Prothena Corporation plc (PRTA) Earnings Call Transcript & Summary

Good morning, everybody, and thank you for attending Citi's 16th Annual Biopharma Conference. I'm Neena Bitritto-Garg, one of the biotech analysts here, and I'm pleased to be joined this morning by the management team from Prothena. So I have with me today, President and CEO, Gene Kinney; and CFO and COO, Tran Nguyen. And we're planning to cover a range of topics from the Company's kind of recent shift in focus to Alzheimer's programs as well as the other wholly owned programs in birtamimab and the partnered portfolio. And before we get into the formal discussion, I just wanted to note that, if you have any questions during the discussion, feel free to e-mail me directly or [ send some ] questions through the online portal, they'll come to me, and I'll try and incorporate them as time permits. So now I just want to turn it over to Gene for some opening remarks.

Well, thanks, Neena, and thanks, first of all for having us. Really appreciate being here today. Yes. So for those that don't know Prothena, maybe just a brief overview of what it is that we do. We tend to focus on dysregulated proteins and their contribution to disease. So think about a protein needing to fold in a certain 3 dimensional confirmation when that process goes awry, and it overwhelms the normal clearance pathways as proteins can tend to accumulate in various organs in the case of the central nervous system, in the brain or in neurons in the brain. In the case of peripheral diseases, in various organs up to and including the heart, which causes a cardiomyopathy and can lead to significant morbidity and in some cases mortality in those diseases. So what we tend to do is really focus on how to intervene in that process, how to target the proteins in what we think is the correct way in order to ameliorate that negative biological outcome and to provide benefit. And what that's brought us to is a fulsome portfolio where we have a number of therapeutics in clinical development, Phase III studies, Phase II studies, Phase I studies and a number of preclinical assets that cover both these peripheral amyloid diseases as well as a number of neurodegenerative diseases, I think you mentioned Alzheimer's disease, and we're very excited about where that portfolio is today. So thanks for having us again and happy to jump into the questions here.

Well, thanks for being here. So yes, so let's start with Alzheimer's disease because, of course, with the recent aducanumab approval, that's become a very hot topic for you guys. And I know we will talk a little bit more about this later on in the neurodegenerative panel that you'll be on as well. But can we just talk a little through your kind of high-level thoughts on the implications of both the aducanumab approval and kind of the subsequent conversations that the approval, the pricing and the launch have kind of driven in the space? And what do you think that kind of means for companies like yourselves in the Alzheimer's space?

Well, I'll tell you what we're encouraged by. I mean so we're very encouraged, first and foremost in the shift of the therapeutic approach in Alzheimer's disease, moving from symptomatic treatment to this first generation of disease-modifying approaches. And what we think that does is, it opens the door not only for better disease modification, i.e., higher efficacy, and maybe even expanding the potential patient population that could advantage from these types of approaches, but also starting to see now a path to thinking about prevention trial. So secondary prevention, ultimately, primary prevention. One of the things that preceded even the aducanumab approval was some very nice data showing iteration and advancements in clinical trial design for these types of disease-modifying treatment of Alzheimer's disease. I'd point to, for example, first, the EMERGE and ENGAGE studies that Biogen conducted, where the introduction of CDR sum of boxes as a clinical assessment scale, seem to really improve the fidelity, and we saw that in the EMERGE study, in particular. We've learned a number of things from that. You saw some further iteration of that in the TRAILBLAZER study that Eli Lilly conducted, they're introducing the iADRS endpoint as a clinical assessment scale, further improving patient selection criteria by introducing tau-PET imaging at baseline, and again, at later time points. And so I think as we continue across the field to improve on these clinical trial design aspects, what we're seeing is more appropriate ways to see the benefit of these types of approaches and sometimes even earlier in the course of treatment, relative to what was required previously. And the final point then on the regulatory side, obviously, what the regulators do with respect to understanding whether substantial evidence of effectiveness has been met and under what paradigm, an accelerated approval or full approval is something that the regulators are responsible for. And we look to them for that guidance in terms of what it will take to get these next-generation of therapeutics that have the opportunity to be better in class or best-in-class through the finish line. And obviously, that's something that we're paying attention to, and we're thinking about as we generate clinical trial designs for our programs.

I think the only thing I'll add to that is, we feel like the story isn't just about Abeta, too, right? I mean I think we're definitely encouraged by the summary basis of approval there and the support the regulators have for the amyloid hypothesis, that lowering plaque will lead to being benefit for patients. We're also looking for to push the field forward in terms of our tau program, right, PRX005 that's partnered with Bristol. I think the more information, the more data we can generate there, then, of course has a positive effects for our dual immunogen vaccine, right? So again, regulatory clarity is great. I think we saw that with aducanumab. We'll see that further here with the potential accelerated approval of donanemab. I think that will inform us in terms of our development pathway. And then, of course, again, anything that we can do to derisk tau increases the value of PRX005, but of course, allows for the dual immunogen vaccine to really come through, and that could be used in both the treatment and a prevention paradigm, right? So that's -- those are basically our suite of programs that we really believe are kind of an end-to-end solution for all time.

So kind of starting with PRX012, your amyloid antibody. A key question that I kind of get from investors is how differentiated it is versus aducanumab, and the other anti-amyloid programs that are in Phase III. So Gantenerumab, Lecanemab and Donanemab, of course. And then, of course, how quickly you can get it to market as well? So I guess we'll start with the first one. If you could talk a little bit through some of the preclinical data that you presented today, that suggests that PRX012 is potentially more potent anti-amyloid antibody versus some of these others, and how you see kind of the potential for a subcutaneously administered product to be kind of differentiated from the others?

Yes, absolutely. It's a great question, and it's exactly what we designed PRX012 to do. So you're referring to PRX012 as Tran kind of introduced, that's a wholly owned monoclonal antibody, it's designed to be best-in-class. And the history here, you're aware of our heritage, it goes all the way back to the initiation of this field, right, with the initial AN-1792 study, bapineuzumab trials. As we saw the clinical trial design, the clinical trial science, the regulatory science, iterating and moving forward over the years, one of the things we recognized was first, appropriate epitope targeting for these types of proteins is very, very important. And we believe, based on our science, the targeting immuno terminus of the amyloid beta protein allows you to both interact with the soluble oligomers or the soluble aggregated forms of the protein, but also, which are known to be synaptotoxic, but also to address the plaque components, right? The deposited forms that actually deposit in the brain parenchyma. And so as we saw these amino terminus targeting antibodies move forward on the backdrop of an improved clinical trial design and regulatory science backdrop, we felt that it was likely that one of these therapies might be approved. And you mentioned some of those from that class of immuno terminus targeting agents, Lecanemab or BAN-2401s, donanemab and aducanumab. Obviously, aducanumab became the first approved under the accelerated approval paradigm. But even back a number of years ago, as we looked at that, we saw a number of limitations. And let's just start with the most obvious. And that was convenience, access, making sure that all patients that could be advantaged by these types of treatments actually had access to them. And we felt that an IV infusion approach even once monthly or more frequently for some of these other agents could be problematic from that perspective. And obviously, access drives compliance, compliance in many, many disease states is related to positive clinical outcomes. So that's a very important element here. And so in order to think about a convenient treatment schedule with a convenient dosing paradigm like subcutaneous, we needed a highly potent immuno terminus targeting anti beta agent. We sought out to do that starting a number of years ago, went through a number of campaigns and selected ultimately PRX012 as the preferred approach there. As you indicated, it's more potent, and we've looked at the potency in terms of interacting with the amyloid beta protein, [ creating ] a 10-fold more potent, for example, than aducanumab. Importantly, it seems to recognize more forms of abnormal amyloid beta than aducanumab as well. So both by ELISA, you see a bigger Emax, also by immunohistochemistry, you can see a very avid binding to more diffused forms of deposited amyloid beta, and we think that's to the advantage of a PRX012 like molecule as well. And most recently at AAIC, the meeting AAIC in Denver, we actually shared that PRX012 is very effective in not only clearing unmodified forms of deposited amyloid beta, but also power contaminated modified forms of amyloid beta as well. And so it really hits all of the abnormal species and brings those, has the ability to, we believe, remove those from the parenchyma of the brain. So we think PRX012 sets up then, both from a convenience, access, treatment, paradigm schedule and schedule of administration perspective as a potential best-in-class. We think that moves the field forward. And as Tran said, then behind that, we also have a tau targeting agent and a dual agent, an active vaccine that targets both amyloid beta at that important amino terminus as well as the tau protein at a region that we think is critically important as well.

Now that was super helpful. So then I guess, just in terms of how quickly you think you can kind of move PRX012 forward. And I think with the donanemab data in hand, the aducanumab approval, donanemab potentially moving towards a filing and maybe an approval at some point next year. In my view, it seems like you should be able to get to a rapid proof-of-concept from a biomarker perspective pretty quickly in a handful of patients in like a Phase Ib type study. And then you should be able to potentially run a small Phase II study in a very kind of selected kind of group of patients. Am I thinking about this correctly? And I guess, just anything else you can tell us about just your thoughts on the development path forward, time lines, things like that?

I think if I can just add in here, I would say a lot is in front of us, which is fantastic as a drug developer, right? We're going to learn a lot. Well, one, we already have learned a lot from the aducanumab approval, right? And all the documentation that came around that. Then we've learned a lot from other folks' Phase II proof-of-concept trials, like the advent of iADRS has definitely been a development welcome development in the industry. That being said, we'll learn a lot from the conversations that Lilly is having with the regulators, right, in terms of the accelerated potential pathway for donanemab. So in terms of what we'll be looking for, I think you're definitely on the right track, Neena, in terms of thinking about like next year, we'll be thinking about putting out -- we'll get PRX012 to the -- I think we just lost Neena -- PRX012 to the clinic here with an IND here in the first quarter. We'll also put out more animal data that will show plaque lowering, right, in the transgenic mouse model. And then, of course, we'll follow that up with human data in 2023, and then we're going to be looking for starting our registrational trial in 2024. So again, a lot of the time to approval will have a lot to do with the conversations that Lilly also has with the regulators. So we'll be watching that closely. And we would like to note that what we loved about the iADRS data that Lilly put out is there was statistical significance at earlier time points, right, at 9 months, 12 months, 15 and 18 months. So again, ultimately, we need to have our own conversations with regulators, too. But that being said, we do -- we're encouraged by the path. Sorry, Gene, I don't if that...

No, absolutely, you're right. Everything you said is spot on. I think to just add maybe a little bit to that. We do think there is a clinical path here that allows us to move the molecule forward as expeditiously as possible. We think generating data around plaque reduction using PET methodology is important to bring into the program at an early time point and early stage. That's something we'll be looking to do. And I think as we continue to build out the size of the total clinical development plan, increase the safety database size. We'll be looking then to bring these types of important functional outcome measures together with that plaque reduction. And so that's really the plan as we think about it from a high level. And I think Tran is spot on at the more detailed level.

So I just want to ask kind of a question that I've gotten from some investors around the potential impact of the ongoing Phase III programs for some of the other anti-amyloid agents, right? So I believe second half of next year, we should be getting some data from both Gantenerumab and Lecanemab. And I guess I'm just curious kind of what you think the read-through is to kind of the broader anti-amyloid field and the broader kind of Alzheimer's R&D space, if one or both of those data sets don't look -- maybe the way that we hope they will.

Well, I mean, obviously, the details matter, right? So it won't surprise you to hear me say that the question of how these succeed or how they don't succeed, what does the actual data say? What have we learned? What was the patient selection criteria? Were there subsets or things were effective, I'd also just point out since you kind of put Lecanemab and Gantenerumab together, that we do view those as maybe a little bit different in terms of the hypothesis they're testing. Lecanemab, of course, is an immuno terminus targeting at a beta agent as is donanemab and aducanumab. Gantenerumab has reported second epitope according to, I think, Roche. And I personally couldn't say what that second epitope brings or subtracts from the equation. So I do think that's a bit of a different test, and we'll see what that brings. We do know that where you target on these proteins matters with respect to result in biological outcome. So I think it is important to have that distinction in your head as you think about the results from any given trial. Said in another way, targeting abeta anywhere is not the same as targeting in a very specific place. And I think one always has to take that into account. So at the end of the day, the field continues to move forward. We learn from the field in terms of clinical trial design, we learn from the field in terms of the regulatory pathway. And obviously, we'll learn from the field to a great extent from these upcoming trials. And clearly, we'll look to the details to tell us how to better refine trials moving forward, so that we can get a better patient selection for our trials, get a faster answer with a more robust dynamic range so that we can actually detect impact of these types of approaches at an earlier and a more robust way.

But I think in terms of your question 2, I think the great news is that you're going to get a lot of these data sets back to back. Right? So there's going to be a wealth of information in a very short period of time. So let's just say 2023, just for a second, that's like if they all land kind of either early, mid, to late '23; '23 will be a data-rich Phase III to pull a lot of information from as we head into our registrational trials, so that we then can, of course, properly design ours, right? So as you know, clinical science is very iterative. So I think we look forward to those data sets, and as Gene already said, I think the details will matter. And we clearly believe that the trials at least from Lecanemab and Donanemab, we've seen clinical data that supports their potential efficacy, right, from the Phase II proof-of-concept perspective.

And maybe bringing this to a real example, I mean, you take a look at, for example, the Eli Lilly TRAILBLAZER study, where they introduced Tau-PET as an inclusion criteria into that study. And from an inclusion/exclusion perspective, excluded patients that were in the highest part of the Tau-PET signal and the lowest part. But within the patients that were included then divided those into 3 groups, the low Tau-PET, medium and the high Tau-PET patients. And most of that clinical benefit was seen in the lower and medium Tau-PET patients. And I think that actually provides at least over the time frame that those patients were observed. So within the context of that type of clinical trial design, it does give you further refinement to think about how to enrich so that you can see a signal at an earlier timepoint in a more robust way. And those are the types of examples that we would look for in emerging data sets as well.

Okay. I guess before we kind of -- because I do want to talk about the rest of your, kind of, Alzheimer's pipeline as well. But before we shift to that, I guess, just closing up on PRX012, is there anything that we should kind of look out for over the next, let's say, 6 months in terms of additional preclinical data or anything like that, that we should kind of keep in mind?

Well, I think -- I think I could say, we're heading towards the clinic here in the first quarter of next year. And then I think we'll look to put out some more preclinical data next year. And then, of course, human data in 2023. So I think that's a fair kind of time line on the PRX012 program.

So I do want to talk about Tau as well. So I know we've already talked on amyloid around kind of the importance of epitope selection. But obviously, that's becoming a very -- I guess, heated kind of topic in the tau space in particular. So I guess, can you talk a little bit about just your thoughts on both epitope selection and the importance of it at a high level? And then also specifically as it relates to tau. And then yes, we'll get into some additional questions on tau after that.

Yes. It's an important question, and it kind of goes quite a bit to our scientific approach in platform. I mean we think about 3 things when we think about interacting with these proteins to ameliorate the biological toxicity that they induce. The first is where to interact with the protein. So what's the appropriate epitope, and I'll circle back to that. The second is, how do we bias the molecules to interact with the abnormal form of the protein, and to the best extent possible leave the normal form and function of the protein intact. Because a lot of these proteins tell us a great example, how important normal homeostatic function, right? And we need to make sure we leave that intact to the best extent possible. And then the third is how to make sure that we're not biased in our approach, how do we actually design the molecules to do what we want them to do in terms of removal of the depositive forms of the protein preventing new protein from being aggregated as it's made and so on and so forth. So we think about those 3 components, we think about where to target, we think about selectivity for the abnormal form, and then we think about mechanism in terms of what we want to do with the protein once we recognize it. And so the -- moving back to the epitope part, we take a more empirical approach. So there's a lot of work out there suggesting that different forms of tau are in the toxic form, right, and provide the toxicity that's relevant to Alzheimer's disease. We take a little bit of a different approach. As you know, tau comes in 6 splice variants, there's discussion about 3R and 4R forms of tau in terms of its relevance to disease. And I think as we look at it, we want to understand what forms of tau without knowing at a structural level, what those look like, what forms of tau are actually driving negative biology. And so we set up a number of biological outcome measures that run everything from cell-based assays, all the way through to in-vivo transgenic mouse studies and then we explore the protein. So tau, of course, over 400 amino acids in length, so -- and a number of post translational modifications. So there's a lot to explore there. You can explore everything from the immuno terminus, all the way through to the carboxy-terminus. You can look at phosphorylated forms, you can look at truncated forms, and that's what we do. In the case of tau, we made antibodies to the -- that canvas all of these different parts of the protein as well as these different post-translational modifications. And we simply ask the question, when we interact with tau here, does it provide a consistent and robust biological benefit across our biological systems? And if the answer is yes, then we feel pretty good that we've addressed 2 questions. First, that epitope or that region of tau is available to interact with in whatever form it is actually causing that biological effect. And second, that interacting with that available space is sufficient to ameliorate that biological outcome. And when we feel comfortable with that, we move the molecule forward, and that's exactly what we did with PRX005, and how we landed in a specific region within the MTBR of the tau protein. Now we've looked at antibodies that interact with other parts of the protein, and at least in our hands, as they're suboptimal, they're either inconsistent in terms of their effects across these different models or they're not as robust as targeting this very specific region within the MTBR. And obviously, unlike PRX012, which is wholly owned, PRX005 is a molecule that's partnered with our collaborators at Bristol-Myers Squibb, clearly, having looked at both this approach as well as the results of targeting this specific region, they made the decision to opt into this PRX005 program earlier this year. So we're delighted to have them as collaborators. And obviously, that's already begun Phase I trial and that's now moving forward.

So I think the key question that I've been getting, at least over the last week is around, there's this other anti-tau antibody that reported some data last week in a kind of more mild to moderate Alzheimer's population that had some kind of mixed results. I guess what's kind of your take on that announcement overall? I mean it's -- I know it is targeting a different epitope, also a different patient population, I think, than what you would be looking at. So there's definitely some differences here. But I guess just what are your thoughts kind of at a high level on that update?

Yes, it's still hard to say. I mean we've probably seen the same thing as everyone else, which is that there was an impact on ADAS-cog/11, and there was I guess, it wasn't statistically significant, let's say, that way. I don't know if there was an impact or not on ADL and CDR sum of boxes and some other endpoints as well. It sounds like the data -- at least there was no report on data on biomarkers, tau-PET and what have you. So a little hard to know what that means right now. I mean as most people will know, CDR sum of boxes contains components of both cognition as well as function. And so given that cognition moved in the ADAS-cog/11, but not in CDR sum of boxes at least in a composite endpoint, what does that mean with respect to function and what happened on ADL. And we just don't have those data yet. So it's very hard to understand what that means. At a high level, it's at least on the face, encouraging. I mean so if at a -- at least what's in our hands, the suboptimal epitope, you're driving some benefit, then that makes us feel very good about our approach, which at least in our hands, again, in the preclinical space, was very consistent and robust in terms of the benefit it provided. I would say as well, we didn't address it, but it's also a different isotype. So that molecule is on an IgG4 isotype, which has reduced effector function. One of the things we shared in our PRX005 program is that when you make that antibody on a fully effector competent isotype, you actually see better biological activity than if you reduce the effector function. So we think across the board, we're very confident in our approach. We like the approach that we've taken from a consistency and robustness of biology perspective. And I think if we're starting to see some activity even targeting at least what's in our hands, the less optimal epitope, then that bodes quite well from a future studies perspective.

So I guess, maybe if you can talk a little bit about just kind of -- I know PRX005 and a Phase I study right now, I guess, can you talk us through kind of some of the next steps for that program and how you're thinking about the development pathway there, kind of the types of patient populations you're thinking about? I know it's early, and I know it is a partner program, but to the extent that you can kind of comment on those things, that would be great.

Yes. So I'm happy to kick it off and maybe, Tran, you want to add some color. But I think very similar to what we spoke about with PRX012, we want to get to tau-PET reduction or assessing tau-PET reduction early in the clinical development program. We think that, that's important. We also think that there are some CSF markers that could be very interesting with respect to target engagement. And we know now subsequent to us kind of really understanding that this was an important epitope through the work of Randy Bateman and others that MTBR tau fragments in the CSF actually are very well correlated to both level of dementia in patients with Alzheimer's disease and the presence of Alzheimer's disease. And so that ends up being an important biomarker, you can look to just to think of that we'll likely have some of those kinds of biomarkers early in the clinical development program as well. But Tran, do you want to talk in any more detail?

Yes. I mean I think we'll look for that CSF data here next year. I think that will be what we look for. And then, of course, that will follow -- be followed by the PET data for tau, and we'll come back to you all later next year and give you the time lines on that. But as you were saying, we're looking to get early signs of pathology reduction, right, in terms of the Phase I. So we'll be really excited about that. And I think if we can -- you can do that in CSF and do that in the PET, I think we really have derisked that. And again, all of that will inure to the dual immunogen vaccine on top of -- as a wholly owned asset for ourselves. So we're excited about all of what we're experiencing on the abeta side and on the tau side. So we're looking forward to that.

Yes. And I think that's really an important point, which is, I think, ultimately, as we think about first generation disease modification and starting to do better then thereafter, both in terms of level of efficacy, but also the patient population that can be treated. One of the places I think the field is already thinking about going is combining these approaches. And as we now are learning more about what you can do and how you can measure the targeting of the amino-terminus of amyloid beta as we've been talking about, the MTBR region in tau. What we've done is generated an active vaccine, and we've presented some nonhuman primate data on this at the AAIC meeting that actually targets both. And it targets both at amino-terminus as well as the MTBR region of tau. And that's -- and what's important about those types of vaccine approaches is, first from a biology perspective, we've learned that you need to avoid a cytotoxic T cell response to these endogenous proteins. That's a very important component. You need to be able to produce roughly equivalent titer, so that one doesn't drive -- the amyloid beta doesn't produce a high titer and the tau is a low titer, you need those to be relatively equivalent. And of course, because Alzheimer's disease tends to be in an elderly population, you need to make sure you can generate a robust immune response. And those elements are all inherent in this vaccine and shown in that nonhuman primate data. So as Tran said, it gives us 2 opportunities. The first is to think about this now as a combined treatment approach for patients that already are diagnosed with Alzheimer's disease, potentially even in the [ normal ] to mild space. But then ultimately, as the field continues to move towards identifying patients at biological risk of disease, starting to think about secondary prevention paradigms, and with success there, ultimately down the line, thinking of primary prevention as an approach.

Absolutely. So I guess just to wrap up kind of the discussion around the Alzheimer's programs. I know we've talked a lot about the kind of amyloid tau vaccine, but I guess, if you could just talk a little bit more broadly about the earlier stage kind of Alzheimer's portfolio that you guys are working on? I know you've got a couple of other programs as well. So maybe if you could just give us some highlights kind of from the rest of the portfolio, that would be great.

Yes. I mean I think in terms of some of the earlier work, obviously, we'll come out and we'll talk about some more of this in specificity as those things are developed. We've got a few things that we've talked about on our pipeline slide, including some partner programs with Bristol-Myers Squibb. So one is in the area of TDP-43, which is a little bit more broadly in neurodegeneration than Alzheimer's disease. We've got an undisclosed target there as well. One of the things that we think quite a bit about is how to maintain specificity in terms of targeting these dysfunctional proteins? You think about tau as an example there, where you really -- the role of tau in microtubule stabilization, preventing axonal shortening and microtubular shortening and maintaining the integrity of the Axon of neurons is actually very, very important. So how do we think about actually further improving the ability to target proteins like tau, not necessarily tau, but like tau both from an intracellular and extracellular perspective? We've been working hard on some of those things. We'll come out and we'll talk about some of those details at the right time. But suffice to say, our portfolio is organic. It has come from the laboratories of Prothena. Those laboratories have a heritage that go all the way back to Elan Pharmaceuticals and before that, Athena Neurosciences, many of the same scientists are still in our laboratories that were at Athena back in the day. So that heritage, that understanding, that knowledge is really something that we take advantage of, and are really proud of. And I think it has generated a robust R&D pipeline, and we expect that to continue.

Okay. So in the last 10 minutes or so, I do want to talk about some of the other programs kind of in your portfolio, and I guess, just staying on the neurodegenerative disease, got to train here for a minute. So you also have an Anti-Alpha-synuclein antibody in development that's being advanced by Roche in a Phase IIb study. So one of the questions that I frequently get from investors is around the topic we've already discussed at epitope selection and how prasinezumab is differentiated from some of the other Anti-Alpha-synuclein programs that have not yielded super positive data in the past. And I guess, also then just what in particular do you think convinced Roche, I guess, to be excited about moving the program forward from the Phase IIa data?

Yes. So two important questions there. One is around the epitope again. And I think the other is just around the clinical data that we've derived to date. I think on epitope, again, a very similar approach on Alpha-synuclein. And Alpha-synuclein being just somewhere around 140 amino acids. And so again, mapping that protein, there are satiated forms, there are truncated forms. So we needed to think about the best way to target alpha-synuclein. And in our hands, there was a certain region kind of to the Carboxy-terminus side. So it's not the extreme Carboxy-terminus, but kind of that direction that, again, provided just very robust and consistent biological outcomes in our hands. It has a great effect on inhibiting cell to cell transmission of alpha-synuclein. We saw reduction of pathology, protection of morphological structures, so cell to cell connectivity, good functional benefit across the board, very effective antibody. It's hard to saying that targeting some other epitopes didn't periodically, -- we might see some inconsistent benefit or some marginal benefit in terms of magnitude. But this region was by far in a way the best region, again in our hands. And so that was really what -- where prasinezumab came from. We took that through a number of clinical trials, first in Phase I partnered with Roche, ultimately and conducted the first Phase II trial. Now in that first Phase II trial, there were a number of very important learnings. And I don't want to understate this in terms of simplicity. But clearly, one of the things you have to understand is you're moving to this more mild population who has the potential to best be advantaged by a disease-modifying approach is you need to know what the right assessment scales are. So what actually progresses over the observation period such that you can actually see a difference? And there -- we were one of the first to actually go out and do that type of study. And lo and behold, we saw progression in untreated or at least not on symptomatic agents like L-DOPA in patients that were over the course of one year. That tended to progress on a scale called the MDS-UPDRS Part III. This is a scale that where physicians assess motor function over that 1-year period. And when we did central reading of that and compared the placebo patients versus the prasinezumab treated patients over that 1-year period, we saw a 35% slowing of that progression. And obviously, that's something that's relatively robust in terms of signal detection. Some of the other parts of the scale, the UPDRS Part I, the UPDRS Part II, didn't really progress to an extent that we could see a difference over that 1-year period in these mild patients. So there's something that you learn as you move these programs forward. We also observed in that study some interesting effects on MRI based approaches, something called arterial spin labeling that looks at function based on an MRI approach. And there, we saw evidence that was consistent from a biological effect perspective. So starting to see these clinical endpoints move, starting to see biological effects that can explain that is very, very encouraging across the board. With those data in hand, our partners at Roche elected to move this into a Phase IIb study, and the goal of that study is really to expand the patient population to include patients that are taking, again, L-DOPA treatment, the symptomatic treatment that many patients are on and really expand the totality of the patient populations that might be appropriate for a drug like prasinezumab and to establish that from a clinical perspective. The other important component of this Phase IIb study, which is known as the PADOVA study is the incorporation of this MDS-UPDRS Part III clinical assessment scale, into an approach that actually means something functionally for patients. And the way that Roche designed that was to set up a time-to-event approach where they actually look at the time it takes for a patient to progress 5 points on this MDS-UPDRS part III. Why does that matter? Well, 5-point progression for patients is meaningful from a functional perspective, they can feel it. It means something to them. And so by delaying the time to progression, which is something we also saw in the previous PASADENA study, that brings in a fuel component that actually is meaningful for patients. And we think that's important both from a patient and a regulatory perspective. So Roche is now conducting that Phase IIb PADOVA study. Obviously, we remain involved, and we're very excited about seeing that move forward. As you mentioned, some other antibodies that have targeted different parts of the protein, maybe targeting approaches that would have been suboptimal in our hands, from preclinical studies did not have success and were subsequently discontinued.

So I just want to briefly touch kind of -- because I know you've done a number of kind of updates to your partnerships and new agreements kind of this year. So prasinezumab was one of them, right? So you opted to kind of receive a royalty rather than do the profit share. So I guess my first question would be kind of -- if we could talk through kind of the rationale for that decision at a high level? And then also kind of with that, just maybe the broader kind of BD strategy because you also did a deal for PRX004, your ATTR antibody with Novo. So I guess, we could also just talk more broadly about kind of what these decisions kind of enables you to do in terms of achieving your goals with the internal portfolio?

Tran?

Yes. Absolutely. Sorry about that, I muted myself. From a synuclein perspective, I think why we made that decision was to focus our resources on PRX012 and our dual immunogen vaccine and also clearly, birtamimab, our other wholly owned program. And so I think we wanted to make sure we allocated proper resourcing around those three. And clearly, Roche was running the Phase II and now the Phase IIb. So that decision was quite easy from a strategic perspective. From a PRX004 perspective, it was ultimately about where we were going to commercialize there. And so it's going to be primarily a cardiology call point. And although we thought we could efficiently do it, we thought the deal that we struck with Novo was a great deal, and we think very highly of those folks and their ability to run cardiovascular outcome trials, right, ultimately. And so we're very excited by the deal that we struck there. And so I think from -- again, that frees up resources for us to focus on our wholly owned programs. And so I think what you're hearing is -- birtamimab, PRX012 and our dual immunogen vaccine, we want to hold on to those, especially now, especially in the Alzheimer's -- well, I'll start with birtamimab, especially with the SPA at a p-value of 0.1, and you have actually data where we're running a confirmatory trial, right? And so we feel very strongly that, that's a very derisked program from a clinical and a regulatory pathway perspective. And also, clearly, from a commercial perspective, we think we can -- it's a very leverageable call point for us. And then, of course, on PRX012 and the dual immunogen vaccine, again, with the regulatory and clinical clarity that we -- that continues to come out around the Alzheimer's field, we feel very confident that we're able to run those registrational trials ourselves. And right, and again, the call point is especially call point from a neurology perspective, as you know, with these antibodies, it went from pills being prescribed by primary care physicians to now being more a referral disease where the primary care is referring into the neurologists or the care and, of course, the antibodies from a prescription perspective. So again, all of that allows us to hold on to those programs as our wholly owned programs through to commercialization.

Definitely. Now that makes sense. I know we're running up on time here, but I do just want to ask one question about birtamimab. So obviously, as you mentioned, right, you did kind of announced earlier this year, the SPA agreement with the FDA on the birtamimab program. So I guess can you walk us through kind of the analysis that you did on the existing data for birtamimab that kind of convinced the FDA to kind of agree to this SPA? And -- yes.

Yes, it's a great question. And obviously, we had run a Phase III study that was discontinued prematurely back in 2018, so it discontinued early. And in that study, as we had fortunately prespecified and actually stratified on a severity factor for this disease Al amyloidosis. So that severity factor or categorization system is known as Mayo staging, Mayo stage I, II, III and IV, Mayo stage IV, obviously, being the most severe patients. And typically, those patients would have an appreciable amount of protein built up in their heart at high-risk of early mortality following diagnosis. And when we looked at the data in its totality, we saw a hazard ratio that suggested about just over 16% relative risk-benefit in favor of birtamimab. But as we dug into the data, what we actually saw was that the only group where we really had meaningful mortality over the observation period of the study because it was discontinued early, was this more severe patient population, so these Mayo stage IV patients, who on their best standard of care, the control arm had a median survival of just over 8 months. So 8 months after diagnosis. Now we had a number of prespecified secondary endpoints that we looked at it 9 months. So as we looked at survival benefit over that 9-month period, what we saw was a hazard ratio on all-cause mortality, a pretty objective endpoint that approach was just under 60% relative risk-benefit on all-cause mortality. So just about 0.41 and change hazard ratio. That's not a robust effect. And so obviously, it caused us to look further into that. One of the first things we did was looked at those key secondary endpoints at the 9-month time point, 0.1 being a measure of function, the 6-minute walk test. That p-value was nominally less than 0.05. And then we looked at a measure of how patients feel a patient-reported outcome called the Short Form 36, that p-value was also under 0.05 on a nominal level. So again, some consistency here across multiple clinical domains. And so that was actually very encouraging. The next step we took was actually an approach to try and convince ourselves that this was spurious, believe it or not. So we actually went through and did all the analysis, we looked at a number of different analyses to factor in different baseline measures and based on any minor differences in those baseline measures adjust the hazard ratio to see if we could explain away this effect by something other than a drug effect, and we failed to do that. And so failing to explain it any other way than a drug effect, we took that data package to FDA. We had extensive dialogue with FDA around a number of points, not the least of which was the data itself. A lot of back and forth just in terms of understanding the data, those conversations ultimately moved to how we would think about a path forward for this type of treatment, given now what we had with a prior post hoc, but effect on all-cause mortality in this very advanced patient population for which there were really no adequate treatments. And so with that, we arrived at an agreement that conducting an additional study, which is the affirm Al study and declaring success at a p-value of 0.1. So again, 0.10, not 0.01, that would be sufficient for registering this drug. And we agreed to do that under the agreement, a Special Protocol Assessment agreement or SPA agreement, which we got agreed to here in February and then announced that to the Street at that time.

Sorry about that.

It's okay.

Well, I noticed we're running a couple of minutes over and for -- my Wi-Fi keeps freezing for some reason. But anyway, I just wanted to thank you both for taking the time to chat with me today. I know we'll see you a little bit later this morning to talk about neurodegenerative diseases, again with a few other companies. So looking forward to that. But thank you again so much. It's been really great.

Thank you, Neena, for having us. Appreciate it.

Thanks, guys.

Bye-bye.