Prothena Q4 2024 Earnings Call Transcript

Quartr
Provided by Quartr
February 20, 2025

There are 11 speakers on the call.

Operator

Good day, ladies and gentlemen, and welcome to the Puthina Biosciences Fourth Quarter and Full Year twenty twenty four 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 I would now like to turn the call over to Mark Johnson, Vice President at Prothena.

Operator

Please proceed.

Speaker 1

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 procina.com and is also attached to a Form eight 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, Doctor.

Speaker 1

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 and A session. Before we begin, I would like to remind you that during today's presentation, we will be making forward looking statements that are subject to certain risks, uncertainties and other factors that could cause actual results to differ materially from those referred to in any forward looking statements.

Speaker 1

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.

Speaker 2

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 Ruthenian's every debt.

Speaker 2

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.

Speaker 2

Our wholly owned clinical programs are nearing significant inflection points in 2025, setting up its transformational year for Prothena. Protamimab is currently the only potential treatment for AL amyloidosis that has demonstrated an early survival benefit in a randomized clinical trial. The survival data from our prior Phase three VITAL trial enabled us to receive a special protocol assessment or SPA agreement with the FDA to confirm these results in our ongoing Phase three AFFIRM AL trial at an unprecedented statistical significance level of 0.1. The primary endpoint in AFIRM 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.

Speaker 2

S. Launch by the second half of twenty twenty six. Birtanumab represents a very attractive potential multibillion dollar global commercial opportunity. This is a rare disease patient population primarily treated by hematologists in amyloidosis specialty centers for which the ongoing bertimimab program is designed to address the significant unmet need of early mortality. In addition, our Alzheimer's disease portfolio PRX12 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.

Speaker 2

PRX12 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 twenty twenty five, we expect to announce initial results from our ongoing Phase one Ascent clinical trial evaluating PRX12 in early Alzheimer's patients with additional data updates throughout the year. Chad will describe the trial and read out in more detail later in his presentation. In addition, our PRX123 dual anti A beta and anti tau vaccine has been granted Fast Track designation and has an IND cleared by the FDA. Thad will describe our confidence in this program and potential next steps as well.

Speaker 2

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. Pratinezumab is being investigated as a potential treatment for early Parkinson's disease. And our partner Roche announced top line results from the Phase 2b PDOVA study in December of twenty twenty four. The PDOVA Phase 2b trial evaluated five eighty six people with early Parkinson's for a minimum eighteen months while on stable symptomatic treatment.

Speaker 2

In the study, pracinezumab showed a potential clinical effect in the primary endpoint of time to confirmed motor 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 prespecified analysis in the approximately seventy five percent of participants treated with Levodopa with a hazard ratio of 0.79 and a nominal p value of 0.0431. In prespecified supplementary covariate adjusted analyses of these endpoints, the effects were even more pronounced and all nominally statistically significant. Consistent positive trends across multiple secondary and exploratory endpoints were also observed that prasinezumab continued to be well tolerated. The Phase 2b PDOVO 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.

Speaker 2

Roche is continuing to evaluate the effects of prasinezumab in open label extension studies from both the Phase two Pasadena and the Phase 2b PDOVA trial. Roche will continue to evaluate the data and work together with health authorities to determine next steps. Moving on to Carametag, an anti amyloid antibody for the potential treatment of ATTR amyloidosis with cardiomyopathy or ATTR Centimeters. Novo Nordisk is currently conducting a Phase two signal detection trial in approximately ninety nine patients with ATTR Centimeters. The trial should complete in the first half of twenty twenty five and we expect Novo to announce results and potential next steps in the second half of twenty twenty five.

Speaker 2

We look forward to future updates from Novo, including potential further clinical development of pramitidine, moving this important new treatment closer to patients. We made significant progress in 2024 with our two partner clinical programs with Bristol Myers Squibb.

Speaker 3

CMS nine hundred and eighty six thousand four hundred

Speaker 2

and forty six, formerly PRX004, 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 four 70 five patient target tau one Phase two trial. The trial is evaluating placebo versus low and high doses of BMS nine

Speaker 3

hundred and eighty six thousand four hundred

Speaker 2

and forty six in patients with early Alzheimer's disease with a primary endpoint of change from baseline in the clinical dementia rating scales from a box of score at eighteen months. Enrollment is ongoing and the trial is expected to complete in 2027. Also in 2024, BMS opted into a global license agreement for PRX19, which included a payment of $80,000,000 As part of the agreement, Prothena has initiated a Phase one first in human clinical trial to evaluate the safety, tolerability, immunogenicity and pharmacokinetics of single ascending and multiple doses in healthy adults. The trial is enrolling and expected to complete in 2026. This is an exciting year for Prothena and our strategic partners.

Speaker 2

To discuss our wholly owned clinical programs in further detail, I will now turn the call over to Chad. Chad?

Speaker 4

Thanks, Gene. I'd like to start my discussion with a review of ritamimab, 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 for 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.

Speaker 4

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 to function and failure and can lead to early mortality. Sertanumab is specifically designed to directly target misfolded light chains, both neutralized toxic soluble light chain aggregates and clear insoluble amyloid deposits in vital organs such as the heart.

Speaker 4

Fertamimab 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 thirty percent of the AL amyloidosis patients who are categorized as Mayo Stage IV at baseline in VITAL, we observe the impressive survival benefit shown on this slide. The Kaplan Meier curve shows early separation resulting in a fifty nine percent risk reduction of all cause mortality at month nine with a nominal P value of 0.021.

Speaker 4

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 bertemimab has been well tolerated with a favorable safety profile across multiple clinical trials. In VITAL and in the ongoing AFFIRM AL trial, we compared britamumab in combination with current standard of care versus placebo with current standard of care. Moving on to Slide 12. Recently presented data from the INDRAMADUS study demonstrates a significant need for a therapy that clears amyloid and addresses early mortality.

Speaker 4

For the VITAL and AFFIRM AL trial, standard of care comprise of bortezomib and often include cyclophosphamide and dexamethasone, the combination referred to as CYBRD 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 ASHA in December 2024 on the Phase III INDROMATA study, clearly shows that the survival curves comparing the addition of daratumumab with VCD to VCD alone do not separate until after approximately fifteen months. This suggests that the addition of daratumumab to this regimen in AL amyloidosis patients does not have an impact on early mortality. However, ritamimab'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 AFIRM AL.

Speaker 4

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 breptamilab. 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:one on betamumab plus standard of care versus placebo plus standard of care. We expect to announce results in the second quarter of twenty twenty five.

Speaker 4

Now, let's review our Alzheimer's portfolio starting with PRX12 on Slide 14. PRX12 is our anti amyloid beta antibody specifically designed with the patient in mind. We believe that a treatment with similar efficacy and safety to currently approved anti A beta therapies, but delivered with less burden in the home, represents significant value for people living with Alzheimer's disease. CRS12 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 PRX12 in the clinic.

Speaker 4

And now let's turn to Slide 15. ASNCT2 is our double blind placebo controlled multiple dose clinical trial evaluating PRX12 in people with early Alzheimer's disease. Each cohort is randomized three to one to receive PRX12 or placebo once monthly for six months. The objectives of the trial are twofold. First is to evaluate the safety, tolerability and immunogenicity of PRX12 in patients with early Alzheimer's disease.

Speaker 4

And the second is to characterize the pharmacokinetics and the pharmacodynamics of PRX12 to find the optimal dose regimen for a registration enabling clinical trial. Starting around midyear, our initial data share will include results from the 5A cohorts shown here. This represents approximately two twenty five participants that are all either APOE4 non carriers or APOE4 heterozygous carriers with early Alzheimer's disease. Additional data readouts and presentations may include any of the following: data from the 3b cohorts, which enrolled approximately 36 participants and who are all APOE homozygous carriers and longitudinal data for some patients who have been on treatment for upwards of twelve and eighteen months at various dose levels from our ongoing ASCENT three open label extension study. Let's move to Slide 16 to review our PRX123 program.

Speaker 4

PRX123 targets key epitopes within the N terminus of A beta and the NCBR 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 C2814 antibody, which also targets areas within the mTBR region, should ponder effects of biomarkers, including mTBR tau243, tau PET and tau217, which has been associated with clinical efficacy. In addition, our partner, Bristol Myers Squibb has advanced BMS986446, formerly known as PRX004, an anti MTBR tau antibody into a robust Phase II trial signaling their confidence in the target. These data points give us further confidence in our PRX123 program and we look forward to providing further updates on its development path later this year.

Speaker 4

I'll now turn it over to Brandon to discuss the commercial potential for our wholly owned program.

Speaker 3

Thanks, Chad. Moving to Slide 18, we are focused on building out our commercial capabilities to support pertinumab as our first potential commercial product. While the standard of care has evolved, there continues to be significant unmet need in the treatment of AL amyloidosis for patients at risk of early mortality. Providers and patients are waiting for an anti amyloid treatment that directly clears amyloid from the heart and other vital organs, leading to early survival benefit. With positive Phase three results for brittumab, we expect to launch in The U.

Speaker 3

S. By the second half of twenty twenty six. This has the promise to make a significant impact on patient outcomes and will be a very attractive commercial opportunity. There are several factors which support our enthusiasm. First, this is an established market.

Speaker 3

Our claims data and market research indicate that as of 2024, there were approximately sixteen thousand diagnosed and treated AL amblytosis patients in The United States, with the vast majority, approximately thirteen thousand, having cardiac involvement, the segment with the highest risk for early mortality. Market size is similar across the five major European markets at approximately fifteen thousand patients with ALM leidosis with cardiac involvement. Given upwards of thirty percent of all ALM leidosis patients are Mayo Stage four, we believe the diagnosed and treated population of Mayo Stage four patients is close to five thousand patients in The U. S. And over five thousand patients in the major European markets.

Speaker 3

Globally, we estimate there are over twenty thousand diagnosed patients with Mayo stage four ALM leukocytes across the major markets, including The United States, Europe, China, Brazil and Japan. Second, with a significant unmet need for treatment options that address early mortality and the observed favorable safety profile to date, we expect very high peak penetration in Mayo stage four patients if approved. And third, this is a rare disease patient population with a targeted call point for hematologists with support from specialized cardiologists are the primary treating specialists. We are prepared to build out our sales force to call on this relatively consolidated prescriber base. And most patients in The U.

Speaker 3

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 in hospitals. As a reminder, with pertamimab, 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 twelve years or more of market exclusive in The United States and ten years or more of market exclusive in Europe.

Speaker 3

Moving to Slide 19. The market dynamics for brittemimab as our first potential commercial product are quite compelling. Our plan is to independently commercialize brittemimab in The U. S. And continue to evaluate launch time in the European markets.

Speaker 3

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 ritamivat. 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 pertinumab. This includes continuing to present our data at at top medical congresses and publications in peer reviewed journals. These ongoing educational efforts are important to further solidify bretamumab's position as a potential new standard of care and to appropriately incorporate bretamumab into treatment guidelines.

Speaker 3

Let's wrap up on ritamimab by reiterating a few key points. First, with positive confirmatory Phase three results, ritamimab has the potential to be the first anti amyloid therapy for AL amyloidosis and ritamimab based regimen will be positioned as first line therapy, becoming the new standard of care for patients at risk of mortality. Second, ritamimab would be the only AL amyloidosis therapy to demonstrate early survival benefit in double blind placebo controlled clinical trials. And third, we expect pertamiv to be a multibillion dollar global market opportunity at peak. Moving to Slide 20.

Speaker 3

As we've discussed, pertamiv 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, PRX12 and PRX123, is very compelling. These programs may enable us to address some very large and underserved market comprised of the millions of pre symptomatic and early symptomatic Alzheimer's disease patients and their families whose needs are not fully met or addressed with today's treatment options. PRX12 as a potential once monthly subcutaneous anti A beta treatment option would be well positioned for the early AD market and some portions of the presymptomatic market population if approved.

Speaker 3

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 Tron for a discussion on our 2024 financial performance and our 2025 financial guidance.

Speaker 5

Thanks, Brandon. Please turn to Slide 20 two. Today, we reported financial results that were in line with our 2024 financial guidance. Please refer to our press release for a detailed breakdown of our financial results. In addition, in 2024, we received an $80,000,000 payment from BMS where they obtained the exclusive global license for PRX19.

Speaker 5

In terms of our 2024 financial performance relative to guidance, we had net cash used in operating and investing activities of $150,300,000 which is at the low end of our guidance range of $148,000,000 to $160,000,000 Net loss was $122,300,000 which is at the low end of our guidance range of $120,000,000 to $135,000,000 As of 12/31/2024, Christina had $472,200,000 in cash, cash equivalents and restricted cash, which is in line with our guidance of $468,000,000 As of 02/20/2025, Christina had approximately 53,800,000.0 ordinary shares outstanding. Additionally, we continue to have a simple capital structure with zero debt. Turning to our 2025 financial guidance on Slide 23, we expect our full year 2025 net cash used in operating and investing activities to be between $168,000,000 and

Speaker 3

$175,000,000

Speaker 5

We expect to end the year with approximately $3.00 $1,000,000 in cash, cash equivalents and restricted cash, which represents the midpoint of the range. The estimated full year 2025 net cash used in operating and investing activities is primarily driven by an estimated net loss of $197,000,000 to $2.00 $5,000,000 which includes an estimated $41,000,000 of non cash share based compensation expense. With that, I'll turn the call back over to Gene to discuss our upcoming milestones.

Speaker 2

Thanks, John. Moving to Slide '25. I'd like to acknowledge and thank the patients, their families, physicians and study site staff who participate in all of our clinical trials. Without their support, we could not elucidate potential impact of the new medicines we're developing. I'd also like to thank our talented Fresenians for their ongoing commitment to advancing protein dysregulation science to make a real impact for the patients and families we serve.

Speaker 2

As we've discussed today, 2025 has the potential to be a transformational year for Prothena with significant clinical readouts from our wholly owned program as well as continued clinical readouts and development from our strategically partnered programs. Looking ahead, we are excited to announce top line results from our confirmatory Phase three AFFIRM AL trial evaluating bertimimab in patients with Mayo Stage four AL amyloidosis. Clinical results from our Phase one AFFIRM trial evaluating PRX12 as a potential best in class treatment in early Alzheimer's disease. Completion and results from Novo's Phase two signal detection trial evaluating Carametug for the treatment of ATTR Centimeters. In addition, we look forward to sharing further clinical development updates for PRX123, prasinezumab, CMS986446 and PRX19.

Speaker 2

I'm proud of Cortina's execution in 2024, setting us up for an exciting year ahead. We're well capitalized with a robust cash position and remain focused on advancing our clinical programs as we strive to become a fully integrated commercial biotechnology company. With that, we'll now open the call for Q and A. Operator?

Operator

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

Speaker 6

Hi, this is Emma on for Yaz. I have two from us, on bertimimab. Firstly, what is considered the best the base and best case scenario into the Phase three Affirm AL, both on the primary endpoint as well as key secondaries? And then with that, how are you thinking about more in detail about the market opportunity in AL amyloidosis, like digging into the commercialization within the therapeutic landscape, especially given the concentrated prescriber base and all those things you talked about? So any additional color on that would be super helpful.

Speaker 6

Thank you.

Speaker 2

Great. Hi, Emma. Thanks for the questions. So first, just in terms of expectations, around the primary endpoint. You know, let me start again by reiterating, you know, the significant unmet need here.

Speaker 2

So, as I'm sure you know, all of the current treatments used in AL amyloidosis today target plasma cells. Obviously, brittanimab is fundamentally different in that regard in that it targets the amyloid directly. And of course, what, you know, is lacking in the current treatment and and Chad exemplified this, in his discussion, around baratumumab, with the INBREMA 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 bertamumab as a differentiated mechanism and as a differentiated product. We did show in our prior study that in particular in our vital trial in our in the Mayo stage four patients that there was a meaningful impact on survival, particularly amongst those that had risk of early mortality.

Speaker 2

So we think that that really is the opportunity and with the spot agreement that we have with the FDA, that ascribed success at a p value of 0.1. We really think being able to demonstrate, that kind of survival benefit, would represent a best case for us. And so, that said, you know, maybe I can ask, Brandon to talk a little bit more about the market opportunity and how that, that that potential to address that unmet medical need then translates into the, excitement that we have around market opportunities. Brandon?

Speaker 3

Thanks, Jean. And, maybe maybe just to orient you to, something in our 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.

Speaker 3

These are patients who are, need to immediately treat it upon diagnosis. It's a rare disease with a consolidated call point. Importantly, what we've learned in our conversations with OLs and in our market research is that an anti amyloid therapy is designed to directly clear amyloid, from the heart and other vital organs and that demonstrates that early survival benefit with a favorable safety profile is a very strong update, especially in those patients at high risk of early mortality. So, you know, as I said in the presentation, at PEAT, the procurement opportunity is well over a blockbuster opportunity in The U. S.

Speaker 3

Globally and a multibillion dollar opportunity globally. Honestly, really looking forward to planning for and executing on the launch in

Speaker 5

the second half of twenty twenty seven.

Operator

Your next question comes from the line of Jay Olson from Oppenheimer.

Speaker 7

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 pertamumab to demonstrate and affirm AL? Thank you.

Speaker 2

Yes. Thanks for the question, Jay. And I'll let Chad speak to some of the baseline characteristics. One of the obvious things that I can point to as we think about, you know, the former VITAL trial and now the AFFIRMEAL trial is the focus on patients in Mayo stage four. Obviously, those are the patients at highest risk of early mortality.

Speaker 2

And, you know, 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, 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 is as a as a plasma cell targeting agent, there's still a relative lack of impact and in fact no impact on on survival across the first fifteen months of that Andromeda trial and of course that, you know, those would be the patients at highest risk of early mortality and where that unmet medical, need, continues to to live. So, we're excited about the opportunity for for brekamumab in that space.

Speaker 2

But let me pass it over to Chad here and maybe he could talk a little bit more about the the baseline characteristics. Yeah. Thanks, Pete.

Speaker 4

Thanks for the question. So the baseline characteristics in a firm are actually, quite similar to those that we saw in the VITAL stage four subjects. Obviously, by design, right? We were we were dying the study to to officially the results we saw in that stage four 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.

Speaker 4

And in fact, it turns out that about eighty percent or so of the subjects who are, participating in the study are on DAR2M. And I think, I'll just maybe end by echoing, you know, with respect to success again,

Speaker 3

you

Speaker 4

know, to to what success really means a P value of 0.1 or less, per the agreement with FDA in this file.

Operator

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

Speaker 3

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 three vital? And I understand there's no active arm going on, but I'm curious about mortality trends.

Speaker 3

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

Speaker 2

Yes. Thanks, Umer, for the questions. Let me just start with the pronto and vital question, and then I can ask, Chad to comment on, on the other parts of your question. So first, in terms of visibility on long term mortality, of course, those trials have, you know, are no longer ongoing. What we do know from the PRONTO trial is that there were nine total deaths, six of those were, from the placebo group and three on active treatment with pertamumab.

Speaker 2

Of course, PRONTO was a patient population that, had previously received chemotherapy or plasma directed therapy and those patients were considered neuthologically stable coming into the study but still had ongoing organ dysfunction. In VITAL, of course, the results are as we've described them in the past. So the Mayo stage four patients in particular, you have a hazard ratio of zero point four one three across the first nine months, representing just something just shy of a sixty percent relative risk benefit. Again, because, that trial is no longer ongoing, there's no long term follow-up in terms of mortality that we can point to. That said, let me, let me see if, Chad has to comment on, on some of the other parts of the question that you asked.

Speaker 4

Yes. Thanks, Jean. So, with respect to the, treatment emergent deaths question. So, so essentially, you know, we were looking at all cause mortality in that study. So, essentially all deaths are counted.

Speaker 4

They're all they all they all matter in the analysis.

Speaker 3

Yes.

Operator

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

Speaker 8

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

Speaker 8

Thanks.

Speaker 2

Yeah. Thank you, Charles, for the question. I'll let Brandon can comment a little bit on some of the market research maybe. But just to kind of reiterate, our view on this which is there's 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 really no opportunity, for meaningful benefit with any of the current approaches that we have for these patients.

Speaker 2

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 0.1, would be very meaningful for this patient population and very meaningful, in the treatment armamentarium. And let me hand it to Brandon to talk to you a

Speaker 3

little bit about how that translates into the market. Yeah. Thank you for the question. Yes, our market research, and specifically our conversations with payers and with OLs, really points to the fact that the unmet need is very widely known. And the Andromeda data that just came out in December confirms this, that early on in this disease course there is nothing that impacts all cause mortality, nothing that impacts mortality.

Speaker 3

And because that unmet need is so well known, anything that shows a separation early as BIDL did and as we're trying to confirm through our firm, will be very meaningful to physicians, their patients, and even to payers, because they do fully realize that there is nothing that helps these patients. And honestly, the all cause mortality gold standard endpoint against standard of care is really what's driving a lot of their very strong interest in the therapy.

Operator

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

Speaker 2

Thanks for taking the question. Congrats on

Speaker 4

the progress. I guess I want to switch gears and just ask one on PRX 12. 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.

Speaker 2

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 so just a reminder, I mean, in this space, particularly as we talk about the anti data class, I think there's two kind of broad categories of of how this field is evolving. On one hand, very much around risk benefit, you know, thinking about, the ARIA relationship to, in the first instance, amyloid reduction and ultimately how both from a temporal perspective as well as a maximum amyloid reduction perspective, how that's translating through to clinical benefit.

Speaker 2

I think the other very important part here as well is treatment burden, something that we talked a little bit about, in in the remarks. I think Chad was talking about this a fair bit. We think treatment burden is is pretty significantly important with respect to commercial uptake of these approaches. Obviously, very important as patients are diagnosed with a, you know, 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, that is amenable to the long term treatment, throughout the disease course. And that's why CRX twelve is designed with the idea of a once monthly subcutaneous at home administration.

Speaker 2

So we think that's incredibly important. But maybe Mark, if you wanna talk a little bit about, just kind of what data we expect and and how we think that's gonna roll out.

Speaker 3

Yeah. Thank you, Jean.

Speaker 1

And so just kind of building on, what Chad presented earlier, looking at, at slide 15 as far as the data that's gonna be shared. So starting around mid year, our initial data share is gonna really be from those first five A cohorts in the ascent to multiple dose trial. This represents about two twenty five 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 APOE four homozygous carriers, as well as longitudinal data for some patients who have been on treatment for as long as twelve or eighteen months, at various dose levels from the ongoing percent three.

Speaker 1

And really just building on what we're looking for for the objectives, you know, evaluating the safety, tolerability, immunogenicity

Speaker 4

of PRS twelve in

Speaker 1

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 less burden in the home represents, and then addresses a significant unmet need for people living with Alzheimer's, in their pain.

Operator

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

Speaker 9

Hey guys, thanks for the questions. A question on the Phase three ALIUM LADOSA study. When you comment around your view that DARA is not impacting the study, are you implying that the control arm is looking more like the control arm from Andromeda? Or are you saying that it does look like the Dara arm there? And so 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 it's studies 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.

Speaker 9

The second question, if I may just sneak in one on 12. 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 AMOLED reduction? And how should we think about what is good in that result that comes out? Thank you.

Speaker 2

Thanks, Mike. Good questions there. Let me start with, your question about Andromeda and Terra and the control arm. And I'll ask Chad to speak about this as well because I think it also fits into, just, you know, our expected timing around the study and, and how that's, how that's enrolling and how we're accruing events from timing perspective. So to be, to be, clear, you know, we do expect the control arm, to behave in a, you know, somewhat similar manner to what we observed in the VITAL trial.

Speaker 2

The VITAL trial, if you look at the control arm, the median survival in that arm was, around eight point three months. That's just a little bit longer than the literature would have expected, which would have been about six months at that time. But obviously, you know, having monthly access to the world's expert treaters in this space, we think it's very reasonable to to see a controlled median survival of approximately eight months. And of course, you can then contrast that against, the effect size that we saw across the first nine months there which is 0.413 hazard ratio on all cause, mortality. So, 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.

Speaker 2

So, 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 fifteen months. And that's certainly evidenced by, the Andromeda data that was presented, at ASH, last year. So, so we look at that and we feel like, you know, we're well, we're well aligned with what we've seen previously, with, VITAL. And obviously that's also true from what we can see both with respect to, the events that are occurring, whether it be from a timing perspective or a quality perspective.

Speaker 2

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

Speaker 4

study, and how that's within our expectation. Right. Yeah. Thank you, Gene. So I think I think Gene actually summarized that quite well, right?

Speaker 4

So as you know, we've, designed a firm, based upon the results that we saw in vitals, in the stage four patients in vitals. And what I, what I can maybe add here is that, and actually not so much add, I think, I think Jean alluded to this, is that, when we look at the timing events in, in, in a firm 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, you know, the timing of these looks to be aligned in suggesting, that our desire to sort of replicate that study look, is, on par. Again, with the DARA piece of things as Jean mentioned, you know, 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, you know, Jean had mentioned our median survival in the vital study, was eight point three months.

Speaker 4

And so, there are two of them that certainly over the first fifteen months or so did not have an impact on survival. So we feel that again, those things combined sort of suggest that there, you know, our control arm should be, should be behaving similarly in the firm as it was in BIPOC.

Operator

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

Speaker 4

Hi. Thanks for taking my question. So for bertamimab, just a quick follow-up on treatment landscape. How many patients are actively treated with current stand up carriers? And did you notice any changes in the market dynamics since Jynxis dara was approved in 2021?

Speaker 4

And secondly, for PRX12 in ASCEND2, can maybe talk about the rationale for the two hundred milligram expansion cohort based roughly 100 patients? Any color will be helpful. Thanks.

Speaker 2

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 wanna talk a little bit about the numbers and

Speaker 3

then, Chad, you can

Speaker 2

you can address the, the excellent question? Sure. Happy to. And in, so what we always

Speaker 3

quote, in our figures is the diagnosed and treated rate. So, the patients that we described in our presentation was sixteen thousand patients in The US. Your question on whether or not that has increased since Dara was approved back in 2021, Yes, yes. I think the number we used then was fifteen hours. So, it has increased, but this is, disease once identified they rapidly treat and they rapidly move them into, trying to make sure that whatever they can to affect the histologic response, which as Jean and Chad described, is not having an impact for, on early mortality.

Speaker 3

So, our figures that we're quoting are the figures that we can identify from treated and diagnosed, not an extrapolated prevalence number.

Speaker 2

Right. So, so I'll address the

Speaker 4

second part of your question which was about the expansion cohort. So, you know, quite frankly, we were able to be a bit opportunistic here, in using that expansion cohort given, patients demand, for the study. So what I mean by that is, in order to for us to enroll our B cohorts, now recall that our B cohorts are those that are able to use homozygous carriers. You know, it takes quite a large number of patients to screen in order to obtain the numbers that we were looking for, in those B cohorts. And that's really because, these equally homozygous carriers make up about fifteen percent of the overall early AD population.

Speaker 4

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.

Speaker 2

But it also then allows for us

Speaker 4

to have a larger data set actually, to help better characterize PRX-twelve. So it kind of is not just opportunistic approach to, randomizing those cohorts.

Operator

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

Speaker 10

I wanted to get a sense about how to think about commercial uptake. So you talked about these Mayo stage four AL patients about five thousand of them in The U. S. How easy are they to find? Like if you have to find them tomorrow, could you?

Speaker 10

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

Speaker 2

Yeah. Thanks, Deneen, for the question. So I'm going to ask Brandon to comment on that. Obviously, right now we're focused on the Mayo stage four patients. But, yeah, maybe you can comment a little bit on, just the identification of those patients.

Speaker 2

Yeah. So, as

Speaker 3

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 diagnosis and then treated.

Speaker 3

In terms of what it takes to initially launch and commercialize, again, we're this would be Proteus' first launch, this would be our first entry in the marketplace and it does take time to get into the contracting and get through and make 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 out there.

Speaker 2

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

Operator

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

Speaker 4

Hey, 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 far for European regulators would be similar to

Speaker 3

what The US has put forth. Thanks.

Speaker 2

Yeah. Thanks, Brian. Great questions. Let me let me start with the the latter part of your question and I'll ask Brandon to to talk a little bit about the build out. So I think, you know, in terms of Europe or any other geography for that matter, obviously the medical need is the same.

Speaker 2

So I think, you know, what I can say is that you know, from a risk benefit perspective, I think that conversation is very similar. You know, as in The US, 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, on these patients, early mortality events. So for those patients that are at high risk of early mortality, there is a significant palpable unmet medical need, that is across all geographies and obviously we would expect, productive dialogue with regulatory authorities across the globe, around that risk benefit profile of the molecule and of the program. So that said, maybe I can talk or maybe I can hand it over to Brandon. He can talk a little bit about commercial build out and

Speaker 3

how we're thinking about that. Yeah. And thank you for the question. And I 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.

Speaker 3

Right? So, the goal of our launch is a very positive first experience. As I said, it is, the first opportunity for Protina to get her name out there commercially, for Protamilave, a new mechanism of action to be available for halo 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.

Speaker 3

What that means is, as we move from top line data to launch, we'll be preparing for a lot of market education, a lot of ensuring that the mechanism is known in the marketplace, And then as we get our label and as we get approved, we'll move on into actually providing the brand, identity for our opportunity in this space. So, I'm really excited about building all that and really excited about that and giving more updates as we get past.

Operator

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

Speaker 2

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

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

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Prothena Q4 2024
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