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spk06: Good afternoon. My name is Audra, and I will be your conference operator today. At this time, I would like to welcome everyone to the Prothena Corporation fourth quarter and full year 2022 financial results conference call. There will be a question and answer session to follow. Please be advised that this call is being recorded at the company's request. I would now like to turn the call over to Mr. Eric Endicott, Prothena's Senior Vice President, Corporate Affairs and Communications. Please go ahead.
spk09: Thank you, operator. Good afternoon, everyone, and welcome to Perthena's investor conference call to review our business progress, our fourth quarter and full year 2022 financial results, and our 2023 financial guidance. Please review the press release we issued earlier today, which is available on our website at perthena.com and is also attached to a form 8K filed today with the SEC. On today's call, Dr. Gene Kinney, our president and chief executive officer, will provide introductory remarks followed by an overview of Prathena's portfolio and development strategy as we continue advancing toward becoming a fully integrated commercial biotechnology company. Following Jean's opening remarks, Dr. Hideki Guerin, our Chief Medical Officer, will provide an overview of the significant achievements and progress made in 2022 across our entire portfolio. Tran Nguyen, our Chief Financial Officer and Chief Strategy Officer, We'll then review our financial results for the fourth quarter and full year of 2022, and we'll discuss our 2023 financial guidance. Jean will then provide closing remarks, and then we will open the call up for a Q&A session where Dr. Wagner-Zago, our Chief Scientific Officer, and Susana Mesa, our Senior Vice President, Strategy and Operations, will also be participants. 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 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.
spk03: Thank you, Eric, and thank you all for joining us today to review our 2022 financial results and business highlights. We're excited today to share Prathena's major achievements in 2022 and how we are advancing a portfolio of drug candidates targeting both neurodegenerative and rare peripheral amyloid diseases. At Prathena, We are driven by our mission to create impactful treatments for the millions of patients that are affected by diseases caused by protein dysregulation. That mission is enabled by our deep scientific expertise, which serves as a unifying thread between our business strategy, our portfolio development, and the dedication that propels Cothenians every day. Turning now to slide five. Today, Prathena is a late-stage clinical biotechnology company with a robust pipeline, which includes four wholly-owned programs and five partner programs. This intentional mix allows us to build a diverse portfolio by leveraging partner payments while still maintaining full upside potential for our wholly-owned assets. For our Alzheimer's programs in 2022, we advanced both PRX-12 and PRX-5 into the clinic, and expect to report top-line Phase I multiple ascending dose data from both programs this year. For PRX123, we have completed several IND-enabling studies and look forward to submitting an IND by year-end. For our Parkinson's disease program, presenizumab is being evaluated by Roche in both the Phase IIb padova and open-label extension portion of the Phase II Pasadena study. We also have two rare peripheral amyloid disease programs. First for Tamimab, a wholly owned program, which is being evaluated in a confirmatory phase three setting and NMC6019, formerly PRX4, which is being evaluated by Novo Nordisk in a phase two study. Collectively, these achievements position us well for a transformational period over the next 24 months. And finally, I will highlight that we remain well-funded to execute on our strategic objectives. We ended 2022 with a strong cash position of $713 million, which included $40 million received for a clinical milestone from Novo Nordisk. Our partnership with Novo, together with our Bristol-Myers Squibb and Roche collaboration, and our wholly-owned programs, allows us to advance our robust pipeline with blockbuster potential, further supporting our goal to address the unmet medical needs of millions of patients affected by diseases caused by protein dysregulation. We believe that our focus on treating and preventing neurodegenerative and rare peripheral amyloid diseases addresses significant unmet medical needs. Our clinical expertise and differentiated approach enables us to advance best-in-class therapies that have the potential to transform the treatment landscape for protein dysregulation diseases. Our focus on developing treatments for neurodegenerative disorders includes therapeutic approaches for Alzheimer's disease and Parkinson's disease, which sadly are growing exponentially. Combined, these two diseases affect an estimated 60 million people globally, a number that is expected to increase rapidly with an aging population. This tremendous social and economic burden is not only experienced by patients, but also by family members, caregivers, and the overall healthcare system. In rare peripheral amyloid diseases, Bertamamab and NNC6019 are being developed in targeted patient populations at high risk for early mortality, which underscores our commitment to develop therapies for patients with an urgent need for improved survival. Before I turn the call over to Hideki, I'd like to highlight several breakthroughs that occurred in 2022 that have meaningfully advanced the overall treatment landscape for Alzheimer's disease. Over the past several months, multiple milestones have been achieved in the Alzheimer's community. Notably, developments include the presentation last November at the Clinical Trials on Alzheimer's Disease, or CTAD, conference of statistically significant and clinically meaningful results across the primary endpoint and all key secondary endpoints from ESI and Biogen's Confirmatory Phase III Clarity AD trial for licanumab. an antibody that targets immunoterminous of A-beta in patients with Alzheimer's disease to both clear plaques and neutralize soluble protofibers. In early January, licanumab received accelerated approval from the FDA for the treatment of early Alzheimer's disease. Notably, the approval was based on Phase II data that demonstrated that licanumab reduced the accumulation of A-beta plaque in the brain which was noted by the agency as a surrogate endpoint reasonably likely to predict positive clinical outcomes. The results from CLARITY-AD, plus the accelerated approval of leucanumab, continues to support the A-beta treatment pathway in Alzheimer's disease, and we believe paved the path for the next generation of plaque-clearing anti-A-beta antibodies, including PRX12, a potential best-in-class subcutaneous treatment for Alzheimer's disease. Another notable development at the CTAD conference was the many scientific advancements in the area of biomarkers. This included research from Dr. Randy Bateman's team at Washington University in St. Louis, which showed that cerebral spinal fluid levels of MTBR tau-243 closely tracked with tau PET, distinguishing amyloid-positive individuals with tau tangles from amyloid-positive individuals without tau tangles. Hideki will cover this exciting data in more detail shortly. At Prothena, we celebrate these advancements and also strive to create novel treatments that further improve efficacy and quality of life for patients. Finding solutions to treat and prevent this disease is crucial. This is why we are advancing one of the most robust Alzheimer's disease portfolios in the industry, guided by our comprehensive therapeutic strategy to address the unmet needs in Alzheimer's. Our portfolio is well positioned in light of these recent scientific advances in the field and positions Prothena as a leader in the transformation of Alzheimer's therapeutic approaches. We are currently advancing three product candidates, PRX12, PRX5, and PRX123, targeting key pathological pathways of the disease cascade, which have the potential to expand from next-generation disease-modifying treatments to combination and prevention paradigms. With that, I'll now turn the call over to Hideki to highlight the progress made across our robust R&D portfolio in 2022.
spk02: Thank you, Gene. I'll start with PRX12, our next generation, patient-centric, subcutaneously delivered investigational treatment for Alzheimer's disease, which targets a key epistope at the immunoterminus with amyloid beta with high biting potency. Frequent data have shown that PRX12 binds to amyloid plaques with very high ability, consistent with the potential for more effective A-beta plaque clearance at lower doses and currently approved NTA beta therapies, allowing for subcutaneous delivery in our clinical trials. PRX-12 is designed with the patient in mind, and we believe it has the potential to be best-in-class, transforming the treatment of Alzheimer's disease. In 2022, the FDA cleared the IND for this program and granted PRX-12's fast-track designation for the treatment of Alzheimer's disease. We then successfully initiated a randomized double-blind placebo-controlled phase one single-sending dose study evaluating the safety, tolerability, immunogenicity, and pharmacokinetics of PRX12 in healthy volunteers and in patients with Alzheimer's disease. The multiple-sending dose portion of the study has commenced, and we expect to report top-line data from the initial dose-level cohort by year-end 2023. We look forward to having a significant presence at the upcoming 2023 International Conference on Alzheimer's and Parkinson's Diseases or ADPD, which begins in late March. Among the planned events are an oral presentation featuring preclinical data showing the superior binding characteristics of PRX12 and the Porcino-sponsored symposium featuring key thought leaders. PRX12 oral presentations will show superior binding of nearly 20-fold higher affinity and avidity with A-beta-prolifibroids when compared to lakenamab and substantially more extensive clearance of pyroglutamate A-beta and plaques of Alzheimer's disease tissue . Our goal with PRX-12 is to offer greater patient accessibility and ease of compliance relative to approved therapies and other immunotumor-targeted treatments currently in development. Compared to first-generation treatments, subcutaneous PRX-12 is also expected to result in smaller fluctuations in antibody concentrations in the brain. I would like to turn now to PRX-5, our NTPR tile targeting monoclonal antibodies. TRX5 is designed to be a best-in-class and TBR-specific anti-TAL antibody. TAL tangos, along with amyloid beta plaques, are pathological hallmarks of Alzheimer's disease, and research indicates that TAL pathology correlates with the clinical and cognitive decline associated with the disease. Early research conducted by Prathena found that targeting specific regions within the MTPR resulted in more consistent and robust production in the pathogenic uptake of TAL into neurons and the downstream neurotoxic effects. As Gene mentioned in his earlier remarks, Dr. Randy Bateman's presentation at BTET 2022 shows MDPR fragments make up the bulk of TAL tangles and the CSF MDPR TAL 243 correlated with TAL PET imaging of the brain at a coefficient of 0.75. These are exciting data that further support the rationale for this target and will continue to inform the team. We recently reported top-line data from the Phase I single-sending dose study evaluating PRX5 in 19 healthy volunteers. The results demonstrated dose-proportional drug concentrations in plasma with robust central nervous system penetration. Single doses from three dose-level cohorts were generally safe and well-tolerated, meeting the primary objective of the study. Exposure in cerebrospinal fluid was measured in the high-dose cohort, and based on the robust exposure of PRX5 in the CSF, which is approximately 0.2% of peripheral levels, substantial target engagement is expected in the CNS. PRX5 had a desirable immunogenicity profile with no persistent PRX5 induced anti-drug antibodies observed. We plan to present these results from the phase one single ascending dose study at an upcoming medical conference. The multiple ascending dose portion of the phase one study is ongoing. The purpose of the phase one multiple ascending dose trial is to evaluate the safety solubility, pharmacokinetics, pharmacodynamics, and immunogenicity following the administration of multiple doses of PRX5 in healthy adults and patients with Alzheimer's disease. We anticipate that these results will help us determine the appropriate dose levels for subsequent clinical studies. Top-line results are expected by year-end 2023. PRX5 is one of three programs being developed in partnership with our colleagues at Bristol-Myers Squibb. For our third Alzheimer's program, PRX123, a dual A-beta Tau vaccine, we presented preclinical data at ADPD 2022 that demonstrated the generation of anti-A-beta and anti-MTBR Tau antibodies that enable phagocytosis of A-beta and neutralization of pathogenic Tau. We look forward to filing an IMD for PRX123 by year-end 2023. This program is exciting because it combines knowledge and mechanisms for both amyloid beta and tau targeting in a single construct, potentially aligning with the prevention as well as therapeutic strategy. Turning now to Prazimizumab and Parkinson's disease. In 2022, Roche, our partner for Prazimizumab, presented data from the Phase II Passage-In Study at ADP 2022. These data are compelling because they support a potential effect on delaying motor progression in Parkinson's disease. In addition to the Passage-In Study, Roche is now conducting the ongoing phase 2b Padova study in patients with early Parkinson's disease. Roche expects to report top-line data from the Padova study in 2024. Now I'd like to discuss the Bacanumab program for the treatment of male stage 4 AL amyloidosis. Certain treatments for AL amyloidosis target the clonal plasma cells that overproduce light chain. While these therapies can reduce new light chain production, they fail to directly address the amyloid that has already been deposited. and is causing organ toxicity and organ failure. Botaminumab is differentiated, and that is designed to deplete the amyloid and soluble aggregates most approximately associated with organ dysfunction. Latina has advanced botaminumab into the ongoing confirmatory phase three, a firm AL study, in patients with male stage four AL amyloid doses under a special protocol assessment, or SPA, agreement with the US FDA with the primary endpoint of all-cause mortality at a significant level of less than or equal to 0.10. Patient recruitment continues to be on track, and the confirmatory Phase III AFIRM-AL top-line data is expected in 2024. In December, at the American Society of Kinetology 2022 Conference, we reported clinical data from the completed Phase III VITO study, which demonstrated in a post-hoc analysis of patients with male Stage IV AL amyloid doses a statistically significant survival benefit of 74% in patients taking Bertanumab versus 49% in patients on placebo at nine months. This reflects a hazard ratio of 0.413 and a p-value of 0.021. Survival benefit of Bertanumab is vital, being consistent across all key baseline variables in male stage 4 patients, reinforcing the strength of the survival data in these patients at a high risk of early mortality. The TAMMAG was generally safe and well-tolerated in the overall population and in NATO Stage 4 patients. And moving now to advances in the ATTR amyloidosis program. PRX4, which has been developed by Novo Nordisk and has been renamed NNC6019, has now advanced into an ongoing Phase 2 clinical study for the treatment of ATTR cardiomyopathy. Novo expects to report top-line data from the Phase 2 study in 2024. At this time, I'd like to turn the call over to Tron for a discussion of our 2022 financial performance and our 2023 financial guidance. Tron?
spk08: Thanks, Sadecki. Today, we reported results that were either in line or favorable to our 2022 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 partnership with Novo Nordisk where we received $40 million related to the Phase II trial of NNC6019 for the potential treatment of ATTR cardiomyopathy. Additionally, in December 2022, we received net proceeds of $172.4 million raised through an underwritten public follow-on offering of 3.25 million ordinary shares. In terms of our 2022 financial performance relative to guidance, we had net cash used in operating and investing activities of $109.3 million, which was in line with our guidance of $108 to $120 million. Net loss was $116.9 million, which was favorable to our guidance of $121 to $137 million. As of December 31st, 2022, Prothena had $712.6 million in cash, cash equivalent, and restricted cash, which exceeded our guidance of $522 million. As of February 17, 2023, Prothena had approximately 52.6 million ordinary shares outstanding. Additionally, we continue to have a clean capital structure with zero debt. Turning to our 2023 financial guidance, we expect our full year 2023 net cash used in operating and investing activities to be between $213 and $229 million. We expect to end the year with approximately $512 million in cash, cash equivalents, and restricted cash, which represents the midpoint of the range. The estimated full year 2023 net cash used in operating and investing activities is primarily driven by an estimated net loss of $250-$275 million, which includes an estimated $46 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?
spk03: Thank you, Tron. Before we talk about our 2023 milestones, I want to first acknowledge and thank our talented Prothena employees for their ongoing commitment to advancing our protein dysregulation science to make a real impact for the patients and families we serve. 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 the 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 diseases caused by protein dysregulation. As you heard today, our dedication to our mission, combined with our diversified best-in-class portfolio and our scientific heritage and human talent, have made possible multiple meaningful achievements in 2022 and have positioned Prothena well for a transformational period ahead. As new data becomes available on the clinical, regulatory, and commercial landscape in the Alzheimer's field, we believe our programs are well-positioned to revolutionize the care of patients suffering from this devastating disease. To that end, we can expect the following key milestones in 2023 and 2024. First, preclinical data demonstrating the superior binding characteristics of PRX12 at the upcoming ADPD 2023 annual meeting. Second, the multiple ascending dose portion of the phase one PRX12 study has commenced, and we are on track to report top line data from the initial cohort by the end of 2023. Third, the phase one multiple ascending dose study for PRX5 is ongoing with top line data expected by year end 2023, further elucidating the potential of targeting the MTBR of tau in treating Alzheimer's. Fourth, for PRX123, we are looking forward to submitting an IND by the end of 2023. Fifth, for presenazumab, we expect that Roche will report top-line data from the Phase IIb Padova study in 2024. Sixth, in our rare peripheral amyloid portfolio, we continue to enroll patients in our Phase III AffirmAL study of recamimab, and continue to anticipate top-line data from that study in 2024. And finally, for NNC6019, we expect that our partner, Novo Nordisk, will report top-line Phase II data in patients with ATTR cardiomyopathy in 2024. I am proud of the progress that Prathena has made in 2022. We have a robust portfolio with multiple wholly-owned assets and strong collaborations. We are well-capitalized, have a robust cash position, and remain focused on executing during the next 24 months. 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'll now open the call for questions. Operator?
spk06: Thank you. At this time, I would like to remind everyone, in order to ask a question, press star, then the number one on your telephone keypad. If you would like to remove yourself from the queue, press star one again. We ask that you please limit yourselves to one question to allow everyone an opportunity to ask a question. We'll go first to Michael Yee at Jefferies.
spk10: Hey guys, good afternoon. Thanks for the update. I'll keep it to one question. With PRX012, I think you've initiated the MAD portion in Alzheimer's patients at the first cohort. Later this year when you have data, can you just describe what you're looking for after treating patients for six months? Are you looking for a certain level of amyloid PET reduction on PET? And how should we contextualize that data and try and compare it to other Alzheimer's antibodies like Likendi? Thank you.
spk03: Yeah, a really important question, Mike, and thanks for asking. So let me just, you know, start by saying that, you know, obviously in the multiple ascending dose study, Our primary objective, obviously, is to continue to establish safety and tolerability over the six-month period. We'll be looking at PK immunogenicity. And as you point out, interestingly, we'll be looking at the pharmacodynamic marker of brain amyloid reduction using PET as the tool to do that. Maybe I can hand it first to Tron, and then maybe Hideki, you can make a comment as well in terms of what our expectations are and how we're thinking about this first-dose cohort relative you know, to other examples of anti-amyloid agents that have shown amyloid reduction by PET. John?
spk08: Thanks, Gene. As you know, Mike, we targeted and modeled the first dose of the MAD phase one to be at the C average concentration level of C average of the 10 mg per kg aducanumab. And so, what we're saying is we believe the first initial dose level cohort will be active. But of course, and Hideki can go into this, we have other dose level cohorts to dial in an optimal, you know, dose for registrational trials later. But again, we're not looking for comparative data. We're looking for active data. And so we'll use the SAD data and also some from the MAD data to further elucidate doses behind the first dose.
spk02: Yeah, and I'll just add, remember, this is a phase one study, so the primary endpoint is safety. We'll, of course, look at pharmacokinetics and pharmacodynamics, as both Gina and Tron have alluded to. And importantly, we'll have additional dose cohorts to look at bracketing that dose.
spk06: We'll go next to Nina Vitrito-Garg at Citi.
spk05: Hey, guys. Thanks for taking my question. Just to follow up on the question that was just asked, could you give us a little bit more detail exactly how many patients we might expect to see data for, for PRX012 later this year. And then also if you can provide any color on, just any more specifics on, you know, kind of exactly the PEP metrics that you'll look at, whether you'll be able to provide us with metrics like the proportion of patients who are amyloid negative or whether we should expect to see results kind of on a centeloid scale and how we should think about that. Thanks.
spk03: Yeah, thanks, Nina. Great questions. So maybe I can hand it over to Hideki to talk a little bit about the multiple-dose study design and some of the elements of that. And you can talk a little bit, maybe, Hideki, as well, about just some of the parameters that we're evaluating from a PET perspective.
spk02: Yeah, so we have, in this first cohort, we have enough patients in order to meet our endpoints, that being safety, pharmacokinetics, and pharmacodynamics as measured by amyloid PET. We will also have MRI to look for any safety issues as well. And so those are the main parameters. We have optional biomarkers as well. So we'll have a very robust data set, remembering, again, that the primary endpoint is safety in this Phase I MAD.
spk08: And we'll also have enough patients in the cohorts, MAD cohorts, to make a statistical analysis as it pertains to the amyloid PET data from a pharmacodynamic perspective. And we'll be looking at, you know, basically a various analysis of centelloids and SUVR reads. Yeah.
spk03: I mean, the other thing I'll just point out, Nina, as a follow-up to your question is, you know, I don't want to lose sight of the fact that the single-dose data, you know, is something that we'll also be talking about this year. And we think that's of importance as well. You know, as you know, with PRX012, given its binding characteristics, and its development as a subcutaneous approach with the target product profile once monthly sub-Q delivery, we think the single-dose data could be quite informative as well just to tell us how closely we've come to our target product profile. So we think all that data will be important. And again, the anticipation is we'll talk about that all together.
spk06: And next, we'll move to Charles Duncan at Cantor Fitzgerald.
spk01: Yeah. Hi, guys. Thanks for taking the question and congrats on a good year of progress. I also had a question on 012 and probably a two-part one. And that is that with regard to the single dose data, could you be presenting that at AAIC or CTAD? And then the second part, is when you talk about sub-Q and being patient-centric, best in class, what exactly are you going to be considering to evaluate whether or not you hit that target product profile?
spk03: Yeah, thank you for the question. So first, I think with respect to where the data will be discussed, obviously we'll wait until we actually are able to speak to that. So clearly that requires not just us targeting a certain meeting, but an abstract being submitted and being accepted. So typically we wouldn't talk about where we would talk about those data until such time as we announce that publicly. I think for the single-dose data, the current expectation should be that we'll speak about the single-dose data along with that first cohort of multiple-dose data. You know, that's the current communication around that. So that's, I think, the right expectation to have currently. I'll mention just from a sub-Q perspective, and maybe I can ask Wagner to talk about some of the characteristics of PRX-12, which we think enable this, you know, it really is about a target product profile. And what we set out to do with PRX-12 was to develop an antibody that by design would lend itself to subcutaneous administration. And that, of course, requires a number of key characteristics being met. You know, it was an intensive screening campaign to develop antibodies with the right characteristics. And, you know, what we're looking for now in our clinical studies is obviously to understand if we've met that. And, you know, at the highest level, what I would say is we're most eager to have a once-monthly sub-Q delivery that provides the same level of occupancy of A-beta as some of these first-generation antibodies which may require much more intensive delivery because of their less optimal profile and characteristics. And so if you think about once-monthly sub-fused single syringe, that's really what we're going for. That's the optimal target product profile for us. We think that that enables potentially patient access. So for patients that have a potential to advantage from these types of treatments, we want to make sure that patients can actually receive these types of treatments. And we think moving to that kind of target profile makes a lot of sense in that regard. So maybe, Wagner, if you could, just a little bit of overview on some of the key characteristics that we looked at as we were developing and ultimately selecting PRx12 to meet that target profile.
spk12: Yes, absolutely, Jim. So for PRx12, we talk about affinity a lot. That's a very intuitive. that if you increase the potency of an antibody, you can dose at much lower doses to reach the same level of target occupancy and the same level of clearance that other antibodies that are lower potency will do. But for it to be subcutanous, an antibody requires additional features. It's not only to be more potent, but we have to remember that this antibody is going to be delivered in a different compartment in the periphery. And from that compartment, from subcutaneous to the blood, there is a barrier. So, as Gina was saying, when we designed PRX12 and had to screen many, many antibodies, we included in the design and in the screening all those additional features that a subcuable antibody needs to have. One is bioavailability, stability, not only in the high concentration solution, but the stability in that same compartment where it's delivered. And all of that was part of the screening, in fact, that raised PRX12 to the top. This is different than a campaign where you normally start with an IV antibody and try to make it a sub-Q. You might encounter some challenges at that point, and we didn't want to because, as Jean said, X12 was born to be a subcutaneous antibody, and we directed that preclinically. So, as was said before, the importance of a phase one for us is sad to confirm that we, that our assumptions to clinically are reading in patients that bioavailability, exposure, all of that is read very early on. That's very important for us because we can tweak our models and ensure that the doses that we selected for the MAD, for example, are appropriate doses, that they are active, and not only that, that they are leading to a target engagement that will be meaningful for the target product profile.
spk06: We'll take our next question from Jay Olson at Oppenheimer.
spk11: Oh, hey, guys. Congrats on the progress, and thank you for taking the question. Can you talk about how you see the reimbursement landscape evolving for Alzheimer's therapeutics, especially with yesterday's comments from CMS and also since PRX012 is designed to be delivered as a sub-Q? And then also maybe in the context of your broader Alzheimer's portfolio with PRX005 and also your dual Tau amyloid vaccines? Thank you.
spk03: Yeah, Jay, really good question. Thank you for them. Maybe I'll ask Tron to also speak to this, but just as a quick kind of overview, I think the announcement yesterday we saw generally as encouraging. I think within, you know, the current NCD, you know, the response to the Alzheimer's Association request to reconsider the prior decision Obviously, it was a little disappointing that that wasn't entertained, but at the same time, I think it was encouraging that CMS came out and did suggest that on full approval within the former NCD construct, they would look to think about almost immediate reimbursement in a much broader context. So, we think that's positive. We think that's a way to actually increase the reimbursement footprint in the near term while still having the ability to reconsider the full NCD moving forward. But that said, as you appropriately pointed out, you know, a subcutaneous approach, you know, particularly those that may be envisioned to occur in the home, could actually be in Part D as opposed to Part B in the Medicare scheme. And, of course, that has different consequences with respect to NCD, national coverage determinations, and we think actually positions – TRX-12 quite well for potential reimbursement in that context. I think the other question that you're kind of asking a little bit may be around the accelerated approval pathway and what that continues to look like. And, of course, we were encouraged by the accelerated approval of licanumab. In particular, the fact that the basis of approval there was based on the Phase II data, and the basis of that approval was really on amyloid plaque reduction as measured by PET. So, we think that that accelerated pathway from our perspective, provided that you can meet the key elements of the accelerated approval pathway, which is a serious disease and an unmet medical need. We think that that continues and remains open as a potential path for PRX12. But at the same time, you know, we're looking at our program in a holistic way. We're thinking about an end-to-end, you know, how do we move this molecule forward through the clinic in a way that's most appropriately ambitious, but at the same time provides us with the broadest data package on which to enter the commercial market. So we're, you know, we do think about that from an end-to-end perspective. But maybe, Tron, I can ask you to comment a little bit further on the decision yesterday that CMS kind of published and how you see the field.
spk08: Yeah, I know. I think just to build on what you said is, I mean, clearly the letter pointed to the fact that they understood that there is more data, meaning how we read it was the phase three data. I think during this review, they didn't look at that. What they said is in order to work expeditiously to get a broader coverage for patients, they wanted to work within the existing, you know, NCD and the CED that they put out there, and they have broadened that. What they've basically communicated that they will broaden that upon full approval. They do mention a registry. There is a registry that, you know, the Alzheimer's Association has. And so we'll see what the details of that are. But at this point, you know, they are broadening it. They're saying, hey, between review of full approval, we'll review the data. At least in that period, you'll get broader coverage potentially through a registry. And then after real-world data is collected and then after review of the phase three data, they would go back and take a look at potentially changing that to something even broader than that. And so I think what they were working with was do we start from, you know, kind of a zero, which is, okay, it'll take nine to 12 months for a new NCD process versus, you know, broadening through a registry. So we do see it as CMS working with, you know, working with FDA and, you know, I think they understand that FDA's job is to approve, you know, or to make the decision on approval of licanumab, and once that happens, You know, they can then review the data and then do what they need to do. But again, we see that as very encouraging. And, you know, again, we will work with regulators to build, again, on what Jean was saying about our path to patients. There are potential paths forward for us that Jean just covered. But also, ultimately, we need to talk to regulators about that. But again, we do feel that accelerated approval is based on unmet need. And as you know, there's millions of patients in the prodromal, the mild stage of the disease. And we think that even according to ESI's, you know, estimates of 100,000 patients in a year after three years of marketing, that's an underpenetrated, you know, market, so to speak. And so there will be an unmet need. And we'll work hard to figure out what our path to patients are. And we'll come back and update you all when that happens. Thank you.
spk06: We'll go next to Brian Abrahams at RBC Capital Markets.
spk00: Hi there. Good afternoon. Thanks for taking my question, and congrats on all the progress. I'm curious, how are you guys envisioning the future dosing paradigm for Alzheimer's beta amyloid antibodies? Do you think this will be finite dosing with amyloid checks, chronic dosing, or some sort of induction maintenance? And I guess I'm curious how that might shape your 012 development strategy with regards to potentially enabling the most robust safety data set for potential accelerated approval.
spk03: Thanks. Thanks, Brian. So, yeah, I think you're exactly right. There are a couple of different monoclonals out there that target slightly different species of amyloid beta and are talking about the dosing paradigm slightly differently. So I think from our perspective, as we think about targeting the most pervasive form of amyloid in the brain, you know, in its misfolded or dysregulated state, it is a chronic treatment paradigm. I think we're aligned with, you know, for example, many of the things that you hear from the folks at ASI and some of the analysis that they've done, particularly from their phase two data set where they had a gap year where they weren't dosing patients. It actually showed that some of the key biomarkers were starting to revert back to worsening during that time. I think there are other approaches out there that target a subspecies of amyloid data post-translational modification where there may actually be less of that material in the CNS. And maybe, you know, I'll ask Wagner to comment on that as well. And I think under those conditions, it may make sense to stop treating after a period of time that that particular species has been eliminated or at least substantially reduced. But that may not be true in the context of all treatments. And, you know, it may or may not lead in long term to a better treatment profile. I think that's something that we'll find out after, you know, longer longitudinal beta sets have come in across multiple compounds, and particularly multiple compounds that target a beta in slightly different ways. Our current view of the data is that chronic treatment is likely needed. The amyloid beta is a key toxic insult in the CNS in the context of Alzheimer's disease. Not only does it cause problems on its own, but it leads to dysregulation of other key proteins, such as tau. You know, one of the key reasons that we talk about PRX1, 2, 3 as a dual amyloid beta tau targeting agent is because we do believe that those biologies are on target pathway. So we do know, for example, that amyloid beta can lead to tau dysregulation, which can lead directly to neuronal dysregulation. So we do think that ultimately A-beta will continue to provide a toxic insult if it's left unchecked. And therefore, it needs to be part of the foundational treatment as we think about disease modification. So maybe, Ivaga, do you want to expand on some of that science?
spk12: Yeah, just to echo what you just said, Gene. What determines the period of treatment is likely what the mechanism is. If you have an antibody that binds to a multitude of toxic forms from all the very small soluble aggregates, all the H-amyloids, you likely need that antibody to be delivered chronically because those small toxic forms can be formed very quickly in the brain of patients. If you remove completely the most compact forms of the plaque and that's what we visualize when you do a PET scan. It doesn't mean that you don't have amorphous material around that can accelerate the position of more amyloid and make it even more solid. If your antibody binds to all those forms, all the pathogenic forms, we see that as a chronic treatment. Now, if the antibody is binding to a post-translation modification that requires time to happen once you got rid of the initial material, then there is, of course, a lag between that and the formation of a new pathogenic form. So it probably wouldn't make sense to have an antibody around if you don't have a target. So, again, it all depends on the mechanism of action of the antibody. And an N-terminal antibody that binds to all pathogenic forms, like licanumab, like PRX12, we think that it makes perfect sense to position as a chronic treatment.
spk08: Just to build on what Gene and Wagner were saying is, clearly, we're going to follow the data here. I think the Phase III data from ClarityAD given what Wagner just said about hitting all the species that could be pathogenic, not just maybe the post-translational modification, you know, pyroglutamate A beta. We know what that results in, in terms of the phase three clarity. We're excited to see the phase three trailblazer two trial from, you know, from Denonimab. And we'll look at that data in terms of the trial designs they have where they dose to amyloid negative and stop. So we'll see how that all affects clinical endpoints, because I think that'll be a great learning, and it'll tell us how to design our registrational trials going forward.
spk06: And we'll move to our next question from Jason Butler at JMP Securities.
spk07: Hi. Thanks for taking the question. Just had one on PRX-5. Just wondering if you could give some comments about what you're looking to take away from the MAD results later this year. I guess, what you've taken from the SAD results in terms of target engagement and how you're thinking about it going forward and how you think about biomarkers specifically, as you mentioned, how 243 CSF and how you could include that in the program. Thanks.
spk03: Yeah, thanks, Jason. Good question. So, I mean, first, you know, just a little bit about how we got to the MTBR region. You know, we... We were, you know, tau is a complex protein, right? It has six splice variants over 440 amino acids and some of those variants. And so understanding how to target that protein in order to ameliorate some of the negative biology that's associated with it when it becomes dysregulated was, you know, quite important. I think the team under Wagner's direction did a great job in really looking at how you target that protein, you know, really exploring aminoterminous targeting antibodies, carboxy terminus targeting antibodies. And really it was this key region within the MTBR region that ended up being something that gave us very consistent and robust biological effects. And so we were encouraged then when we started to see some really compelling work in the field, start to focus in on these MTBR region and the MTBR containing fragments. So for example, Mark Diamond's work suggesting that these MTBR fragments are critically important in the cell to cell transmission of dysregulated tau. And also, as we mentioned in the call, Randy Bateman's work at WashU really suggesting that when you evaluate these MTBR-containing fragments in the CSF, they much better track with not only CalPET, but also with potential level of dementia in patients with Alzheimer's disease. So we were encouraged by that. To your question specifically in the multiple-dose study, again, I'd be remiss And Hideki would definitely correct me if I didn't say that, you know, the primary objective of that study is safety tolerability. But as you say, we are interested in looking at CSF target engagements. We're interested in particular in these MTBR fragments. And I don't know, Hideki or Wagner, if you want to speak to kind of the nature of the fragments that we'll be evaluating in the context of potential pharmacodynamic effect in the central nervous system compartments here like the CSF.
spk12: Yeah, I'll just reiterate. Go ahead, Wagner. You go first. Maybe on the identity. So we will provide the full detail of what fragments we are looking for, but certainly they are not different from the fragments reported as fragments that track well with the disease progression by WashU, for example. And it's a great opportunity for us. We have a very good understanding of what is the engagement of the target that we want to reach full potential for this antibody. So, we'll use that as a confirmation of our assumptions for dose selection and activity in the brain as well. And the details about the assays that we're going to be using, we'll review that once we have the data and the full data set. I just want to mention that we are extremely I'm lucky that we found the MTBR domain of DAO as being impactful via screening. It was an empirical determination, but at the same time, the field developed to a point that today we can measure MTBR in the CSF. Not long ago, it was a mystery why MTBR is not present in the CSF while the other fragments are, and it was a question of sensitivity. So now we are in a position where we have what we believe is one of, or if not the best anti-MTBR antibody that binds to multiple sites in the MTBR-containing fragments, but also the assay that allows us to confirm that it has the activity that we designed antibody to have in the CNS. And with all of that, basically you can make your recommendations for a phase. to read out, and I'm just going to add one more element as these studies become bigger. There is another element that also helps us in decision-making, which is the availability of fat ligands for tau that we can use to track directly intracellular pathology. So, all of that is part of the plan, but I'll let Hideki talk about it.
spk02: Yeah, I just wanted to reiterate that we're very pleased with the FAD results that were announced earlier. It's very safe, tolerable, and In particular, the CSS data show we have 0.2% penetration, which we're extremely pleased with, because that really indicates a substantial target engagement. And as far as the MAD data, as Wagner mentioned, we will have not only safety, but we'll have the CSS data in terms of MTBR engagement from the CSS in Alzheimer's patients. So that's all data we expect by the end of the year.
spk06: And at this time, there are no further questions. I will turn the call back over to Gene Kenney for closing remarks.
spk03: Well, thanks, Operator. And I want to thank you all for joining us on the call today. We appreciate your interest in Perthena. And over the coming months, we look forward to sharing further updates on our program. Thank you all.
spk06: That does conclude today's conference call. Thank you for your participation. You may now disconnect.
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