-AL, especially with regards to the utilization of daratumumab? And then also, what would be a clinically meaningful OS benefit for britamumab to demonstrate in AFIRM-AL?

Yeah, thanks for the question, Jay. And I'll let Chad speak to some of the baseline characteristics. One of the obvious things, you know, that I can point to as we think about, you know, the former VITAL trial and now the AFIRM-AL trial is the focus on patients in Mayo Stage 4. Obviously, those are the patients at highest risk of early mortality. And, you know, given that significant unmet medical need in that patient population, That's obviously where we've chosen to focus the AFIRM-AL trial, that in addition to the two-to-one randomization that we're using in the AFIRM-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 daratumumab brings along with it, what we're finding, and 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 survival across the first 15 months of that Andromeda trial. And of course, those would be the patients at highest risk of early mortality and where that unmet medical needs that continues to live. So we're excited about the opportunity for recalumab in that space. But let me pass it over to Chad here. Maybe you can talk a little bit more about the baseline characteristics. Yeah, thanks, Gene.

Thanks for the question. So the baseline characteristics in a firm are actually quite similar to those that we saw in the vital stage four subjects, obviously by design, right? we were finding the study to to recapitulate the results we saw in that stage four population in vital with respect to daratumumab um as you may know daratumumab is able to be used in this study in the firm al um at randomization and in fact it turns out that about 80 or so of the subjects who are um participating in the study are on daratumumab um and i think i'll just maybe end by echoing And, you know, with respect to success, again, you know, to us, success really means a value of 0.1 or less, you know, per the agreement with FDA in this class.

Your next question comes from Umar Rassat 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 mortality trends beyond the 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'm just curious about the mortality trends. Second, for the stage four analysis from vital, there were a lot of treatment emergent deaths, treatment emergent TEA deaths 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.

Yeah, thank you 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, you know, 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 pertamomab. Of course, PRONTO was a patient population that had previously received chemotherapy or plasma-directed therapy, and those patients were considered hematologically stable coming into the study, but still had ongoing organ dysfunction. In vital, of course, the results or as we've described them in the past. So the Mayo Stage 4 patients in particular, you have a hazard ratio of .413 across the first nine months representing just something just shy of a 60% 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.

So with respect to the treatment of urgent deaths question, so essentially, we were looking at all cause mortality in that study. So essentially, all deaths are counted. They all matter in the analysis.

Your next question comes from the line of Charles C. Duncan with Cantor Fitzgerald. Please go ahead.

Thank you. Gene and team, congrats on a good year of progress. looking forward to a lot of news 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 assume that any statistic difference is important to patients, but I'm I'm kind of wondering if Brandon has any thoughts with regard to demand for the drug going forward, if there was, you know, call it a minimum effect size in terms of time to death, but statistically significant versus a much larger, has there been any work that has, you know, gone to KOLs that suggests that there might be difference in interest in using the drug. Thanks.

Yeah, 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 medical need for which there 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 SPA agreement, where the p-value would be less than 0.10, 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 into marketing.

Yeah, thank you for the question. Yes, our market research, specifically our conversation with payers and with OLS, 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, that 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 Vidal did, and as we're trying to confirm through our firm, will be very meaningful to physicians, their patients, and even to payers, because they do fully realize that there is nothing that helps these patients. And 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 this.

Your next question comes from Jason Butler with Citizens JMP. Please go ahead.

Thanks for taking the question. Congrats on the progress. I guess I want to switch gears and just ask one on PRX12. Can you maybe talk 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.

Yeah, 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 publicly. 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 you know 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 the 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 pretty significantly important with respect to commercial uptake of these approaches. Obviously, very important as patients are diagnosed with a 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 PRX-12 is designed with the idea of a once-a-monthly subcutaneous at-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.

Yeah, thank you, Gene. And so just kind of building on what Chad presented earlier, looking at slide 15 as 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 five A cohorts in the Ascent 2 multiple-dose trial. This represents about 225 participants, all that are either APOE4 non-carriers or APOE4 heterozygous patients with early Alzheimer's. Additional data readouts throughout the year could include data from the 3B cohorts that have the APOE-4 homozygous carrier, as well as longitudinal data for some patients who have been on treatment for as long as 12 or 18 months at various dose levels from the ongoing Ascent 3. And really just building on what we're looking for for the objectives, you know, evaluating the safety, tolerability, immunogenicity of PRS-12 in patients with early Alzheimer's. And second, to evaluate the pharmacokinetics and pharmacodynamics, really to find that optimal dose regimen for a 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 Jeffrey. Please go ahead.

Hey guys, thanks for the questions. For a question on the Phase 3 ALM-Lidosis 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 the DERA arm 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 the study's been going on for a few years now, and so the curves do sort of separate over that period of time, and maybe that's an explanation for why the study's been going on for so long. The second question, if I may just sneak in one on O and two, when you do read out the data, has your expectations for what is successful change over time in terms of what you would expect on ARIA and N-load reduction, and how should we think about what is good in that result that comes out? Thank you.

Yeah. Thanks, Mike. Some good questions there. Let me start with your question about Andromeda and DERA and the control arm. And I'll ask Chad to speak about this as well, because I think it It also fits into just, you know, our expected timing around the study and how that's enrolling and how we're accruing events from a timing perspective. So to be clear, you know, we do expect the control arm to behave in a, you know, somewhat similar manner to what we observed in the VITAL trial. The vital trial, if you look at the control arm, the median survival in that arm was around 8.3 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, you know, 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 deratumumab and the Andromeda study is that the inclusion of deratumumab does not seem to have an impact on early mortality events, particularly those occurring across the first 15 months. And that's certainly evidenced by the Andromeda data that was presented at ASH last year. So we look at that and we feel like, you know, we're well aligned with what we've seen previously with VITAL. And obviously, that's also true from what we can see, both with respect to the events that are occurring, whether it be from a timing perspective or a quality perspective.

But maybe let me hand it over to Chad, and he can speak a little bit more about this, and maybe a little bit about just the overall timing of the study and how that's within our expectations right yeah thank you gene so i think i think gene actually summarized that quite well right um so as as you know we've we've um designed a firm um based upon the results that we saw in vital um the stage four patients in vital um and what i what i can maybe add here is that and actually not so much and i think i think gene alluded to this is that um when we look at the timing events in a firm so far obviously in a blinded way that the timing events and the nature of those events they're actually quite similar to what we observed in the vital study so um you know the timing of these looks to be aligned and suggesting um that our our desire to sort of replicate that study is on par um again with the dara piece of things as jean mentioned you know slide 12 clearly shows that the introduction of dara um with standard of care does not seem to have any impact on early events and um again you know gene invention our meeting survival in the vital study uh was 8.3 months and so um certainly over the first 15 months or so did not have an impact on survival so we feel that again um those things combined sort of suggest that that our control arm should be behaving similarly in the firm as it was in Biden.

Your next question comes from Rudu Lee from Chardon. Please go ahead.

Thanks for taking my question. So for Tamimab, just a quick follow-up on treatment landscape. How many patients are actually treated with current stand-up care? And did you notice any changes in the market dynamics since Gingis Darrow was approved in 2021? And secondly, for PRX-12, you can maybe talk about the rationale for the 200 milligram expansion cohort with roughly 100 patients. Any color would be helpful.

Okay, great. So, yeah, let's talk, and it's a great question because, actually, as we talk about some of these numbers, we are talking about patients that are actively being treated today. So, maybe, Brandon, do you want to talk a little bit about the numbers, and then, Chad, you can address the X-12 question? Sure, happy to.

And what we always quote in our figures is a diagnosed and treated rate. So the patients that we described in our presentation was 16,000 patients in the U.S. Your question on whether or not that has increased since DARA was approved back in 2021, the answer is yes. I think the number we used then was 15,000. So it has increased, but this is a disease once it's identify, they rapidly treat, and they rapidly move them into trying to make sure that whatever they can to affect the heathenologic response, which as Jean and Chad described, is not having an impact on early mortality. So our figures that we're quoting are the figures that we can identify from treated and diagnosed, not a extrapolated prevalence.

Right. So I'll address the second part of your question, which was about the expansion cohort. So, you know, quite frankly, we were able to be a bit opportunistic here in using that expansion cohort given patient's 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. You know, 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 equally homozygous carriers make up about 15% 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 carriers. But it also then allows for us to have a larger data set, actually, to help better characterize PRX-12. So it kind of is an opportunistic approach to randomizing those B cohorts.

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 4 AL patients, about 5,000 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 stage 4 patients in a label, or could it expand to less severe patients?

Yeah, thanks, Dadeen, for the questions. So, I'm going to ask Brandon to comment on that. Obviously, right now, we're focused on the MEA stage 4 patients.

But, yeah, maybe you can comment a little bit on just the identification of those patients. yeah so um as i i think i mentioned in my previous comment 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 um over time uh 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 that pocket of diagnosed and then treated um in terms of what it takes to initially launch and commercialized, again, where this would be protein's first launch, this would be our first entry in the marketplace. And it does take time to get into the contracting and get through and make make physicians aware of the new treatment options. So our long term vision certainly is to get to a multi billion dollar opportunity. But in the near term, we will take times in order to get that.

And I think one of the, you know, Brandon has mentioned this thing, but I think one of the key things about this disease is that as these patients are diagnosed or treated, So this is a treated disease today, and obviously, I think that's an awareness level that these physicians have as patients are coming in and getting it.

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. I'm curious if we 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 the bar for European regulators would be similar to what the U.S. has put forth.

Great question. Let me start with the latter part of your question and then I'll ask Brandon to talk a little bit about the buildout. So I think in terms of Europe or any other geography for that matter, obviously the medical need is the same um so i think you know what i can say is that that you know from a risk benefit perspective uh i think that conversation is very similar um you know as as in the u.s it is also true in europe and in other geographies which is the current treatments which are focused solely on the plasma cell targeting treatments uh do not have an impact on on these patients uh early mortality events so for those patients that are at high risk of early mortality there is a significant palpable medical need that is across all geographies and obviously we would expect productive dialogue with regulatory authorities across the 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 to Brandon he can talk a little bit about commercial build-up how we're thinking about yeah thank you for the question.

We are very excited to talk about commercial build out. We probably won't go into too many details today, but what I can describe is the goal. So the goal of our launch is a very positive first appearance. It is the first opportunity for Christina to get our name out there commercially, for the mechanism of action to be available for anal amygosis patients. And our goal is to ensure that from the patient, the physician, the institution, and the payer is seamless and provides the right services so that the patient can get access to the treatment of the patient. 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 market education, a lot of ensuring that the mechanism is known in the marketplace, And then as we get our label and as we get approved, we'll move on into actually providing the brand identity for our opportunity in this space. So I'm really excited about building all that and really excited about that and getting more updates as we get past our plans.

I now turn the call over to Gene Keeney 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 Prathina, and we look forward to sharing further updates on our program.

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