Ladies and gentlemen, thank you for standing by and welcome to Prothena's Fourth Quarter Full Year 2021 Financial Results Conference Call. All lines have been placed on mute to prevent any background noise. After the speaker's remarks, there will be a question and answer session. If you would like to ask a question during this time, simply press star followed by the number one on your telephone keypad. If you would like to withdraw your question, again, press star one. We ask that you please limit yourself to one question. Thank you. Jennifer Zibuda, you may begin your conference.
Thank you, operator. Good afternoon, everyone, and welcome to Prothena's Investor Conference Call to review our business progress, our fourth quarter and full year 2021 financial results, and 2022 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. On today's call, Dr. Gene Kinney, our President and Chief Executive Officer, will highlight Prothena's progress across our portfolio in 2021, as well as our organizational evolution as we continue advancing towards becoming a fully integrated biotechnology company. Following Gene's comments, Tran Nguyen, our Chief Financial Officer and Chief Strategy Officer, will review our financial results and performance for the fourth quarter and full year of 2021 and will provide our 2022 financial guidance before turning it back to Gene for closing remarks.
We will then open the call for Q&A and be joined by Dr. Hideki Garren, our Chief Medical Officer, and Dr. Wagner Zago, our Chief Scientific Officer. Before we begin, I would like to remind you that during today's presentation, we will be making forward-looking statements that are subject to certain risks, uncertainties, and other factors that could cause actual results to differ materially from those referred to in any forward-looking statements. For a discussion of the risks and uncertainties associated with our forward-looking statements, please see our press release issued today as well as our most recent filings with the SEC. We disclaim any obligation to update our forward-looking statements. With that, I'd like to turn the call over to Gene.
Thank you, Jen, and thank you all for joining us to review our 2021 financial results and business highlights. 2021 was a productive year for Prothena, marked by meaningful progress in our R&D portfolio, which represents the culmination of multi-year efforts. We're hopeful that these efforts will soon lead to impactful treatments for the millions of patients and families that are affected by diseases caused by misfolded proteins. In 2021, we also continued to attract and retain highly talented professionals with excellent track records to support our transition towards becoming a fully integrated biotechnology company. Additionally, we ended the year with a strong cash position, which included $200 million in partner payments from our collaborations with leading pharmaceutical organizations, including Bristol Myers Squibb, Novo Nordisk, and Roche.
These collaborations are part of an intentional mix of wholly owned and partnered assets, which allows us to have a broad pipeline with blockbuster potential, further supporting our growth as a company. Prothena is driven by our mission to make a real impact for the patients and families we serve. That mission is enabled by our deep scientific expertise in protein dysregulation, which serves as a unifying thread between our business strategy, our portfolio development, and the dedication that propels our team every day. We believe that our focus on slowing, stopping, and treating neurodegenerative and rare peripheral amyloid diseases addresses significant unmet medical needs, where our biology-directed engine, our clinical expertise, and our market positioning will enable us to advance best-in-class therapies that have the potential to transform the lives of patients. Our focus on neurodegenerative diseases includes Alzheimer's and Parkinson's, which sadly are growing exponentially.
Combined, these two diseases affect an estimated 60 million people globally today. The significant burden is not only experienced by patients, but also by caregivers and the overall healthcare system. In rare peripheral amyloid diseases, birtamimab and PRX004 are being developed in targeted patient populations at high risk for early mortality, which underscores our strategy to develop therapies for patients with an urgent need for improved survival. Since our inception, our core guiding principle has been to follow the science empirically and without bias. This rigorous approach to the advancement of medicine allows us to discover underlying pathophysiological properties and design molecules that optimally target pathogenic proteins and consequently have the greatest probability to slow or prevent disease.
Over the years, we have refined our approach to include what we believe is an unparalleled knowledge of disease pathology and expertise in empirical epitope mapping, advancing only those molecules that show a robust and consistent biological effect in the reduction of disease. Using our unique biology-directed engine, which leverages our deep know-how, today, we've been able to advance three programs into mid-to-late clinical stages and six discovery candidates toward the clinic, with five potential new INDs projected by 2026. Prothena's understanding of protein dysregulation is based on many decades of scientific discoveries in the field. Much of our team, including Wagner, our Chief Scientific Officer, who's on the call today, have contributed key scientific and clinical discoveries in our field and have built a scientific heritage within Prothena that allows for an informed approach for the development of potentially best-in-class therapeutic candidates.
Last year, we continued to add to this deep scientific heritage with the addition of key personnel, such as Hideki, our Chief Medical Officer, who is also present on our call today. Before we dive into the progress we made this year, I wanted to take a moment to highlight the breakthroughs that we as a field have made in advancing treatments for Alzheimer's disease. 2021 was a milestone year for the Alzheimer's community. Notable developments included the FDA-accelerated approval of the first disease-modifying therapy, significant advancements in clinical study design, including optimized patient selection strategies, advancements in the use of biomarkers, including blood-based biomarkers, an increased prominence of iADRS as a clinical outcome measure, and a growing amount of evidence generated across multiple clinical datasets confirming the benefit of anti-A-beta therapies that interact with the N-terminus of that target.
This progress stands on the shoulders of many great scientists, including Prothena's late co-founder, Dr. Dale Schenk, and multiple Prothena scientists who carefully observed and followed the iterative scientific and clinical trial design learnings to bring forth this new class of therapy to patients with Alzheimer's disease. At Prothena, we have celebrated these advancements but also believe that further improvement is needed. This is why we are advancing what we believe is one of the most comprehensive therapeutic strategies to treat Alzheimer's disease. We have developed three product candidates targeting key pathological pathways of the disease cascade, which expand from next generation, potentially disease-modifying treatments to potential combination and prevention strategies. Our portfolio takes advantage of the scientific and clinical trial design advances and positions Prothena as a leader in the transformation of Alzheimer's therapeutic approaches.
With that, let me now focus on highlighting some of the progress made across the portfolio in 2021. I'll start with PRX012, a potential best-in-class, patient-friendly, subcutaneous delivery treatment for Alzheimer's disease, targeting a key epitope at the N-terminus of amyloid beta with high binding potency. To date, preclinical data has shown that PRX012 binds to amyloid plaques with high avidity, consistent with the potential for more effective A-beta plaque clearance at substantially lower doses than approved anti-A-beta therapies. New preclinical data presented at the Alzheimer's Association International Conference, or AAIC, this past summer demonstrated that PRX012 significantly cleared both pyroglutamate-modified and unmodified A-beta plaque in brain tissue at concentrations that are expected to be reached in the CNS with subcutaneous administration on a convenient treatment schedule. We believe that PRX012 has the potential to transform the field of Alzheimer's disease.
Our goal with PRX012 is to offer greater patient accessibility and compliance relative to the approved therapy and other N-terminus-targeted treatments currently under development. Compared to first-generation treatments, subcutaneous PRX012 is also expected to result in smaller fluctuations in brain antibody concentrations. This feature may allow us to differentiate on both efficacy and safety endpoints. Because of its high binding potency and suitability for subcutaneous administration, PRX012 has the potential to serve as a foundational anti-A-beta treatment for patients with Alzheimer's disease. We intend to fully leverage the learnings from upcoming clinical, regulatory, and commercial milestones from other first-generation anti-A-beta therapies to maximize the probability of success for our PRX012 program. In 2021, we also brought our tau-targeting monoclonal antibody, PRX005, into the clinic. PRX005 is designed to be a best-in-class anti-tau antibody by specifically targeting an epitope within the microtubule-binding region, or MTBR.
Tau tangles, along with amyloid beta plaques, are pathological hallmarks of Alzheimer's disease, and research indicates that tau pathology is related to the clinical and cognitive decline associated with disease. By leveraging our unbiased biology-directed engine, we found that targeting specific regions within the MTBR resulted in more consistent and robust reduction in the pathogenic uptake of tau into neurons and the downstream neurotoxic effects. At the 15th International Conference on Alzheimer's and Parkinson's Diseases, or ADPD, in March of last year, we presented new preclinical data showcasing PRX005's ability to reduce tau pathology and downstream behavioral deficits in multiple in vitro and preclinical in vivo models. PRX005 is one of three programs being developed in partnership with our colleagues at Bristol Myers Squibb, and for which we received an $80 million option payment in 2021.
We also advanced a third Alzheimer's program, our dual A-beta tau vaccine, from discovery to preclinical development in 2021. For the first time, we presented data at AAIC on our dual A-beta tau active vaccine. This vaccine is a multi-epitope, single-agent vaccine designed to target the two key pathologies associated with Alzheimer's disease, amyloid beta and tau. Our data showed that vaccination of mice, guinea pigs, and non-human primates generated a robust and balanced immune response to the intended epitopes on amyloid beta and tau without a cytotoxic T cell response to these endogenous proteins. Importantly, the resulting antibody response to these vaccines had the appropriate impact in functional studies, promoting both phagocytosis of A-beta plaque and blockade of tau transmission in vitro.
Our vaccine offers the exciting possibility to combine amyloid beta and tau targeting into a single construct, potentially aligning with a prevention strategy. Turning to prasinezumab in Parkinson's disease, Roche, our partner for prasinezumab, presented data at AD/PD in March of last year. New analyses from part one of the phase II PASADENA study highlighted prasinezumab's greater effect on slowing clinical decline in subgroups of patients that exhibited more rapid disease progression. These data, when combined with previously discussed data sets from the study, further add to the idea that selective targeting of alpha-synuclein at a key region within the C-terminus may provide a disease-modifying impact in patients with early Parkinson's disease. In May of last year, the first patient was dosed in the phase IIb PADOVA study, for which we received a $60 million milestone payment, and the study is currently being conducted by Roche.
In addition to our progress in neurodegeneration, we also made significant advancements in our rare peripheral amyloid disease portfolio. 2021 was an important year for our birtamimab program. In February last year, we announced that we had reached an agreement with the FDA under a special protocol assessment, or SPA agreement, which allowed for the initiation of our confirmatory phase III AFFIRM-AL study, where the pre-specified alpha for study success was defined as 0.1. This SPA agreement followed from multiple discussions with the FDA Division of Cardiology and Nephrology and AL amyloidosis expert physicians on the overall safety of birtamimab and previously observed survival benefit in patients with Mayo Stage IV AL amyloidosis in the VITAL study. We initiated our global registrational AFFIRM-AL study last year and are currently enrolling patients. Current treatments for AL amyloidosis target the clonal plasma cells that overproduce light chain.
While these therapies can reduce new protein production, they fail to directly address the amyloid that has already deposited and is causing organ toxicity. Birtamimab is differentiated as it's believed to remove the amyloid most proximally associated with organ dysfunction. We have extensively published on birtamimab's well-defined epitope and depleter mechanism of action, which we believe provides for broad recognition of different types of light chain protein that may be present in the organs of patients with this disease. Moving now from AL amyloidosis to ATTR amyloidosis. Following the completion of our phase I study of PRX004, we announced that Novo Nordisk acquired our ATTR business in July of 2021. This transaction is consistent with our commitment to expedite promising treatments to patients in need.
We are confident that Novo will leverage its extensive expertise in developing therapies for cardiovascular diseases to advance this promising treatment to patients on an expedited timeline. As part of this agreement, Prothena is eligible to receive development and sales milestone payments of up to $1.23 billion, which included a $60 million upfront payment received last year. Current treatment approaches are focused on the reduction of new transthyretin production or the stabilization of the normal homo-tetrameric form of this protein. PRX004 is a differentiated approach with a depleter mechanism of action that is designed to target and remove the resident protein. Moreover, PRX004 targets a key region of transthyretin that is not available in the normal homo-tetrameric structure, and as such, uniquely interacts with only non-functional forms of this protein.
In addition to our portfolio accomplishments, we've also made significant organizational progress this last year as we continue to build an industry-leading, fully integrated company. We strengthened our management team and Board of Directors to best position Prothena for long-term growth and success. Starting with our Board of Directors, in May, we appointed to our board Dr. Sanjiv Patel, CEO of Relay Therapeutics and an established leader with significant industry experience. In April, we appointed Dr. Hideki Garren as our Chief Medical Officer. Hideki has extensive expertise and a successful track record of advancing neurological and rare disease programs through late-stage development, registration, and launch. In October, our CFO, Tran Nguyen, was appointed to the additional and newly created role of Chief Strategy Officer, and Brandon Smith was promoted from Chief Business Officer to Chief Operating Officer.
These expanded roles support our continued transition to a fully integrated biotechnology company focused on neurodegenerative and rare peripheral amyloid diseases. This is an exciting time for Prothena. We are encouraged by the significant progress we have made over the past year, and we are looking towards our future. At this time, I'd like to turn the call over to Tran for a discussion of our 2021 financial performance and our 2022 financial guidance. Tran?
Thanks, Gene, and good afternoon, everyone. Today, we reported results that were either in line with or favorably exceeded our 2021 financial guidance. Please refer to our press release for a detailed breakdown of our financial results. As Gene mentioned during his opening remarks, last year, we strengthened our capital position. First, with our strong collaborations, where we received $200 million in payments from our strategic partners in 2021, which includes an $80 million option payment from BMS for the U.S. rights for PRX005, $60 million upfront payment from Novo Nordisk for the acquisition of our ATTR amyloidosis business, and a $60 million payment from Roche for the advancement of prasinezumab into the phase II-B PADOVA study. Additionally, during the year, we received net proceeds of $175 million raised through equity offerings.
In terms of our 2021 financial performance relative to guidance, we had net cash provided by operating and investing activities of $92 million, which was in line with our guidance of $85 million-$95 million. Net income was $67 million, which exceeded our guidance of $50 million-$60 million. As of December 31, 2021, Prothena had $580 million in cash equivalents and restricted cash, which was in line and at the top of the range of our guidance of $570 million-$580 million. Also, we continue to have a clean capital structure with zero debt. Now turning to our 2022 financial guidance.
We expect our full year 2022 net cash used in operating and investing activities to be $120 million-$132 million, which includes an expected $40 million clinical milestone payment from Novo related to PRX004. We expect to end the year with approximately $454 million in cash equivalents and restricted cash, which represents the midpoint of the range. The estimated full year 2022 net cash used in operating and investing activities is primarily driven by an estimated net loss of $154 million-$170 million, which includes an estimated $32 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?
Thanks, Tran Nguyen. Before we talk about our 2022 milestones, I want to first acknowledge and thank our extraordinarily talented employees for their ongoing commitment to advancing our protein dysregulation science to make a real impact for the patients and families we serve. It's a privilege to work alongside my colleagues at Prothena, and I could not be prouder of their accomplishments. I'd also like to thank the patients, their families, physicians, and study site staff who participate in our studies. Without their support, we could not elucidate the potential impact of these new medicines we're developing. Over the past year, our team has delivered on multiple milestones, further advancing Prothena as a leader in addressing devastating proteinopathies.
As you heard today, our dedication to our mission, combined with our differentiated strategy, our diversified portfolio, and our scientific heritage and human talent, have made possible multiple meaningful achievements in 2021 and have positioned Prothena well for an exciting year ahead and beyond. As new data becomes available on the clinical, regulatory, and commercial landscape in the Alzheimer's field, we believe our programs, which have been advanced through our unique and rigorous biology-directed engine and designed to be best in class, are positioned to transform the care of patients suffering from this disease. We are on track and expect to submit an IND filing for PRX012, our anti-A-beta product candidate, this quarter. For PRX005, we are expecting top-line phase I data this year, further elucidating the potential of targeting MTBR tau in treating Alzheimer's.
We're looking forward to multiple scientific congress presentations throughout 2022, beginning with preclinical presentations at AD/PD in March, highlighting first, our new alpha-synuclein vaccine, and second, additional data on our dual A-beta tau vaccine, for which we are planning to submit an IND next year. For prasinezumab, new data will be presented at AD/PD in March, and we are expecting data from the phase II-B PADOVA study in 2024, both of which will be communicated by our partners at Roche. In our rare peripheral amyloid portfolio, we continue to enroll patients in our phase III AFFIRM-AL study of birtamimab, and anticipate top-line data from that study in 2024. Additionally, Novo Nordisk announced plans on their year-end earnings call to initiate a phase II trial during the first half of this year for PRX004 in patients with ATTR cardiomyopathy.
Prothena made excellent progress in 2021. We have a well-balanced portfolio with multiple wholly owned assets, coupled with strong partnerships and collaborations that could allow us to receive up to $365 million in partner payments over the next five years. We expect to make additional progress across our R&D pipeline this year, and we look forward to continuing to provide additional portfolio updates when appropriate. With that, we will now open the call up to Q&A. Operator?
As a reminder, if you would like to ask a question at this time, please press star then one on your telephone keypad. Please limit yourself to one question only. Your first question comes from the line of Charles Duncan with Cantor Fitzgerald. Your line is open.
Hey, good morning, Gene, and team. Congrats on a great year of progress last year. Hard to compete with that one, but I had a quick question on PRX012, and that is relative to the upcoming IND. It sounds like you're ready for this quarter. I guess I'm wondering, when would you anticipate being able to start, you know, clinical studies with that? Could that be shortly, within the first half of this year? Would that become a partnering candidate anytime soon?
Would you be able to take that through, say, clinical proof of concept?
Thanks, Charles, for the question. Maybe I can start, and Hideki can comment as well. I mean, first, you're correct on PRX012. We are expecting the IND filing this quarter. Obviously, you know, there's a time that occurs after that filing where we interact with the agency, and we would expect to begin the phase I clinical trials thereafter. What we're envisioning right now in that phase I program is a single -dose study and a multiple -dose component of that study. And you know, I think on your other question around partnering, right now, we feel that we are in a very good position to develop that molecule.
Some of the advances in the Alzheimer's field, we think, have made it in such a way that we can actually think about proof of concept studies in this space for a company the size of Prothena. We think we're uniquely positioned and well positioned, given our heritage and our expertise and experience in this space, to bring this molecule forward on our own. That certainly is our current plan. Maybe, Hideki, do you want to speak further to any of the near-term clinical plans with PRX012?
You might be on mute, Hideki.
Might be on mute there. Yep. All right. Well,
Hello?
We'll take my answer as wholesome. Oh, you there? There you go. Hi, Hideki. How are you? Yeah, maybe you wanna comment further. Yep.
Yep. You can hear me okay?
Yes, we can hear you.
Okay, great. Thanks. Yeah, no, you stated it quite well, Gene. As a reminder, PRX012 is our high -potency anti-A-beta compound. Because it is high potency, we are giving it subcutaneously. So that's why it should have advantages both in terms of safety tolerability as well as convenience for patients. As Gene stated, we are beginning with a single ascending dose study as well as a multiple ascending dose study very shortly after the IND is cleared, and we will do those in healthy volunteers and patients.
Great. Thank you, Hideki.
I think all of that will culminate in data in 2023.
Right. Great. Thanks for the question, Charles.
Your next question comes from the line of Michael Yee with Jefferies. Your line is open.
Hey, guys. Thanks for the question, and congrats on the progress. We had a question around maybe helping Wall Street think about some of the scenarios in 2022, with regards to the fact that perhaps Wall Street seems a bit mixed or skeptical around Alzheimer's, specifically for PRX012, which is the class. The idea that, you know, what are the scenarios and what are the thoughts around if we have negative results from the industry this year versus positive results, and also how that relates to partnering or strategic pharma interest and how much that data plays a role in their thinking about the value of Alzheimer's. Thank you.
Yeah. Thanks, Mike, for the question. I mean, I think there are several events that we can look to this year in the field. Certainly a lot of data coming, I'd say over the next 18 months. Starting in April, you know, we'll learn the final language around the NCD determination by CMS. We know what that draft language looks like. You know, clearly there's been a lot of commentary that's occurred in the public comment period, and we'll look forward to seeing where that lands, I think here in April. Of course, you know, we think, you know, based on what we've read and what we've seen, you know, that could play into how Eli Lilly thinks about donanemab from an accelerated approval perspective.
What we understand is that there's a rolling submission there consistent with their breakthrough status. Obviously, when they submit that final clinical section, how much is in that, you know, would probably lead one to think more about accelerated versus full approval. That's something that we'll look to this year to kind of see how that plays out. We have data coming from, you know, the phase III trials in the latter part of this year from both gantenerumab and lecanemab, formerly BAN2401. Those are, you know, very a little bit different in terms of molecules and what they mean and how they test the biology, I think.
You know, we probably don't have time to get into that here, but they are a little bit different, with lecanemab being a little bit more N-terminus targeting, gantenerumab having a dual epitope, and the resultant biology therefore is a little bit different. Also, you know, a little bit different in terms of clinical trial design, how they're powered, the prior data that they're powered on. Of course, as we roll into next year, we'll see the donanemab data set. You know, that'll be interesting to see, particularly coming off the phase II TRAILBLAZER-ALZ. A lot of information. I think the relevant thing for PRX012, you know, there's a couple of things to talk about.
First, from an NCD perspective, you know, we think that the language there, regardless of what it ends up being, really has the greatest impact to these nearer -term candidates that we just discussed. I think for PRX012, at this point in time, less of an impact in terms of how we think about the clinical development of that molecule, the overall program. Given what Hideki said already about the potential of subcutaneous administration, you know, we can actually even think about some of these early IV drugs being potentially in Part B where a drug like PRX012 could be considered for Part B, obviously with different implications there around the final coverage determination.
I think, you know, the other component here is I'd be remiss if I didn't state is that there's an awfully good opportunity to learn from these trials. You know, we're gonna have the benefit here of learning across these trials about primary outcome measures, duration of treatment, patient selection. As we move our program forward, we fully anticipate incorporating those learnings into the PRX012 program. From our perspective, just a wealth of information is coming, all to the benefit of the PRX012 program. Let me pause there and ask Tran if he might have some comments on how he sees this as well, just from a strategic perspective moving forward.
Yeah. No, absolutely. Thanks. Thanks, Gene. I think, you know, you said it best in terms of over the next 18 months, you've got donanemab data. This, you know, looks like middle of next year. And then, of course, you have gantenerumab and lecanemab data later this year. And Gene already discussed some of the differences between gantenerumab and against both donanemab and lecanemab. But all that being said, I think a lot of the data that's already been recently announced, so to speak, on lecanemab and donanemab have helped basically to raise a lot of awareness in the field already in terms of, you know, the effectiveness of both of those programs, you know, the positive phase IIs. And that's why those programs only have to do one phase III.
From that perspective, we've learned a lot already from those programs and we're just excited to get to our data here next year in 2023. Then, of course, we will account for the phase III data that come out they do have before we start our registrational trials in 2024. You know, I think everything's in front of us. I think from a strategic perspective, I think. You know, as we answered Charles' question right now with the advent of iADRS as a potential endpoint, we think that's really democratized Alzheimer's clinical development and made it affordable for companies like ourselves.
Right now we expect to wholly own this program all the way through to commercialization, given the call point is a specialty call point, and it's a call point that we're clearly keenly focused on from a neurology perspective. We're really excited for what's ahead of us and for the field too. Thanks for the question.
Your next question comes from the line of Neena Bitritto-Garg with Citi. Your line is open.
Hey, guys. Thanks for taking my question. So I apologize if somebody already asked about this, but I was just wondering if you could give us an update on, you know, the status of enrollment in the AFFIRM-AL study. I was also just curious if you could comment on, you know, how much enthusiasm you're getting from investigators, you know, in enrolling that study. Thanks.
Yeah. Thanks, Neena, for the question. I'll ask Hideki to jump in on the recruitment and level of excitement part of the question. I'll just say that, you know, we're continuing to guide to top line data there in 2024. We're obviously very excited about that program. As I mentioned in my opening remarks, that program came back following, you know, multiple discussions with both the FDA and experts in the AL amyloidosis community, where, you know, we had observed a very promising survival benefit in the Stage IV patients in our prior VITAL study. Also, you know, obviously on the totality of the safety data set.
Bringing that back under a SPA with the division of cardiorenal, at a predefined success value, alpha value of 0.10, obviously we felt, you know, was prudent to do, and we're very excited about moving that molecule forward. Maybe Hideki, do you wanna speak just a bit to some of the operational components of the study?
Sure. Yes. Thanks, Gene. Just to say off the top line, we're expecting top -line data in 2024. We're on track for that. We're seeing a lot of enthusiasm from sites. We just held an investigator meeting that was extremely well attended, that we are activating sites on a very much an active up slope now, and we have randomized patients within the study. We're doing everything and anything we can in order to maintain our enthusiasm. For example, we're going back to sites we've already used in prior studies, so they know us quite well. We have a very much a hands-on, white -glove type of approach to these sites so that they have a direct communication with us. We're engaging patient advocacy organizations like the Amyloidosis Alliance and Amyloidosis Foundation.
We're present at medical conferences like ASH and EHA. We're very, very active out there. We're also growing an MSL field force through ES sites. We're very much on track for our 2024 readout.
I think the other thing to add too, Hideki and Gene, is that the data that continues to come out from daratumumab in AL amyloidosis, although they've gotten accelerated approval, you know, the survival data is still not yet mature, and there's no survival benefit even out to around two years with that data. For patients at, you know, high risk of early mortality in the trial, you know, in their own trial that have already passed away, clearly there's still a high unmet need here for a depleter mechanism like birtamimab.
Of course, the data set that we showed within kinda the first nine to 12 months that we could make a potential that we have a potential survival benefit with a hazard ratio of 0.413 on a post hoc analysis, yes, but that's also supported by our SPA. We're looking forward to confirming those data in 2024. We're excited by the way the field is setting up, and clearly our mechanism is really relevant in the patient population we are holding the trial in for Mayo.
Your next question comes from the line of Jay Olson with Oppenheimer. Your line is open.
Oh, hey, thanks for taking the question, and congrats on all the progress. Maybe just to follow up on that last question. As you look ahead to the AFFIRM-AL study, where you have a really favorable -looking SPA that you mentioned, can you just comment on the current unmet need in AL amyloidosis, including the mixed results from standard of care chemotherapies, the anti-CD38 antibodies that you touched upon earlier? Potential for new entrants, like I think there's a potential BCL-2 inhibitor from Zentalis. Longer term, where you see birtamimab fitting into the treatment paradigm, and your plans to commercialize whether you'll do that alone or with a partner? Thank you.
Yeah. Thank you, Jay. So great questions there. Maybe I can ask Wagner to speak a little bit about this because I think part of what you're asking, Jay, and Tran touched on this, is, you know, the relative differences between targeting protein production, which is what the majority of kind of standard of care approaches do, versus targeting for removal the resident amyloid that has already aggregated and deposited on critical organs. And you know, what we believe is most proximal to actually leading to organ dysfunction. So maybe, Wagner, do you wanna speak just a little bit about that from a mechanism perspective, and then we can jump back and talk about the commercial component?
Yes. Yeah. I think these are essentially the two very important differentiators between lecanemab and the other class that is attempting to slow down the disease progression by going after the source, right? We are talking about light chain that is a precursor of an amyloid that deposits in these organs. When the patients are diagnosed, there is a massive amount of amyloid already there. It makes sense that one would reduce the production of new amyloid, and that's what these plasma cell therapies, and there are many mechanisms that we can lay here. CD38 is one of them.
It makes sense that that would be one step, but also, another step that will make sense is to remove the amyloid that's already causing toxicity directly to the cells in the organ, particularly in the heart. The myocytes are being directly affected by the amyloid. An antibody like lecanemab, from our perspective, is the only opportunity that we have to really reverse a process that has been built for a long period of time. Even in these patient populations that we classify as Mayo Stage IV. These are newly diagnosed patients. We are not talking about different stages of the disease. We're talking about a subpopulation that somehow is at a higher risk of progression, but that amyloid is already causing so much damage that you can see via biomarkers, you can identify those.
Particularly in that population, it's very urgent that you have to remove that amyloid because the consequence will be death. Maybe there is another population that could wait a little bit longer, and the plasma cell therapies could lead them to a point, at least, of extension. The patients at highest risk, it's urgent again, that the amyloid has to be removed as quickly as possible to reverse an ongoing process of toxicity.
That's a great segue.
We believe it's. Yeah.
That's a great segue, Wagner, into the BCMA target. I mean, look, you know, different ways to better control, you know, light chain production is going to be more competition on the mild side, is what we're seeing from the datasets from multiple diseases, AL and ATTR. From that perspective, going back to what Vagner just said, for, you know, for patients that are at high risk for early mortality due to the existing amyloid deposited in the heart, you're going to need a depleter mechanism in order to remove that to have any chance at benefiting that patient. That's showing up in the dara data. From that perspective, we're highly encouraged about our AFFIRM-AL trial and our position, you know, in the disease.
We can then start thinking about potential for combination therapies in terms of mild patients, because again, these mechanisms are complementary. I think those are great questions, Jay, from that perspective. Again, from a commercial perspective, it's our intention to wholly own this program and commercialize it ourselves. It's a very leverageable sales call point for us, calling on hematologists. We know where up to 75% of the patients are. They're at 500 centers. It's a very, you know, it's a very leverageable call point for us. We're excited to commercialize it on our own, and we're looking forward to data in 2024. Thanks for the question.
Your next question comes from the line of Kennen MacKay with RBC Capital Markets. Your line is open.
Hey, thanks for taking the question. Maybe just a housekeeping question on PRX012 and then one on AFFIRM-AL. From your conversations with the FDA, what is gating the IND for PRX012 at this point? Following up on the AFFIRM-AL question, it looks like there are 117 potential clinical trial sites listed on ClinicalTrials.gov, but with only 150 or so patients planned for enrollment, that doesn't quite feel right. Maybe as you look at the trial, how many sites are you planning on opening? I'd love to understand sort of where that is in terms of number of planned sites being opened. Thanks.
Yeah. Thanks, Keenan. Two good questions. I think the first on PRX012, I think what you're kind of asking is what's gating from an IND perspective. You know, obviously this is you know, the operational pick and shovel work. We just need to get you know, our work done. We need to get all the reports finalized. We need to get the IND compiled and filed. That's, you know, we look forward to doing that. As I said, the team's on track. They're working hard. We expect that to be done here in the first quarter. On the AFFIRM-AL trial, you had asked specifically about number of trial sites relative to number of patients. You know, obviously this is a rare disease.
You know, we know these sites well. These are expert centers across the globe. The number of these sites we've worked with in the past, as Hideki had mentioned earlier, in our prior phase III VITAL study. You know, these are sites that are, for the most part, well-known to us. You know, our sites that we know see the patients, for which we're hoping to recruit into the AFFIRM-AL trial. Maybe I'll let Hideki speak a bit more on that latter topic. If you don't mind, Hideki.
As you mentioned, and Gene and clinicaltrials.gov, we have 117 sites recruited, and that's about right. Remember the trial has a total enrollment, 150 subjects, 100 to, you know, for time now, there's 50 to placebo. That's about right. We don't wanna spread ourselves too thin. 117 approximately sites. We're looking at additional sites, by the way. That's about right in terms of enrolling the study on time.
The other thing to mention too is, again, when we first enrolled this trial, you know, we were doing all comers, right? From Mayo Stages I through IV. This time around, this is Mayo Stage IV, newly diagnosed. Again, this is idiopathic disease. You know, it's equal in regions of the U.S. and Europe. We just wanna make sure we're, you know, as Hideki just said, that we leave no rock unturned, and we wanna make sure we do enroll as fast as we can. Hence a lot of the sites we have already worked with, and we're looking for new sites. You know, we're working with some new sites in that number too, that you quoted, and that's on clinicaltrials.gov.
It's just making sure we try to get as expeditiously enrolled as we can.
Your next question comes from the line of Gobind Singh with JMP Securities. Your line is open.
Hey, good evening. Thanks for taking the questions. Just curious on a few things on the light chain and the doses commentary. Are you guys hearing anything for Darzalex on the 2021? I think it was about $6 billion. How much of that is it getting traction in light chain since it was approved there? Curious on the stuff within the Alzheimer's program on the OpEx, the guidance. How much of that, if there is any even for, Like, being planned for PRX012 in that and this. If you can comment any specifics about that $150, I think $270 that you mentioned, Tran, how much of that is being baked to that program would be helpful.
For the dual vaccine data that you guys presented last year, can you comment at all specifically on pyroglutamate A-beta data that you saw in any of the models that were there? That's it for me.
Okay. Great questions, Govind. Thanks. The three questions here are just around, from an AL perspective, you know, where do we—how much do we think Darzalex getting usage, kind of break out a little bit, the guidance around PRX012 and then, a little bit more around the dual vaccine and what we've presented there. Maybe I can ask, Tran, do you want to address the first two, and maybe Vagner, you can talk a little bit about the dual vaccine and what we've presented?
In terms of the AL breakout for Darzalex in terms of their 2021 revenue, we don't have a sense of how much of that is AL, too, to this point. Clearly, I think a lot of it is multiple myeloma driven. In terms of our costs, that being said, it's probably around 20% of our OpEx cost is going to be birtamimab. I think from that perspective, it gives you a sense of how that's rolling, and clearly that'll go into 2023 and into 2024. With that, I'll maybe turn it over to Wagner in regards to the other question.
Yeah. I'll repeat the question. The question was on whether we have data supporting clearance of pyroglutamate with our vaccine. You all remember last year we presented data showing that PRX012 by targeting the N-terminal portion of A-beta could also clear pyroglutamate from plaques of tissues derived from Alzheimer's patients. We think that all the N-terminal antibodies will do the same thing. Whether you are acting directly, binding directly to pyroglutamate like donanemab or any other one of the A-beta, N-terminal A-beta antibodies, they can also, like, PRX012 can indirectly clear pyroglutamate because the microglia and the macrophages, when they are eating the plaques and digesting the plaques, they are not selective on a molecular basis.
They're gonna bind and internalize the binding site of the antibody, but also all the other toxic entities that are part of the plaque. That's why I believe that, like PRX012, the other N-terminal antibodies also do the same. Our vaccine was designed based on the knowledge that we built over many years and more recently with PRX012. You will stay tuned, but don't be surprised if a vaccine that's designed to generate antibodies that bind to the N-terminal portion of A-beta would also promote pyroglutamate clearance.
Your next question comes from the line of Tazeen Ahmad with Bank of America. Your line is open.
Hi, good afternoon, guys. Thanks for taking my questions. One for Tran and one for Gene, if I might. Tran, you did get a $60 million milestone payment from Roche for the Parkinson's program. Should we expect any other milestone payments in 2022? Gene, I was just curious about your thoughts on ATTR. It's obviously now in de novo with him, but just given the recent news flow on other programs that have had data, namely BridgeBio. Just was curious to get your thoughts about the use of six-minute walk as a primary endpoint or whether or not you think ultimately mortality should be used to figure out the efficacy of this class of particular drug and how you might be differentiated.
From not only Bridge, but also the Alnylam approach. Thanks.
Thanks, Tazeen, for the question. I'll take the Roche question. Yes, thank you for the. We did receive the $60 million for the phase II-B PADOVA trial last year. That will be the remaining clinical milestones. The rest will be regulatory, first commercial sale, and then, of course, achieving certain tiered sales milestones in the program. We look forward to, of course, those milestones too, but that's the update on the prasinezumab program. Then I'll let Gene answer your second question.
It's a good question on ATTR and, you know, it's related to what we were discussing around AL amyloidosis and birtamimab. Inasmuch as, you know, much of the current focus in the field is targeting the production of protein. You know, it's a little bit different in ATTR because the normal form of the ATTR protein that underlies its normal function is this homotetrameric state, the four units. You've got kind of two ways to turn off the source of protein coming into this pathological pathway, if you will, right? One way is to just silence the production of protein. These will be your siRNA approaches, you know, and, you know, your antisense approaches and what have you. The other is to stabilize the normal form, right?
These are your stabilizers, like the acoramidis molecule that you're referring to, as well as tafamidis, Pfizer's compound in this space. What have we learned, you know, in the field about that approach, i.e. reducing new protein coming into the pathway? What we've learned is that, you know, it's best exemplified, I think, in Pfizer's data set with tafamidis, that you can see a survival benefit. In fact, you know, they saw, I believe a hazard ratio over a 30-month period of about 0.7, so about a 30% relative risk benefit on mortality, which is obviously meaningful.
When you dig into the data that Pfizer disclosed, what you see is that the majority of that effect is in New York Heart Association Class I, II patients. Very, very little effect. I think the p-value is 0.78, if I remember correctly, in New York Heart Association Class III patients. This would argue, I think, what Tran was referring to earlier, that when you target the front end of this biological pathway, the production side, that, you know, you need to survive long enough, if you will, to actually achieve the benefit of reducing new protein coming into these pathways. That's what it seems to speak to me and to us.
Therefore, you know, a little bit more of a mild patient population might be a place that's appropriate for those types of approaches. Of course, when you move to a more mild patient population, then, you know, the progression of functional endpoints like six-minute walk, which you mentioned, might be a little bit harder to measure change over time because it may just change more slowly. I'm speculating a bit, but I think it's a reasonable conclusion. Where PRX004 differentiates is in its mechanism of action. It's not designed to reduce new protein coming into the pathway. It's designed to address the resident protein that's already aggregated and causing dysfunction at the organ level and to remove that protein.
The way PRX004 was designed was to interact with a region or an epitope that is not available in the homotetrameric form, the normal form, but is available when that form is in a non-normal state. Therefore, we can target that, we believe, and target that material for removal. We, you know, refer to that as a depleter mechanism of action. It's leveraged information that we can see is somewhat similar from a biology perspective between AL amyloidosis and ATTR, even though they're different diseases, with AL being a little more of an aggressive disease in terms of function or functional decline, I should say. You know, we think that the field may very well move in the same direction, which is for patients with appreciable amounts of resident amyloid causing dysfunction.
A depleter mechanism of action like PRX004 may be uniquely suited for those patients. Ultimately, you may think about combination approaches since those mechanisms of action are complementary. As you mentioned in your question, Tazeen, we did have an agreement with Novo Nordisk in this space. We're very happy with that agreement, and they're now taking that forward. They've announced in their earnings call here this month that they expect to start a clinical trial in ATTR cardiomyopathy here in the first half of this year. We're real excited to see that move forward.
You know, obviously, we think working with Novo, particularly on this program, gives us an opportunity to bring that type of medicine to patients on an expedited timeline. We're very happy with that collaboration. I think, maybe, Tran, did you wanna also mention on this? Did you have additional points?
Yeah, absolutely. I mean, I think the tafamidis data is the Bible that everyone's been working from. Clearly, I think, BridgeBio and Alnylam have seen that data set, and it corroborates basically what Gene was just discussing, which is that a stabilizer really worked much better in milder patients, right? The New York Heart Association Class 1 and Class 2 patients and wasn't very efficacious in the Class 3 patients. I think those mechanisms, both silencers and stabilizers, went to the more milder population to actually better their survival readout, although they might wanna extend past 30 months. That being said, that's what they were trying to do.
When you go to milder patients and then you say, "Okay, let's have them, you know, progress in a one-year time period," I think the first look at that was that that's a pretty tall task from the BridgeBio data. From that perspective, we'll see here shortly on Alnylam, and maybe that was just an artifact of BridgeBio's trial, but that is something you have to think about in terms of, again, enrolling a milder patient to advantage you in your mechanism on survival. That's really what we learned from that. I would say, again, from what Gene was saying, from a depleter perspective, we are thinking about, you know, the more advanced patient population.
We're looking forward to the cardiomyopathy phase II trial that Novo is gonna run here and initiate here in the first half of this year. We're looking forward to, you know, basically further clinical studies as needed. Thank you for the question.
That is all the time we have for questions. I'd like to turn the call back to Gene Kinney for closing remarks.
Well, thank you, Josh, and thank you all for joining us. We appreciate your interest in Prothena, and over the coming months, we look forward to sharing further updates on our program. Thank you.
This concludes today's conference call. Thank you for your participation. You may now disconnect.