This conference call transcript was computer generated and almost certianly contains errors. This transcript is provided for information purposes only.EarningsCall, LLC makes no representation about the accuracy of the aforementioned transcript, and you are cautioned not to place undue reliance on the information provided by the transcript.
spk07: 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 Zabuda, you may begin your conference.
spk01: Jennifer Zabuda 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 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. Jean Kinney, our President and Chief Executive Officer, will highlight Provena'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 Jean'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 Jean for closing remarks. We will then open the call for Q&A and be joined by Dr. Hideki Garan, 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. And with that, I'd like to turn the call over to Gene.
spk04: 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. Patina 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, Bertamumab and PRX4 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 processes 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 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. Praveena'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 Prathena 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 data sets confirming the benefit of anti-data therapies that interact with the immunoterminists of that target. This progress stands on the shoulders of many great scientists, including Prathena's late co-founder, Dr. Dale Shank, and multiple Prothena scientists who carefully observe and follow 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've developed three product candidates targeting key pathological pathways of the disease cascade, which expand from next-generation potentially disease-modifying treatment to potential combination and prevention strategies. Our portfolio takes advantage of the scientific and clinical trial design advances and positions Prathena 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 PRX12, a potential best-in-class, patient-friendly, subcutaneous delivery treatment for Alzheimer's disease, targeting a key epitope at the immunoterminus of amyloid beta with high binding potency. To date, preclinical data have shown that PRX12 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 PRX12 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 PRX12 has the potential to transform the field of Alzheimer's disease Our goal with PRX12 is to offer greater patient accessibility and compliance relative to the approved therapy and other immunoterminous targeted treatments currently under development. Compared to first-generation treatments, subcutaneous PRX12 is also expected to result in smaller fluctuations in brain antibody concentration. This feature may allow us to differentiate on both efficacy and safety endpoints. Because of its high binding potency and suitability for subcutaneous administration, PRX12 has the potential to serve as a foundational anti-ABETA 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-ABETA therapies to maximize the probability of success for our PRX12 program. In 2021, we also brought our tau-targeting monoclonal antibody, PRX5, into the clinic. PRX5 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. With diseases, or ADPD, in March of last year, we presented new preclinical data showcasing pathology and downstream behavioral deficits in multiple in vitro and preclinical in vivo models. PRX-5 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. Our data showed that vaccination of mice and primates generated a robust
spk09: and balanced immune response to the intended epitopes on amyloid beta and tau without a cytotoxic T cell response to these endogenous proteins.
spk04: Importantly, the resultant 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 potentially aligning with a prevention strategy. Turning to presenazumab and Parkinson's disease, Roche, our partner for presenazumab, presented data at ADPD in March of last year.
spk09: New analyses from part with presenazumab's greater effect on subgroups of patients that exhibited more rapid disease progression.
spk04: 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. also made significant advancements in our rare peripheral amyloid disease portfolio. 2021 was an important year for our Bertamamab 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 three affirm AL study, where the pre-specified alpha for study success was defined as 0.1. The SPA agreement followed from multiple discussions with the FDA Division of Cardiology and Nephrology and AL Emily Dosen's expert position on the overall safety of vertamumab and previously observed survival benefits in the vital study. We initiated our global Registration of FIRM-AL study last year and are currently enrolling patients.
spk09: Amyloid doses target the clonal 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.
spk04: Bertamamab is differentiated as it's believed to remove the amyloid most proximally associated with organ dysfunction. We have extensively published on Bertamamab's well-defined epitope and depleter mechanism of action, which we believe provide 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 one study of for cardiovascular diseases to advance this promising treatment to patients on an expedited timeline. As part of this agreement, Perthena 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 trans-thyretin production with a depleter mechanism of action that is designed to target and remove the resident protein. Moreover, TRX4 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-expositioned Perthena for long-term growth and success. Starting with our board of directors, in May, we appointed to our board Dr. Sanjeev Patel, CEO of Relay Therapeutics, and an established leader with significant industry experience. In April, we appointed Dr. Hideki Guerin 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, Chang Wen, 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 Perthena. 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 Tron for a discussion of our 2021 financial performance and our 2022 financial guidance. Tron? Thanks, Gene.
spk03: Good afternoon, everyone. Today, we reported results that were either in line with or favorably exceeded or 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 PRX-5, $60 million upfront payment from Novo Nordisk for the acquisition of our ATTR amlidosis business, and a $60 million payment from Roche for the advancement of prasinezumab into the Phase 2b 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, operating and investing activities of $92 million, which of $85 to $95 million. in cash, cash equivalents, and restricted cash, which was in line and at the top of the range of our guidance of $570 to $580 million. Also, we continue to have a clean capital structure with zero financial guidance. We expect our full year 2022 net cash used operating and investing activities to be $120 to $132 million, which includes an expected $40 million clinical milestone payment from Novo related to PRX4. We expect to end the year with approximately $454 million in cash, 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 to $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 model.
spk04: I want to first acknowledge and thank our extraordinarily talented employees, 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 Prathena, 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.
spk09: Without their support, we could not elucidate the potential impact of these new medicines we're developing.
spk04: Over the past year, our team has delivered on multiple milestones. further advancing Perthena as a leader in addressing devastating proteinopathy. 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 Perthena 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 PRX-12, our anti-ABETA product candidate, this quarter. For PRX5, we are expecting top-line Phase I data this year, further elucidating the potential of targeting MTBR, PAL, in treating Alzheimer's. We're looking forward to multiple scientific Congress presentations throughout 2022, beginning with preclinical presentations at ADPD in March, highlighting, first, our new alpha-synuclein vaccine, and second, additional data on our dual A-beta-TAL vaccine, for which we are planning to submit an IND next year. Procrastinazumab, new data will be presented at ADPD in March, and we are expecting data from the Phase 2b 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 3 Affirm AL study of Bertamamab 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 two trial during the first half of this year for PRX4 in patients with ATTR cardiomyopathy. Coupled with strong partnerships and collaboration that could allow us to receive up to $365 million
spk09: our R&D pipeline this year, and we look forward to continuing to provide additional portfolio updates when appropriate.
spk04: With that, we will now open the call up to the Q&A.
spk09: Operator?
spk07: As a reminder, if you would like to ask a question at this time, please press star, then the number one on your telephone keypad. Please limit yourself to one question only. Your first question comes from the line of Charlie.
spk09: That's not a great question. It's 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.
spk11: I guess I'm wondering when would you anticipate being able to start You know, clinical studies, would that be shortly within the first half of this year? And would that become a partnering candidate any time through, say, clinical proof of concept?
spk04: Yeah, thanks, Charles, for the question. Maybe I can start, and Hideki can comment as well. But first, you're correct on PRX-12. 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
spk09: component of that study.
spk04: And 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 as such a way that we can actually think about proof of concept studies in this space for a company the size of Prothena. So we think we're uniquely positioned and well-positioned given our heritage and our expertise and experience in the space. to bring this molecule forward on our own, and that certainly is our current plan. But maybe, Hideki, do you want to speak further to any of the near-term clinical plans with X12?
spk03: You might be on mute, Hideki.
spk11: I might be on mute there, yeah.
spk04: All right. We'll take my answer. It's wholesome. There you go. Hi, Hideki. How are you? So, yeah, maybe you want to comment further. Yep.
spk12: Yep. You can hear me okay? Yep, we can hear you. Okay, great. Thanks. Yeah, no, you stated it quite well, Gene. As a reminder, PRX-12 is our high-potency anti-ABETA compound. And because it is high-potency, we are giving it subcutaneously. And so that's why it should have advantages both in terms of safety, tolerability, as well as convenience for patients. And as Gene stated, we are doing a single-sending-dose study, as well as a multiple-sending-dose study very shortly after the IMG is clear. And we will do those in healthy volunteers and patients.
spk03: All of that will culminate in data in 2023. Great. Thanks for the question, Charles.
spk07: Your next question comes from the line of Michael Yee with Jefferies. Your line is open.
spk02: 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 with PRX012, which is just the class. And 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.
spk04: yeah thanks mike for the question i mean i think there are several events that we can look to this year in the field um 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 that could play into how Eli Lilly thinks about the nanomaps in there, consistent with their breakthrough status. And 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.
spk09: So that's something that we'll look to. this year to kind of see how that plays out.
spk04: And then we have data coming from, you know, the phase three trials in the latter part of this year from both Gantt-Nurimab and Mecanimab, formerly Gantt-2401, 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, Mecanimab being a little bit more immunoterminous targeting.
spk09: Again, the prior data that they're powered on.
spk04: And then, of course, as we roll into next year, we'll see the Denanamab data set, particularly coming off the Phase II trailblazer. So a lot of information. I think the relevant thing for PRX-12, you know, there's a couple things to talk about. First, from an NCD perspective, 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 PRX12, 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. And 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 TRX-12 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 say it, is that there's an all an awfully good opportunity to learn from these trials. So we're going to have the benefit here, the learning across these trials about primary outcome measures, duration of treatment, patient selection. And as we move our program forward, we fully anticipate incorporating those learnings into the PRX-12 program. So from our perspective, just a wealth of information coming all to the benefit of the PRX-12 program. Let me pause there and ask Tron if he might have some comments on how he sees this as well, just from a strategic perspective moving forward.
spk03: Yeah, no, absolutely. Thanks, Gene. I think, you know, you said it best in terms of over the next 18 months, you've got Denonimab data that, you know, looks like middle of next year. And then, of course, you have Gantanerimab and Lecanimab data later this year. And Gene already discussed some of the differences between Gantanerimab against both Denonimab and Lecanimab. But all that being said, I think a lot of the data that's already been recently announced, so to speak, on Lecanimab is and Denonimab have helped basically raise the effectiveness of the positive Phase IIs.
spk09: And that's why those programs only have to do one Phase III. So 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.
spk03: And then, of course, we will account for the Phase III data that come out. They do that before we start a registrational trial in 2024. So, you know, I think everything's in front of us. And I think from a strategic perspective, I think as we answered Charles' question right now with the advent of of iAdress as a potential endpoint. We think that really democratized Alzheimer's clinical development and made it affordable for companies like ourselves. So right now, we expect to wholly own this program all the way through to commercialization, given the call point as a specialty call point. And it's a call point that we're clearly keenly focused on from a neurology perspective. So we're really excited for what's ahead of us and for the field, too. Thanks for the question.
spk07: Your next question comes from the line of Nina Petrito-Garrick with Citi. Your line is open.
spk05: 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 AFIRM AL study. And I was also just curious if you could comment on, you know, enrolling in that study. Thanks.
spk04: Yeah, thanks, Dina, for the question. So 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, you know, you know, a very promising survival benefit in day of stage four patients in our prior vital study. And also, you know, obviously on the totality of the safety data set. So bringing that back under a spa with a division of cardio renal 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.
spk12: Maybe the operational components of the study? Sure. Yes. Thanks, Gene. Just to say off your expense up again in 2024.
spk09: On track for that. And we're seeing a lot of busy happen from sites we just saw them. That's good.
spk12: I mean, that was extremely well attended, that we are have activated sites on a very much active upslope now. and we have everything and anything we can in order to maintain our disease.
spk09: For example, we're going back to sites that we've already used in power studies, so they know us quite well.
spk12: There's very much a hands-on, white-glove type of approach to these sites so that they have a direct communication with us.
spk09: We're engaging patient advocacy organizations like the Analoid Alliance and Analoid Justice Foundation.
spk12: And we're present at medical conferences like ASH and EHA. So we're very, very active out there. We're also growing at MSL, MSL field force, the EHA site. And so we're very much on track for 2024.
spk03: I think the other thing to add, too, continues to come out from daratumumab and ALMidosis, although they've gotten it for years with that data.
spk09: So for patients at, you know, high risk of early mortality in their own trial that have already passed away, clearly there's still a high unmet need here for a depleter mechanism like botanumab.
spk03: And, of course, the data set that we 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. So 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 a firm ale.
spk07: Your next question comes from the line of Jay Olson with Oppenheimer. Your line is open.
spk08: 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 AFIRM 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 chemotherapies, the anti-CD38 antibodies that you touched upon earlier, and then potential for new entrants, like I think there's a potential BCL-2 inhibitor from Zentalis. And longer term, where you see Bertamamab fitting into the treatment paradigm and your plans to commercialize, whether you'll do that alone or with a partner. Thank you.
spk04: yeah thank you jay uh so great questions there maybe maybe i can ask um wagner to speak a little bit about this because i think i think part of what you're asking jay and tron touched on this is you know the relative differences between targeting protein production which is what the 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. And so maybe, Wagner, do you want to speak just a little bit about that from a mechanism perspective, and then we can jump back and talk about the commercial component?
spk12: I think there's essentially the two very important differentiators between the erythema and the other class that is attempting to slow down the disease progression by going after the source. 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, sleep D38 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.
spk09: The myocytes are being directly affected by the amyloid.
spk12: And in an antibody like birtanumab,
spk09: from our perspective, is the only stage four. So these are newly diagnosed patients. We're not talking about different stages of the disease. We're talking about a cell population causing so much damage that you can see via biomarkers.
spk12: You can identify those. And particularly in that population, it's very urgent that you have to remove that amyloid because the consequence will be that. Maybe there is another population that could wait a little bit longer. Endoplasmic cell therapies could lead them to a point at least of extension. But the patients at a highest risk, it's urgent, again, that that amyloid has to be removed as quickly as possible to reverse an ongoing process of toxicity.
spk03: That's a great segue, Wagner, into the BCMA target. I mean, look, different ways to better control light chain production is going to be more competition on the mild side, is what we're seeing from the data sets from multiple diseases, AL and ATTR. So from that perspective, going back to what Wagner just said, 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. and that's showing up in the DERA data. And so from that perspective, we're highly encouraged about our firm AL trial and our position, you know, in the disease. And then we can then start thinking about potential for combination therapies in terms of mild patients because, again, these mechanisms are complementary. So I think those are great questions, Jay, from that perspective. And, 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. So it's a very leverageable call point for us. So we're excited to commercialize it on our own, and we're looking forward to data in 2024. Thanks for the question.
spk07: Your next question comes from the line of Kenan McKay with RBC Capital Markets. Your line is open.
spk06: Hey, thanks for taking the question. Maybe just a housekeeping question on X12 and then one on Affirm. What is, from your conversations with the FDA, what is gating the IND for X12 at this point? And then following up on the Affirm ALs, It looks like there are 117 potential clinical trial sites listed on CLIN trials, but with only 150 or so patients planned for enrollment, that doesn't quite feel right. So maybe as you look at the trial, how many sites are you planning on opening? And I'd love to understand sort of where that is in terms of number of planned sites being opened. Thanks.
spk04: Yeah, thanks, Henry. So two good questions. So I think the first on X-12, I think what you're kind of asking is what's gating from an IND perspective. And, 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. So that's, you know, we look forward to doing that. As I said, the team's on track. They're working hard. And we expect that to be done here in the first quarter. On the AFIRM AL trial, you had asked, specifically about number of trial sites relative to number of patients a rare disease um you know we we know uh these sites well these are expert centers across the globe um the number of these sites we've worked with in the past uh as hideki had mentioned earlier um in our prior phase three um vital study and so you know these are sites that are for the most part well known to us and, you know, our sites that we know see the patients for which we're hoping to recruit into the AFIRM AL trial. But maybe I'll let Hideki speak a bit more on that latter topic, if you don't mind, Hideki.
spk12: Sure, sure, yeah. So as you mentioned, in qnan.com, we have 117 sites listed, and that's about right. Remember, the trial has a total enrollment of 150 subjects, 102 students. Over time, I'm at 52 acetyl. So that's about right. We don't want to spread ourselves too thin. And so 117 approximately. We're looking at additional sites, by the way. That's about right in terms of growing the study on time.
spk03: So the other thing to mention, too, is, again, when we first enrolled this trial, we were doing all comers, right, from Mayo stages one through four. And this time around, this is Mayo stage four newly diagnosed. And so, again, this is idiopathic disease. You know, it's equal in regions of U.S. and Europe. So we just want to make sure we're, you know, as – Hideki just said that we leave no rock unturned, and we want to make sure we do enroll as fast as we can. So, 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 two that you quoted, and that's on clinicaltrials.gov. But it's just making sure we try to get as expeditiously enrolled as we can.
spk07: Your next question comes from the line of Gobind Singh with JMP Securities. Your line is open.
spk10: Hey, good evening. Thanks for taking the questions. Just curious on a few things on the light chain amlidosis commentary. Are you guys hearing anything for Darzalex on 2021? It was about $6 billion. How much of that is getting traction in light chain since it was approved there? And curious on the Alzheimer's program and the Outback guidance, how much of that, if there is any, even for like being planned for PRX 12 and that and this, if you can comment any specifics about that 150, I think 170 that you mentioned, Trent, how much of that is being baked to that program would be helpful. And then 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?
spk04: Okay. Great questions, Govan. Thanks. So, kind of the three questions here are just around, from an AL perspective, you know, where do we, how much do we think Darzalex is getting usage? Kind of break out a little bit the guidance around X12 and then a little bit more around the dual vaccine and what we've presented there. So, maybe I can ask, Tron, do you want to address the first two and maybe, Wagner, you can talk a little bit about the dual vaccine and what we've presented?
spk03: So in terms of the AL breakout for DERA in terms of their 21 revenue, we don't have a sense of how much of that is AL to this point. Clearly, I think a lot of it is multiple myeloma driven. And then in terms of our costs, that being said, it's probably around 20% of our OpEx cost is going to be Bacamabab. And so I think from that perspective, it gives you a sense of how that's rolling, and clearly that'll go into 23 and into 24. So with that, maybe I'll turn it over to Wagner in regards to the other question.
spk12: Yes, I'll repeat the question. The question was on whether we have data supporting clearance of PyroBlue with our vaccine. And you all remember last year we presented data showing that PRX12, by targeting the N-terminal portion of A-beta could also clear tyroglutamate from plaques of tissues derived from Alzheimer's patients. We think that all N-terminal antibodies will do the same thing. Whether you are acting directly, binding directly in PyroBlue, like Denonimab, or any other one of the A-beta, N-terminal A-beta antibodies, like X12, can indirectly clear uh pyroglue because the micro microglia and the macrophages when they are eating the plaques and digesting the plaques they are not selective on a molecular base they are going to buy internalize the the binding site of the antibody but also all the other toxic entities there are be part of that that block and that's why i i believe that uh like prx12 the other internal antibodies also do the same. Our vaccine was designed based on the knowledge that we built over many years and more recently with X12. So you will stay tuned, but don't be surprised if a vaccine that binds to the N-terminal portion of the data would also promote pyoglutamate clearance.
spk07: Your next question comes from the line of Tazeen Ahmed with Bank of America. Your line is open.
spk00: Hi, good afternoon, guys. Thanks for taking my questions. One for John and one for Gina Fine Mike. John, you did get a $60 million milestone payment from Roche for the Parkinson's Should we expect any other milestone payments in 2022? And then, Jean, I was just curious about your thoughts on APTR. It's obviously now in Novo's hands, 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 on-island approach. Thanks.
spk03: Yeah, I'll take the Roche question. So, yes, thank you. We did receive the $60 million for the Phase IIb Padova trial last year. So that will be the remaining clinical milestones. The rest will be regulatory, first commercial sale, and then, of course, achieving certain tier sales milestones in the program.
spk09: So we look forward to that.
spk03: I look forward to, of course, those milestones too, but that would be the update on the Pracinezumab program. And then I'll let Gene answer your second question.
spk04: Yeah, so it's a good question on ATTR. And, you know, it's related to what we were discussing around AL amyloidosis and bertamumab in as much as, you know, much of the current focus in the field is targeting the production of protein. And, you know, it's a little bit different in ATTR because the normal form of the ATTR protein that underserves or underlies its normal function is this homotetromeric state, so four units. And so you've got kind of two ways to turn off the source of protein coming into this pathological pathway, if you will.
spk09: One way is to just silence the production of protein.
spk04: So these are your siRNA approaches and your antisense approaches and what have you. The other is to stabilize the normal form. So these are your stabilizers, like the eidos molecule that you're referring to, as well as tefamidase, Pfizer's compound in this space. And so what have we learned, you know, in the field about that approach, i.e., reducing new protein coming into the pathway? And what we've learned is that, you know, and that's exemplified, I think, in Pfizer's data set with the faminus, is that you can see a survival benefit. In fact, they saw the 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 1-2 patients. Very little effect. I think the p-value is 0.78, if I remember correctly. in New York Heart Association Class III patients. So this would argue, I think, what Tron was referring to earlier, that when you target the front end of this biological pathway, the production side, that 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. And therefore, 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 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. So I'm speculating a bit, but I think it's a reasonable approach. uh it's a reasonable conclusion where perex4 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 perex4 was designed was to interact with a region or an epitope that is not available in the homo-tetrameric form, the normal form, but is available when that form is in a non-normal state, and therefore we can target that, we believe, and target that material for removal. So we 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. And so we think that the field, may very well move in the same direction, which is for patients with an appreciable amount of resident amyloid causing dysfunction, a depleter mechanism of action like PRX4 may be uniquely suited for those patients. And ultimately, you know, you may think about combination approaches since those mechanisms of action are complementary. So, you know, as you mentioned in your question, Suzanne, you know, 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. So we're really excited to see that move forward. And, 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. And so we're very happy with that collaboration. I think maybe, Tron, did you want to also mention on this?
spk03: Did you have additional points? Yes. Absolutely. So, I mean, I think that's a feminist data is the Bible that everyone's been working from. And clearly, I think BridgeBio and LNILAM have seen that data set. And it corroborates basically what Gene was just discussing, which is a stabilizer really worked much better in milder patients, right, the New York heart patients. I think those mechanisms, both silencers and stabilizers, went to the more milder population to actually better their service. So then when you go to milder patients and you say, okay, let's have them progress in a one-year time period, I think the first look at that was that that's a pretty tall task from the bridge bio data. So from that perspective, what that is something you have to think about in terms of, again, enrolling a more milder patient to advantage you in your mechanism on survival. So that's really what we learned from that.
spk09: And I would say, again, from what Jean was saying,
spk03: From a depleter perspective, we are thinking about, you know, a more advanced patient population, and so we're looking forward to the cardiomyopathy phase two trial that Novo is going to run here and initiate here in the first half of this year, and we're looking forward to, you know, basically further clinical study for the question.
spk07: That is all the time we have for questions. I'd like to turn the call back to Gene Kinney for closing remarks.
spk04: Well, thank you, Josh, and thank you all for joining us. We appreciate your interest in Perthena, and over the coming months we look forward to sharing further updates on our programs. Thank you.
spk07: This concludes today's conference call. Thank you for your participation. You may now disconnect.
Disclaimer