Prothena Corporation plc (PRTA) Q4 2024 Earnings Report, Transcript and Summary

Good day, ladies and gentlemen, and welcome to the Prothena Biosciences Fourth Quarter and Full Year 2024 Financial Results Conference Call. My name is Pam, and I will be your coordinator for today. [Operator Instructions] I would now like to turn the call over to Mark Johnson, Vice President at Prothena. Please proceed.

Thank you. Good afternoon, everyone, and welcome to today's call to review Prothena's business progress fourth quarter and full-year 2024 financial results and 2025 financial guidance. Please review the press release we issued earlier today, which is available on our website at prothena.com and is also attached to a Form 8-K filed today with the SEC. In addition, we are using supplemental slides, which are available on the Events and Presentations 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 Prothena'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. Tran 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 Gene 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 5. Our mission at Prothena 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 have created a robust portfolio of therapeutic drug candidates targeting both neurodegenerative and rare peripheral amyloid diseases as shown on Slide 6. 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 Prothena. 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 7. Our wholly-owned clinical programs are nearing significant inflection points in 2025, setting up a transformational year for Prothena. Birtamimab 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 3 VITAL trial enabled us to receive a special protocol assessment or SPA agreement with the FDA, confirm these results in our ongoing Phase 3 AFFIRM-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. Birtamimab represents a very attractive potential multi-billion dollar global commercial opportunity. This is a rare disease patient population primarily treated by hematologists in amyloidosis specialty centers for which the ongoing birtamimab program is designed to address the significant unmet need of early mortality. In addition, our Alzheimer's disease portfolio, PRX012 and PRX123 includes unique programs designed to address the unmet needs of the millions of pre-symptomatic and early symptomatic AD patients and their families. PRX012 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 1 ASCENT clinical trials evaluating PRX012 in early Alzheimer's patients with additional data updates throughout the year. Chad will describe the trial and readout in more detail later in his presentation. In addition, our PRX123 dual anti-A-beta and anti-tau 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 8. 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 Prothena. Prasinezumab is being investigated as a potential treatment for early Parkinson's disease. And our partner Roche announced topline results from the Phase 2b PADOVA study in December of 2024. The PADOVA Phase 2b trial evaluated 586 people with early Parkinson's for a minimum of 18 months while on stable symptomatic treatment. In the study, prasinezumab showed a potential clinical effect in the primary endpoint of time to confirmed motive 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 co-variant adjusted analysis of these endpoints, the effects were even more pronounced and all nominally statistically significant. Consistent with positive trends across multiple secondary and exploratory endpoints were also observed and prasinezumab continued to be well-tolerated. The Phase 2b PADOVA results, along with prior clinical study results, support 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 2 PASADENA and the Phase 2b PADOVA trial. Roche will continue to evaluate the data and work together with health authorities to determine next steps. Moving on to coramitug, an anti-amyloid antibody for the potential treatment of ATTR amyloidosis with cardiomyopathy or ATTR-CM, Novo Nordisk is currently conducting a Phase 2 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 coramitug, 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 within the microtubule binding region or MTBR of tau. In 2024, BMS initiated the 475 patient TargetTau-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 in the clinical dementia rating scale sum of boxes 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 PRX019, which included a payment of $80 million. As part of the agreement, Prothena has initiated a Phase 1 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 Prothena and our strategic partners. To discuss our wholly-owned clinical programs in further detail, I will now turn the call over to Chad. Chad?

Thanks, Gene. I'd like to start my discussion with a review of birtamimab, our anti-amyloid treatment for AL amyloidosis. We are nearing the completion of our confirmatory Phase 3 AFFIRM-AL clinical trial. The trial is being conducted with a primary endpoint of time to all-cause mortality, but 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 organ. 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 amyloid deposits which cause organ damage, dysfunction and failure and can lead to early mortality. Birtamimab Is specifically designed to directly target misfolded light chains, both neutralize toxic soluble light chain aggregates and clear insoluble amyloid deposits in vital organs such as the heart. Birtamimab, with its differentiated anti-amyloid mechanism speaks 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 3 AFFIRM-AL trial. In the approximately 30% of the AL amyloidosis patients who were categorized as Mayo Stage 4 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 nine 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 six-minute walk test distance and SF36 physical component summary score. And birtamimab has been well-tolerated with a favorable safety profile across multiple clinical trials. In VITAL and in the ongoing AFFIRM-AL trial, we compared in birtamimab 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 AFFIRM-AL trials, standard-of-care comprised of Bortezomib and often include Cyclophosphamide and Dexamethazone, the combination referred to as CyBorD 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 AFFIRM-AL trial. This slide, which was adapted from a presentation at ASH in December 2024 on the Phase 3 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, birtamimab's differentiated mechanism is specifically designed to address directly the disease pathology, 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 birtamimab. The prior survival data from our Phase 3 VITAL trial enabled us to receive a SPA agreement with the FDA to confirm these results in our ongoing Phase 3 AFFIRM-AL 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 2:1 on birtamimab for 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 PRX012 on Slide 14. PRX012 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. PRX012 is a humanized IgG1 monoclonal antibody designed to have highly potent binding with high affinity and avidity, 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 PRX012 in the clinic, and now let's turn to Slide 15. ASCENT-2 is our double-blind placebo-controlled multiple-dose clinical trial evaluating PRX012 in people with early Alzheimer's disease. Each cohort is randomized 3:1 to receive PRX012 or placebo once monthly for six months. The objectives of the trial are twofold. First is to evaluate the safety, tolerability, and immunogenicity of PRX012 in patients with early Alzheimer's disease. And the second is to characterize the pharmacokinetics and the pharmacodynamics of PRX012 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 A cohorts 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 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 12 and 18 months at various dose levels from our ongoing ASCENT-3 open-label extension study. Let's move to Slide 16 to review our PRX123 program. PRX123 targets key epitopes within the end terminus of A-beta 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 treatments targeting the mid-region of TAU, which showed some early signals of activity. In particular, in a very small number of participants, these ICE 2814 antibody, which also targets areas within the MTBR region, showed positive effects of biomarkers, including MTBR tau-243, tau PET, and p-tau-217, which has been associated with clinical efficacy. In addition, our partner, Bristol Meyers Squibb has advanced BMS 986446, formerly known as PRX005, an anti-MTBR tau antibody into a robust Phase-2 trial signaling their confidence in the targets. 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 program.

Thanks, Chad. Moving to Slide 18, we are focused on building out our commercial capabilities to support birtamimab 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 3 results for birtamimab, we expect to launch in the U.S. 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 AL amyloidosis 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 IV, we believe the diagnosed and treated population of Mayo Stage IV 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 IV AL amyloidos 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 to date, we expect very high peak penetration Mayo Stage IV patients if approved. And third, this is a rare disease patient population with a targeted call point for hematologists with support from specialized cardiologists, 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 birtamimab, 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 exclusive in the United States and 10 years or more of market exclusive in Europe. Moving to Slide 19. Market dynamics for birtamimab as our first potential commercial product are quite compelling. Our plan is to independently commercialize birtamimab 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 experts in the field through our extensive clinical programs for birtamimab. We will continue to collaborate with these KOLs in the broader AL amyloidosis community to ensure they are fully aware of and informed on the unique role of the anti-amyloid like birtamimab. This includes continuing to present our data at top medical congresses and publications in peer-reviewed journals. These ongoing educational efforts are important to further solidify birtamimab's position as a potential new standard of care and to appropriately incorporate birtamimab into treatment guidelines. Let's wrap up on birtamimab by reiterating a few key points. First, with positive confirmatory Phase 3 results, birtamimab has the potential to be the first anti-amyloid therapy for AL amyloidosis and birtamimab-based regimen will be positioned as first-line therapy, becoming the new standard of care for patients at risk of mortality. Second, birtamimab would be the only AL amyloidosis therapy to demonstrate early survival benefit in double-blind placebo-controlled clinical trials. And third, we expect birtamimab to be a multi-billion dollar global market opportunity at peak. Moving to Slide 20. As we've discussed, birtamimab is the perfect opportunity for Prothena 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, PRX012 and PRX123 is very compelling. These programs may enable us to address some very large and underserved markets. Comprised of the millions of presymptomatic and early symptomatic Alzheimer's disease patients and their families whose needs are not fully met or addressed with today's treatment options. PRX012 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 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 AD segments. And now, I'd like to turn the call over to Tran for a 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 PRX019. 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 million to $160 million. Net loss was $122.3 million, which is at the low end of our guidance range of $120 million to $135 million. As of December 31, 2024, Prothena 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, Prothena 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 million and $175 million. We expect to end the year with approximately $301 million 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 million 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, Tran. Moving to Slide 25. I'd like to acknowledge and thank the patients, their families, physicians, and study-side 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 Prothenians 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 are excited to announce top-line results from our confirmatory Phase 3 AFFIRM-AL trial evaluating birtamimab in patients with Mayo Stage IV AL amyloidosis. Clinical results from our Phase 1 ASCENT trials evaluating PRX12 as a potential best-in-class treatment in early Alzheimer's disease. Completion and results from Novo's Phase 2 signal detection trial evaluating Coramitug for the treatment of ATTR-CM. In addition, we look forward to sharing further clinical development updates for PRX123, Prasinezumab, BMS-986446, and PRX019. 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&A. Operator.

[Operator Instructions] And your first question comes from Yasmeen Rahimi with Piper Sandler. Please go ahead.

Hi, this is Emma on for Yas. I have two from us on birtamimab. Firstly, what is considered the best - the base and best case scenario into the Phase 3 AFFIRM-AL, both on the primary endpoint as well as key secondary? And then with that, how are you thinking about more in detail about the market opportunity in AL amyloidosis, like digging into the commercialization within the therapeutic landscape, especially given the concentrated prescriber base and all those things you've talked about? So any additional color on 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 amyloidosis today target plasma cells. Obviously, birtamimab is fundamentally different in that regard, and that it targets the amyloid directly. And of course, what is lacking in the current treatments and Chad exemplified this in his discussion around daratumumab with the enrollment 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 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 IV 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, 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 opportunity. Brandon?

Thank you. Maybe just to orient you to something in our earnings presentation 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. And it's a rare disease with a consolidated call point. But importantly, what we've learned in our conversations with OLs and our market research is that an anti-amyloid therapy designed to directly clear amyloid from the heart and other vital order 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 birtamimab opportunity is well over a blockbuster opportunity in the U.S. alone and a multi-billion dollar opportunity globally. I honestly really looking forward to planning for and executing on the launch in the second half of 2026.

Your next question comes from the line of Jay Olson 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 AFFIRM-AL, especially with regards to the utilization of daratumumab? And then also what would be a clinically meaningful OS benefit for birtamimab to demonstrate in AFFIRM-AL? Thank you.

Yes, thanks for the question, Jay. 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 AFFIRM-AL trial is the focus on patients in Mayo Stage IV. Obviously, those are the patients at highest risk of early mortality and given that significant unmet medical need in that patient population, that's obviously where we've chosen to focus the AFFIRM-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 dara, which obviously has become much more widely used in terms of the plasma cell targeting agents in this space. And that as 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 is probably not all that surprising 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, that those would be the patients at highest-risk of really mortality and where that unmet medical need continues to live. So we're excited about the opportunity for birtamimab 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, 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 4 subjects, obviously by design, right? We were deciding the study to recapitulate The results we saw in that Stage 4 population in VITAL. With respect to daratumumab, as you may know, daratumumab is able to be used in this study in AFFIRM-AL at randomization, and in fact, it turns out that about 80% or so of the subjects who are participating in the study are on daratumumab. And I think - I'll just maybe end by echoing, you know, with respect to success again to us, success really means a p-value of 0.1 or less per the agreement with FDA in this file.

Your next question comes from Umer Raffat 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 2 PRONTO in previously treated as well as for Phase 3 VITAL? And I understand there's no active arm going on, but I'm curious about the mortality trends. Second, for the Stage 4 analysis from VITAL, there were a lot of treatment emergent deaths - treatment emergent - TEAE 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 3 at baseline? Thank you very much.

Yes, 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 - 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 birtamimab. 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 are as we've described them in the past, so the Mayo Stage IV patients in particular, you have a hazard ratio of 0.413 across the first nine months representing just - something just shy of 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. Thanks, Gene. So with respect to the treatment-emergent question, so essentially, we were looking at all-cause mortality in that study. So essentially all tests are counted. They're all matter in the analysis.

Yes.

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 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 assume that any statistic 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 death, 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? Thanks.

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 real - 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 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 SPA agreement where the p-value would be less than 0.10 would be very meaningful for this patient population, 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 and specifically our conversations with payers and with KOLs 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 VITAL did and as we're trying to confirm to 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 therapy.

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

Hi. Thanks for taking the question and congrats on the progress. I guess I want to switch gears and just ask one on PRX012. 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.

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 publicly. So just a reminder, I mean in this space, particularly as we talk about the anti-beta 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 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 long-term treatment throughout the disease course, and that's why PRX012 is designed with the idea of a once 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.

Yes. 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 5A cohorts in the ASCENT-2 multiple-dose trial. This represents about 225 participants, all that are either APOE4 are non-carriers or APOE4 heterozygitis patients with early Alzheimer's. Additional data readouts throughout the year could include data from the 3 B cohorts that have the APOE4 homozygous carriers 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 the objectives evaluating the safety, tolerability immunogenicity of PRX012 in-patients with early Alzheimer's and second, to evaluate the pharmacokinetics and pharmacodynamics, really to find 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 let burden in the home represents and addresses a significant unmet need for people living with Alzheimer's MFA.

Your next question comes from Michael Yee with Jefferies. Please go ahead.

Hi guys, thanks for the questions. Question on the Phase-3 AL amyloidosis study. When you comment around your view that dara is not impacting this 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 dara arm there, I just wanted to understand your expectations as it relates to how you powered the study and what you assume your control arm did given the fact that the study has 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 012, 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 amyloid reduction? And how should we think about what is good in that result that comes out? Thank you.

Yes. Thanks, Mike. Good questions there. Let me start with your question about ANDROMEDA and data and the control arm. And I'll ask Chad to speak about this as well because I think it also fits into just 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, we do expect the control arm to behave in a 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, having monthly access to the world's expert treaters in this space, we think it's very reasonable to see a control medium 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 a mortality event rate 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 ANDROMEDA study is that the inclusion of daratumumab 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 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 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.

Yes, thank you, Gene. So I think Gene actually summarized that quite well, right? So as we've designed a firm based upon the results that we saw in VITAL - Stage IV patients in VITAL. And what I can maybe add here is that - and actually not so much and I think Gene alluded to that is that when we look at the timing events in the firm so far, obviously in a blinded way, the timing events and the nature of those events, they are actually quite similar to what we observed in the VITAL study. So the timing of these looks to be aligned in suggesting that 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 medium survival in the VITAL study was 8.3 months, and so daratumumab certainly over the first 15 months or so did not have an impact on survival, so we feel that again those things combined sort of suggest that there - our control arm should be behaving similarly in the AFFIRM as it was in VITAL.

Your next question comes from Rudy Li from Chardan. Please go ahead.

Hi, thanks for taking my question. So for birtamimab, just a quick follow-up on treatment landscape. How many patients are actively treated with current standard of care and did you notice any changes in the market dynamics since J&Js Dara was approved in 2021? And secondly, for PRX012 in ASCENT-2, can you maybe talk about the rationale for the 200 milligram expansion cohort with roughly 100 patients? Any color would be helpful. Thanks.

Okay, great. So yes, let's talk - and it's a great question because actually as we talked 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 Chad, you can address the extra question?

Sure, happy to. And in - so 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. On your question on whether or not that is increased since Dara was approved back in 2021? The answer is yes. I think the number we used then was 50. So it has increased, but this is a disease once identified we rapidly treat and they rapidly move them into trying to make sure that whatever they can to affect the hematologic response, which as Gene 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 diagnosed, not an extrapolated prevalence number.

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 patients' 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 APOE 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 dataset actually to help better characterize PRX012. So it kind of is an opportunistic approach due 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 IV 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 IV patients in the label or could it expand to less severe patients? Thanks.

Yes, thanks, Tazeen, 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 - 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 we get newly diagnosed patients that those would then move into that bucket of diagnosed and treated. In terms of what it takes to initially launch and commercialize, again, we're - this will be Prothena's first launch, this will be our first entry in the marketplace and it does take time to get into the contracting, get through and make physicians aware of the new treatment option. So our launch revision certainly is to get to a multi-billion dollar opportunity. But in the near term, it will take time in order to get that update.

And I think one of the - Brandon has mentioned this, 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 diagnosed.

We only have time for one more question, and that is from Brian Abrahams of RBC Capital Markets. Please go ahead.

Hi, guys. Thanks for taking my question and congrats on the continued pipeline progress. I'm 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 the bar for European regulators would be similar to what the U.S. has put forth. Thanks.

Yes. Thanks, Brain, great questions. Let me start with the latter part of your question. And then I'll ask Brandon to talk a little bit about the build out. I think in terms of Europe any other geography for that matter. Obviously, the medical need is the 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 is 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 an early mortality event. 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 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 buildup, how we're thinking of that.

Yes. Thank you for the question. And 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 goals, right. So the goal of our launch is a very positive first experience. As I said, it is the first opportunity for Prothena to get our name out there commercially for birtamimab as a mechanism of action to be available for AL amyloidosis patients, but our goal is to ensure that from the patient, the physician, the institution and the payer is seamless and provide the right services so that the patient can get access to the treatment that they need. 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 of that and really excited about that, giving more updates as we get past top-line data.

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 programs.

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