Prothena Corporation - Earnings Call - Q4 2024

Executive Summary

• Q4 2024 was a relatively quiet financial quarter ahead of multiple 2025 readouts: revenue was $2.1M, net loss was $58.0M ($1.08 per share), and quarter-end cash and restricted cash stood at $472.2M with no debt.
• 2025 cash burn guidance was set at $168–$175M with an expected year-end cash balance of ~$301M (midpoint), and estimated net loss of $197–$205M (includes ~$41M SBC), positioning the company to fund key milestones, notably birtamimab Phase 3 AFFIRM-AL topline in 2Q25 and PRX012 Phase 1 readouts starting mid-2025.
• Narrative and call tone emphasize birtamimab’s potential to address early mortality in Mayo Stage IV AL amyloidosis under an FDA SPA (success at p≤0.10) and to drive the transition to a fully integrated commercial biotech if positive; management reiterated a potential U.S. launch by 2H 2026 on success.
• Strategic updates include BMS’s $80M global license for PRX019 and the BMS-led Phase 2 TargetTau-1 for BMS-986446 (formerly PRX005); Roche’s Phase 2b PADOVA in early Parkinson’s narrowly missed the primary endpoint but showed consistent positive trends, with next steps to be determined with health authorities.

What Went Well and What Went Wrong

What Went Well

• Clear 2025 clinical catalysts: AFFIRM-AL topline (2Q25) and PRX012 Phase 1 updates starting mid-2025, with management framing 2025 as “transformative” and indicating a path to BLA submission and potential U.S. launch by 2H 2026 if AFFIRM-AL is positive at p≤0.10.
• Strengthened external validation and optionality: BMS paid $80M for PRX019 global rights; Prothena initiated a Phase 1 trial and remains eligible for up to $617.5M in milestones plus tiered royalties.
• Parkinson’s program signals (prasinezumab): despite missing the primary endpoint, PADOVA showed a hazard ratio of 0.84 (p=0.0657), stronger signals in levodopa subgroup, and consistent positive trends across secondary/exploratory endpoints, supporting continued development discussions with regulators.

Management quotes:

• “We expect 2025 to be a transformative year for Prothena... topline data next quarter from the confirmatory Phase 3 AFFIRM-AL... at a statistical significance level of 0.10” — Gene Kinney, CEO.
• “With positive Phase III results for birtamimab, we expect to launch in the U.S. by the second half of 2026” — Brandon Smith, COO.

What Went Wrong

• Minimal operating revenue and ongoing losses: Q4 revenue was $2.1M, net loss $58.0M (EPS $(1.08)); sequential and YoY results reflect a biotech profile with limited recurring revenue (excluding Q2’s one-time-heavy revenue).
• R&D intensity remains high: Q4 R&D of $50.2M (Q4 2023: $61.9M) and FY R&D of $222.5M (FY 2023: $220.6M); the full-year increase driven by higher clinical and personnel costs, underscoring continued cash utilization.
• Prasinezumab’s PADOVA missed its primary endpoint (despite positive trends); Roche must confer with health authorities regarding next steps, introducing execution/timing uncertainty for this partnered asset.

Transcript

Operator (participant)

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. 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 Prothena. Please proceed.

Mark Johnson (VP)

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.

Gene Kinney (President and CEO)

Thank you, Mark, and thank you all for joining us today. Let's begin on slide five. 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 six. Our portfolio has four wholly-owned and four partnered programs across late to mid to early stages of clinical development.

This intentional mix allows us to leverage the benefits of working with key strategic partners to rapidly advance these treatments to patients while maintaining financial upside for 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 seven, 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 III VITAL trial enabled us to receive a special protocol assessment or SPA agreement with the FDA, confirmed these results in our ongoing phase III 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 I ASCENT clinical trials, evaluating PRX012 in early Alzheimer's patients with additional data updates throughout the year. Chad will describe the trial and readouts in more detail later in his presentation. In addition, our 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 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 Prothena.

Prasinezumab is being investigated as a potential treatment for early Parkinson's disease, and our partner Roche announced top-line results from the phase II-B PADOVA study in December of 2024. The PADOVA phase II-B 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 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 in 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 prasinezumab continued to be well tolerated. The phase II-B 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 II PASADENA and the phase II-B PADOVA trials. 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-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 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 II trial. The trial is evaluating placebo versus low and high doses of BMS-986446 in patients with early Alzheimer's disease, with a primary endpoint of change from baseline in the Clinical Dementia Rating-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 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 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?

Chad Swanson (Chief Development Officer)

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 III 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, seeks 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 are 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 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 SF-36 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 birtamimab 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 AFFIRM-AL trial, standard of care comprised of bortezomib and often include cyclophosphamide and dexamethasone, the combination referred to as CyBorD or BCD. Recently, daratumumab has emerged as a standard treatment in clinical practice and is allowed to be used as standard of care at randomization in our AFFIRM-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 BCD to BCD 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 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 birtamimab. 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 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 two-to-one on birtamimab 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 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 three-to-one 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 III-B 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 N-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 CTAD 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, E2814 antibody, which also targets areas within the MTBR region, showed positive effects on biomarkers, including MTBR Tau-243, Tau PET, and Tau-217, which has been associated with clinical efficacy. In addition, our partner, Bristol Myers Squibb, has advanced BMS-986446, formerly known as PRX005, an anti-MTBR Tau antibody, into a robust phase II trial signaling their competence 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 program.

Brandon Smith (COO)

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 III 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 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 to date, we expect very high peak penetration in Mayo Stage IV patients if approved. Third, this is a rare disease patient population with a targeted call point for hematologists with support from specialized cardiologists as the primary treating specialist. We are prepared to build out our sales force to call on this relatively consolidated prescriber base. 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 exclusivity in the United States and 10 years or more of market exclusivity in Europe. Moving to slide 19, the 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 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 birtamimab. 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 birtamimab.

This includes continuing to present our data at top medical congresses and publications and 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 III results, birtamimab has the potential to be the first anti-amyloid therapy for AL amyloidosis, and a 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 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. PRX012, as a potential once-monthly subcutaneous anti-Aβ 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 segment, 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.

Tran Nguyen (CFO and Chief Strategy Officer)

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 activity of $150.3 million, which is at the low end of our guidance range of $148 million-$160 million. Net loss was $122.3 million, which is at the low end of our guidance range of $120 million-$135 million. As of December 31, 2024, Prothena had $472.2 million in cash, cash equivalent, 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 activity to be between $168 million 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 activity is primarily driven by an estimated net loss of $197 million-$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.

Gene Kinney (President and CEO)

Thanks, Tran. 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 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 III AFFIRM-AL trial evaluating birtamimab in patients with Mayo Stage IV AL amyloidosis.

Clinical results from our phase I ASCENT trials evaluating PRX012 as a potential best-in-class treatment in early Alzheimer's disease. Completion and results from Novo's phase II 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 (participant)

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 one on your telephone keypad to raise your hand and join the queue. If you would like to withdraw your question, simply press star one 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. Your first question comes from Yasmeen Rahimi with Piper Sandler. Please go ahead.

Hi, this is Emma on for Yasmeen. I have two from us on birtamimab. Firstly, what is considered the best, the base and best-case scenario into the phase III 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 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.

Gene Kinney (President and CEO)

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 in that it targets the amyloid directly. And of course, what is lacking in the current treatments, and Chad exemplified this in his discussion around birtamimab 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 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?

Brandon Smith (COO)

Thanks, Gene. And maybe just to orient you to something in our earlier 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 need to be immediately treated upon diagnosis. It's a rare disease with a consolidated call point. And importantly, what we've learned in our conversations with KOLs and in our market research is that an anti-amyloid therapy designed to directly clear amyloid from the heart and other vital organs and that demonstrates that early survival benefit with a favorable safety profile has a very strong uptake, especially in those patients at high risk of early mortality.

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. Honestly, really looking forward to planning for and executing on a launch in the second half of 2026.

Operator (participant)

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

Jay Olson (Managing Director and Senior Analyst)

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.

Gene Kinney (President and CEO)

Yeah, thanks for the question, Jay. And I'll let Chad speak to some of the baseline characteristics. One of the obvious things that I can point to as we think about the former VITAL trial and now the 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 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 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. Maybe he can talk a little bit more about the baseline characteristics.

Chad Swanson (Chief Development Officer)

Yeah, thanks, Gene. Thanks for the question. So the baseline characteristics in AFFIRM-AL are actually quite similar to those that we saw in the VITAL stage IV subjects. Obviously, by design, right? We're designing the study to replicate the results we saw in that stage IV 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 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 field.

Operator (participant)

Your next question comes from Umer Raffat with Evercore. Please go ahead.

Umer Raffat (Senior Managing Director)

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 II PRONTO and previously treated, as well as for phase III 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 median dFLC in phase III at baseline? Thank you very much.

Gene Kinney (President and CEO)

Yeah, thanks, Umer, for the questions. Let me just start with the PRONTO and VITAL question, and then I can ask Chad to comment on the other parts of your question. So first, in terms of visibility on long-term mortality, of course, those trials 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.

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 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 a comment on some of the other parts of the question that you have.

Chad Swanson (Chief Development Officer)

Yes, thanks, Gene. So with respect to the treatment emergent 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.

Gene Kinney (President and CEO)

Yeah.

Operator (participant)

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

Charles Duncan (Managing Director and Senior Research Analyst)

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 suggests that there might be difference in interest in using the drug? Thanks.

Gene Kinney (President and CEO)

Yeah, thank you, Charles, for the question. 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, 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.

Brandon Smith (COO)

Yeah, 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 through AFFIRM-AL, 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.

Operator (participant)

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

Jason Butler (Managing Director)

Thanks for taking the question. 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.

Gene Kinney (President and CEO)

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-amyloid class, I think there's two kind of broad categories of how this field is evolving. On one hand, very much around risk-benefit, 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 and 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.

Mark Johnson (VP)

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 three 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.

Second, to evaluate the pharmacokinetics and pharmacodynamics, really to find that optimal dose regimen for registration-enabling trial. 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.

Operator (participant)

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

Michael Yee (Managing Director)

Hey guys, thanks for the questions. Question on the phase III 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? 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 has 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 has been going on for so long.

The second question, if I may just sneak in one on [another one too], 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.

Gene Kinney (President and CEO)

Yeah, thanks, Mike. Some good questions there. Let me start with your question about ANDROMEDA and DARA 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.

Obviously, having monthly access to the world's expert treaters in this space, we think it's very reasonable to see a control median survival of approximately eight months. Of course, you can then contrast that against the effect size that we saw across the first nine months there, which was 0.413 hazard ratio on all-cause mortality. 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 frame to what we observed in VITAL. 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.

That's certainly evidenced by the ANDROMEDA data that was presented at ASH last year. We look at that and we feel like we're well aligned with what we've seen previously with VITAL. 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. 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.

Chad Swanson (Chief Development Officer)

Right, yeah. Thank you, Gene. So I think Gene actually summarized that quite well, right? So as you know, we've designed AFFIRM-AL based upon the results that we saw in VITAL, in stage four patients in VITAL. And what I can maybe add here is that, and actually not so much, and I think Gene alluded to this, is that when we look at the timing events in AFFIRM-AL so far, obviously in a blinded way, but the timing events and the nature of those events, they're actually quite similar to what we observed in the VITAL study. So the timing of these looks to be aligned and suggesting 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 median 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 our control arm should be behaving similarly in AFFIRM-AL as it was in VITAL.

Operator (participant)

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

Rudy Li (Senior Research Analyst)

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 DARA was approved in 2021? And secondly, for PRX012 in ASCENT-2, can you maybe talk about the rationale for the 200 mg expansion cohort with roughly 100 patients? Any color would be helpful. Thanks.

Gene Kinney (President and CEO)

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 Chad, you can address the Excel question.

Brandon Smith (COO)

Sure, happy to. And 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. 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 identified, they rapidly treat and they rapidly move them into trying to make sure that do 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 and diagnosed, not an extrapolated prevalence number.

Chad Swanson (Chief Development Officer)

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 Aβ population. So that gives us the ability to recruit 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 PRX012. So it kind of is an opportunistic approach to randomizing those B cohorts.

Operator (participant)

Your next question comes from Tazeen Ahmad with Bank of America. Please go ahead.

Tazeen Ahmad (Managing Director in US Equity Research)

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? 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 a label, or could it expand to less severe patients? Thanks.

Gene Kinney (President and CEO)

Yeah, 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 yeah, maybe you can comment a little bit on just the identification of those patients.

Brandon Smith (COO)

Yeah. So as 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. Over time, these patients do come in. It is a rare disease. So we fully expect that as you get newly diagnosed patients, that those would then move into that bucket of diagnosed and then treated. In terms of what it takes to initially launch and commercialize, again, this would be Prothena's first launch. This would be our first entry into the marketplace. And it does take time to get into the contracting, get through, and 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, it will take time in order to get that update.

Gene Kinney (President and CEO)

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

Operator (participant)

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

Brian Abrahams (Managing Director and Co-Head of Biotechnology Research)

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. Thanks.

Gene Kinney (President and CEO)

Yeah, thanks, Brian. 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 buildout. So I think in terms of Europe or 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 that current treatments, which are focused solely on the plasma cell targeting treatment, do not have an impact on these patients' early mortality events. So for those patients that are at high risk of early mortality, there is a significant palpable unmet medical need that is across all geographies.

Obviously, we would expect productive dialogue with regulatory authorities across the globe around that risk-benefit profile of the molecule and of the program. That said, maybe I can talk or maybe I can hand it over to Brandon. He can talk a little bit about commercial buildout and how we're thinking of that.

Brandon Smith (COO)

Yeah, and thank you for the question. And we are very excited to talk about commercial buildout. We probably won't go into too many details today, but what I can describe is the goals. 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. And our goal is to ensure that from the patient, the physician, the institution, and the payer, it's seamless and provides 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 getting more updates as we get past top-line data.

Operator (participant)

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

Gene Kinney (President and CEO)

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.

Operator (participant)

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