I'm Charles Duncan. I'm a Senior Analyst at Cantor, and I'm excited to introduce the next neuro innovator that we think is really has an interesting path forward and in the near term. So we rate the stock with an overweight rating, and it's a pleasure to introduce Dr. Gene Kinney, the company's CEO, Mark Johnson, the company's head of IR. He's the guy, source of all good information. And Tran Nguyen, the company's CFO. So, why don't we get started with this? You know, in the past, Prothena has been kind of a highflyer stock. Lot of focus on it post the monoclonal antibody approvals that we've seen in Alzheimer's. But now the stock is trading at, you know, a discount, I believe, to the growth opportunities, but also only, well, under two times cash.
I guess the question that I have for you, Gene, is, and you know, other folks chime in, what do you think is least well understood by investors at the current trading range about Prothena?
First, Charles, thank you for having us. It's always delightful to be up here with you and have a chance to talk a little bit about the pipeline. You know, I think in terms of, you know, where we've been focused in moving the science forward, as you accurately mentioned, our focus is really on differentiated therapeutics in areas of protein misfolding. So it takes us into a number of interesting spaces, certainly the central nervous system, where we focus on diseases like Alzheimer's and Parkinson's, and we can get into some detail around some of our upcoming readouts. But also in these peripheral amyloid diseases areas like AL amyloidosis, ATTR amyloidosis. And I think, you know, to the point that you're making about what may not be well understood about the company is really the foundational science. How do we think about these targets?
Yeah.
How do we think about targeting these proteins in the context of the biological disorder of the diseases that they cause? What do we know about how the proteins lead to disease, and what's the best place to intervene? And in many ways, it's a unique solution for each program. Just to kind of give you a little bit of sample, as we think about our AL amyloidosis phase III program, that molecule, birtamimab, is a monoclonal antibody that targets a denatured form of the protein.
Okay.
So if the offending protein in this disease is light chain protein and when light chain is appropriately assembled with heavy chain to form immunoglobulin, we really don't wanna interact with it. We don't wanna perturb that normal function. But as light chain actually starts to misfold and aggregate and form more toxic conformations that can lead to heart failure, it becomes an appropriate target for an interventional approach. And so making sure that we understand how to intervene and target the protein in that abnormal state while leaving the normal state intact, is something that we think quite a bit about. We can point to other disease areas like Alzheimer's disease.
Yeah.
Here, the key is that you want to be able to both remove the amyloid that's deposited in the brains of individuals with Alzheimer's disease, but there's also a component of the amyloid protein that lives in soluble, toxic conformations. And you wanna make sure that you can target those forms of protein as well. And so our monoclonal antibody targeting Alzheimer's disease, PRX012, is designed to interact with a area of the protein that has the potential to do both of those things and make sure that it has the appropriate mechanism, for the appropriate disease, application.
I think this year, we've been very focused on progressing our clinical portfolio, progressing our trials, our phase III trial for birtamimab and AL amyloidosis, our phase I studies, for PRX012 and Alzheimer's disease, and of course, to also continue to make progress on our partner programs, and those includes partnerships with Roche around prasinezumab for our Parkinson's disease efforts. With Bristol Myers Squibb, of course, where we've worked with them on a monoclonal antibody targeting the tau protein in Alzheimer's disease. And just recently, this year, they've opted into a second program, which we call PRX019.
Yeah.
So we're working with them on that program as well. And then of course, Novo Nordisk, who we're working with in a phase II study, targeting ATTR amyloidosis. So obviously, a lot of work ongoing. I'll ask Mark maybe to speak about some of the things we're looking forward to in the next six months or so. But, you know, really a lot of progress being made across a pretty rich portfolio.
Hold that thought c ause I'm gonna ask that question.
Okay, very good.
Because definitely we wanna unpack the progress and unpack what that could result in in terms of value creation. But you mentioned or alluded to, you know, really being able to engineer monoclonal antibodies, and you're not just raising antibodies to any antigen that's out there. You have a differentiated approach. So you mentioned amyloid, you mentioned birtamimab, right? But what about for prasinezumab in Parkinson's, or even your tau antibody that you mentioned on Bristol Myers? Help us understand how that's a very targeted, differentiated approach.
Yeah. Well, let's start with prasinezumab. Prasinezumab targets a protein called alpha-synuclein, which we think is kind of the smoking gun with respect to cause and progression of Parkinson's disease. If you think about amyloid beta in the context of Alzheimer's that protein's about 38-42 amino acids in length. As we move to alpha-synuclein, that can be upwards of 140 amino acids in length. So as you start to think about the complexity of how to target that protein, how is it actually causing dysfunction in the context of disease? We take an approach where we really look across the entirety of the protein.
In the case of Parkinson's disease, alpha-synuclein, and prasinezumab, we tested antibodies that targeted alpha-synuclein in many different ways, including targeting different epitopes, the amino terminus, the carboxy terminus, the mid region. But also thinking a little bit about the aggregation processes that are important in the context of disease. U ltimately developed prasinezumab, which we have tested and shown has over a four hundredfold selectivity or preference to aggregated forms of alpha-synuclein over the non-aggregated forms.
Okay.
And that's very important because the non-aggregated forms have normal function and we want to preserve that function to the best ability possible. The aggregated forms we know lead to dysfunction in the context of Parkinson's disease, and so obviously interacting with those forms is quite important. We've also noted in a number of studies that prasinezumab or the mirroring precursor to prasinezumab has very unique capabilities when we test it preclinically. So it has the ability to not only reduce alpha-synuclein, but to provide functional benefit in that context, both at the morphological, synaptic, and behavioral level. So that consistency of effect, that robustness of effect, was something that was very important to us as we started to understand how to target that protein and how to actually have optimal biological activity before we ever moved it into the clinic.
And we'll talk about that readout, later on this year.
Yeah.
It's coming up soon.
Absolutely. Yeah, so we're excited to see the results of the PADOVA.
And then tau, what about tau? Your approach to-
Yeah, tau is a little bit different. I mean, again, now you get into even a more complex protein, so six splice variants, two major isoforms of tau up to four hundred and forty amino acids in length. So really understanding not only what happens to tau in the context of disease, the truncations that take place, the post-translational modifications that take place, but which of those are more or less relevant in the abnormal behavior of tau in terms of how it relates to Alzheimer's disease. One of the areas of science that we were very interested in was the science that was starting to understand how cell-to-cell transmission of abnormal tau takes place.
Sure.
You know, I point to the work of Marc Diamond and others, which suggested that there is a key region within the tau protein that's quite important for that. This is the MTBR region. Our monoclonal antibody does target the MTBR region.
MTBR, microtubule-
Binding region.
Binding region.
Exactly. And-
Needs to attach to something to move forward, right?
Indeed, indeed. And so, what we've found is, at least in our preclinical studies, by targeting that area, we're very efficient in preventing or blocking that cell-to-cell transmission process. which we think is important in the context of the propagation of the disease in its normal state. That molecule, PRX005, was ultimately licensed by Bristol Myers Squibb in our collaboration there. They've now initiated a phase two study with that molecule, and they've recently reported a little bit of data at some scientific meetings showing the design of that phase II study, and so we're very eager for them to enroll that study and interested in the results there.
So I have to say that this is a company that has, more so than most of my coverage or all, more external validation from corporate partners than any other. So I'm intrigued with that. What is it that attracts people too. It seems like your deep engineering experience. You've been around the block with regard to antibodies for a while. So what is it that brings partners, and could we see more in the future, or are you moving forward on your own now?
Yeah, I think, you know, we've been very thoughtful about our partnerships. We have I think at this point, seven molecules that have cleared the IND, so in the clinical process. These have all come from our internal laboratories. So it is an organic pipeline. It's a rich pipeline.
Yeah.
Each of those is a different molecular entity. And I think, you know, in areas where we feel that partnering with the right partner can add value, either with respect to bandwidth to move these molecules more quickly through the clinical process and towards patients, we'll elect to go ahead and do that. Areas where we feel that we have unique expertise, where we can do that on our own, and that we have the right capital structure to do that, we'll retain full rights to those programs. And so it's not a mistake that about half of our programs are partnered, about half are unpartnered. We think that's a good mix for today. And so we're very happy with that, and it really breaks down along that thinking of, do we have the right expertise?
Do we have the right bandwidth? Do we have the right capital structure? And do we feel like we can move these things forward as expeditiously as the data warrants to patients? And I think in cases where we can do that on our own, we will. In cases where it's aided by a good partnership, we will do that. And I will say we're very fortunate. We have quite strong partnerships with very, very good partners. Prasinezumab is partnered with Roche.
Yes.
We enjoy that partnership, and I think that molecule has benefited from that partnership. We have a multiple program partnership with Bristol Myers Squibb. And again, both on the tau effort and now the PRX019 effort, we're very happy with that engagement and very happy with working with Bristol Myers Squibb. And of course, the collaboration with Novo Nordisk has been excellent. They, you know, clearly, as you think about outcomes types of studies, have done more of that than most in the field, and so we feel very fortunate to be able to work with them on the ATTR monoclonal antibody.
So let's dig in. How about we talk about some of those programs, especially the one that you may move forward yourself, and that's birtamimab. But before we do, one last question with regard to the platform and capabilities and target product profile, and, you know, I have to ask because I haven't seen a lot of data, but tell me what you've seen out of PRX012 that reinforces your conviction in the design elements of that molecule, and, and then we'll talk about the future.
Okay, well, maybe I'm gonna let Mark speak to PRX012 just for a moment, just in terms of what we have said what we've seen, and a little bit about what we're looking forward to.
Okay.
Yeah, absolutely. Well, thank you again, Charles, and thank you, Gene. So I think with PRX012, we're really excited with the phase I multiple dose trial that we're running right now. We have several active cohorts, as you know.
Okay.
And really what we're trying to do with this study is develop a fulsome data set that provides a dose-response curve that really helps elucidate what are gonna be the important next steps and inform us of where we go next to add value to that program. And so at this point, we're continuing to run those cohorts. We expect to have an update later this year, and as we've said before, that update is either gonna be data from some of those cohorts or potentially a timing update with more granularity on when you would see that data. You know, everything is moving forward. The trial itself is enrolling well, has enrolled well. There's a lot of interest in a once-monthly subcutaneous offering for an anti-A-beta.
So the fact people ask us, "You know, there's other treatments that are out there, the IV infusions that are approved. How are you gonna be able to enroll this?" That hasn't been an issue. There's a lot of interest in the product-target product profile that we're providing.
So it sounds like from an engineering standpoint, you're satisfied that you have a drug that could be a once, once-monthly drug. It sounds like perhaps if you're moving up cohorts, I assume you're moving up dosing, that you have a drug that is moving A- beta, and one that is doing so relatively safely. And so, would you agree with my perspective or my interpretation of what you just.
Yeah, I think at this point, you know, the trial is going as we planned, right?
Yeah.
DSMB clearance to the higher dose cohorts, and really what we're trying to do here is get as much information as possible so that we can help figure out what that dose is going to look like as we go forward to pivotal trials.
Sure.
I gotta tell you, I much prefer you having more data than less data. I'm always annoyed with a gene therapy company that rolls out one or two or three patients' worth of data, so I'm looking forward to that. It sounds like, if I heard you, that we may hear an update by the end of the year? Not necessarily data, but an update on where you stand.
That's right. Yeah.
Okay.
Yep.
Okay. Any questions at this point on that program, 012? Okay. 'Cause that has been a question. People have wondered about this a lot in the past, but, you know, it's horrible to make sausage on stage, right? And I kind of feel like that's where you're at. But I, as a scientist, prefer more data than less.
At the end of the day, Charles, what we're looking for is a best-in-class profile for a subcutaneous, once-monthly, at-home administration which we think will really open up a market.
Multiple doses, right?
Yeah.
Multiple months.
That's correct.
That's right.
Okay. Okay. Maybe we'd already try and optimize for, from an efficacy and safety standpoint, what, what do you see moving forward there?
I think if we're, if we're looking at the, the competitive landscape, I think we kind of understand where these molecules are at 18 months, right? And so ultimately, we do. Although we'll produce data at the right time, it'll have multiple time periods on it. But I think we wanna get to what we think is a competitive efficacy and safety profile, right? And I think we understand that getting by 18 months down to, let's say, 22 centiloids or lower, things like that drive efficacy, right?
And ultimately what drives even more efficacy is actually trial design. What we've learned from Lilly, who of course just got approved with Kisunla, also forcing Eisai to go look at their data from phase III to also show similar kind of efficacy results, which they're saying that patients that are earlier in disease do a lot better, lower on the tau PET scores, or even lower on the plasma p-tau217 scores.
Those things are highly correlated with 40%-45% efficacy, depending on if you look at iADRS or you look at CDR-SB at 18 months. Those give us great confidence in terms of moving forward, right, with an appropriately therapeutic dose. I think that's where we think the differentiation will be going forward in terms of trial design. I think that's something we pay a lot of attention to. I mean, Lilly's even went so far as to beyond even genotyping, right? Talked about patients that are at risk for higher ARIA, like people who have, like.
Bringing up a good point, yeah.
More superficial siderosis at baseline or more macrohemorrhage at baseline. So if you can think about that and enrolling patients with less of those, you can start to mitigate beyond even genotyping in terms of ARIA.
Although you do have a cohort that you're running on APOE4 homozygotes.
Homozygotes. That's correct. That, you know.
Intriguing
It's clearly a population that's very small, right?
Yeah.
The larger population or the non-carriers and the heterozygotes. You actually kind of have to enroll everybody in order to enroll that genotype, too. But that all being said, just kind of like you said, we are looking at that in the cohort B, multiple dose.
But that's innovation. I mean, the other companies didn't enroll homozygotes.
That's right.
And that's a step forward.
Yeah.
That tells you something about your perspective on product profile. Any other questions at this point on 012?
I'll just add, you know, that with the advent of effective treatments that are available now I think, you know, this is what we should expect. The field is now moving forward quickly. We're learning things about risk factor, risk factors for ARIA. We're learning about things like, you know, which patients might be more likely to provide a better effect size, in terms of which patients to enrich around enrollment. And I think as those learnings will continue, right? And to your point, you know, the APOE4 homozygous patients, you know, really have been understudied to date.
Yeah.
One of the goals that we had, even with this phase one, was to make sure we could take a systematic look at patients with APOE4 homozygosity, and make sure that we understood what those patients look like, you know, even at same dose levels and what have you. And that's not something that's been done very systematically to date, but I think, you know, it's something that we were very interested in doing. And to your point, it's part of learning from the clinical trials in front of us, right? So this is all a learning process. We're learning from the folks that have gone before, just as, I think folks have learned from some of our initial studies, way back when. So it's as science is supposed to be. It continues to iterate and continues to progress.
What do you think about the dosing regimen that is suggested by Lilly? Dose to a certain amyloid level, and then forget it. You don't need it anymore. I mean, that seems to me to be an artifact of the pro.
I love the continual progress towards the rise of the blood biomarkers like plasma p-tau217 for both diagnosis and prognosis, right? And already being used today for prognosis. And what we liked about that measurement, even within Lilly's own trial, is, if we all recall, I think it's, like, an average of 47 weeks on therapy, right, for Kisunla. But if you look at their data from 12 months- 18 months, actually, plasma p-tau217 actually goes up, which is really interesting, right? So although I think their study is set up really nicely, like you said, for dose cessation, and ultimately the label was up to basically the doctor and the patient to have that discussion.
Sure.
But we just started the conversation with the discussion will be around plasma p-tau217. So which direction is that going in? Kinda tells you. Should you stay on the drug? Should you do dose maintenance, or should you go ahead and dose the same, right? And so I think that's something that I look forward to on the diagnosis side, but it's already being used on the prognosis side.
I suppose if you have a Q monthly dosing, and it's sub-Q, and you have less area, it's probably less important to stop dosing. I don't know. I mean, seems like that's a big burden.
Yeah, I think there's still you know, there's a lot of information coming out in the field around this. I mean, Eisai has published some recent data suggesting that continued dosing is of some benefit.
Yeah.
Obviously, Eli Lilly has a different view. I n terms of what the additional benefit is. As Tran said, I think some of the biomarkers, when you stop dosing, clearly move in the direction opposite of where they go when you start dosing. So, you know, but to the, you know. I think the FDA made this point in their advisory committee meeting minutes, which is that really, the study wasn't run to definitively answer that question.
Sure.
So I think, you know, in one way, we can say that we don't have the data that directly speaks to that at this point. But at the same time, I think Eisai's data is compelling, that continued dosing may bring some benefit with it. So to the point of.
Seems like it would do.
Convenience, right? That's, that's important.
Seems like it would do. I mean, amyloid continues to accumulate, and then you bring in tau, right? Yeah, so future lies ahead. We'll look forward to that date, that data by the end of the year, but we will look forward to updates and we're rooting for you. Why don't we turn our thoughts to birtamimab? Because, I was actually telling an investor why I like this story at lunch, and, I was saying, "You know, not only is it a good value, but you've got a near-term readout," and that is phase III. AFFIRM gonna read out in light chain amyloidosis. So what gives you confidence in that phase three, how it's going, and what that readout could look like?
Maybe I can start a little bit on that and then ask Mark and Tran to speak to kind of what we're expecting here. So I think, you know, in terms of the data around birtamimab, again, I had already mentioned it's relatively unique in terms of how it interacts with light chain We've had that very well defined. We know the epitope that it interacts with. We know that that epitope is only available during certain conformations of the protein.
Okay.
So we think it gives it some unique properties. We've also shown in the preclinical space that it not only interacts with the deposited amyloid, and most important in the context of AL amyloidosis, at least when we're talking about survival, is cardiac involvement. So, you know, that amyloid that deposits in the heart does deposit in other areas and cause dysfunction as well, but also, there are these soluble intermediates. These soluble intermediates, there's quite a bit of literature in AL amyloidosis suggesting that they may be directly cardiotoxic at the level of the cardiomyocyte.
Okay.
And we've shown that birtamimab also interacts with those species. So it's a relatively unique approach, targeting these intermediate species, which could be toxic in their own right, as well as the amyloid, which we know causes dysfunction in the context of disease. So what we've done there is obviously taken that through a number of clinical studies. One of the studies was called the VITAL study. The VITAL amyloidosis study showed, among other things, a robust survival benefit in patients with advanced disease. So these are patients with advanced cardiac disease due to AL amyloidosis. There's a staging system called the Mayo staging system.
Mm-hmm.
These would be Mayo Stage IV, IV being the most advanced patients. If we look to the literature, the median survival of patients with Mayo Stage IV, we'd expect to be somewhere in the four- to six-month range following diagnosis. In our VITAL study on standard of care, best standard of care control arm, we saw a median survival of 8.3 months and a hazard ratio on all-cause mortality of 0.413, so approaching, not quite, but approaching a 60% relative risk benefit on all-cause mortality.
Yeah, yeah.
We also saw some other very encouraging effects on other clinical domains. We took that information and entered into a dialogue with the FDA, had some back and forth with them, talked about the data in its totality, and ultimately entered into a Special Protocol Assessment agreement, or a SPA agreement, with the FDA, where at an alpha now of point one.
Yeah.
So 0.10, we can confirm of the prior effects that we've seen, on all-cause mortality, and that would provide us a path to registration of the drug. This is a wholly owned program.
Yeah.
So we look forward to not only seeing the readout of that study, but ultimately potential commercialization. It's a space where we feel we can commercialize ourselves, and we feel that not only is there a significant unmet medical need here, but we think a very, very reasonable commercial opportunity.
Let me ask you a question about this. Between the time of VITAL and the time of enrolling this particular study, has standard of care changed? Do you think that there's any way that patients are doing better, and so even though they're Mayo stage IV, they're not like they used to be? I mean, what is the risk in this study in your perspective?
Yeah, so the big.
Point one is pretty low alpha.
Yeah. Point one is a,
Or pretty high alpha.
Yeah, a good alpha.
Yeah.
It's a good alpha to have in your phase III.
A good direction.
Regarding registrational study. I think to answer your question, there are a couple key differences between VITAL and the current AFFIRM study.
Yep.
One key difference, obviously, is that we're focused on these more advanced patient in the AFFIRM study, whereas VITAL was a broader patient population.
Sure.
The other, I think, major component is that we're doing a two-to-one randomization in the current AFFIRM study, as opposed to a one-to-one randomization. Obviously, two to two on active or bortezomib active drug versus control. And then the third is there's an increased usage of daratumumab in the current background therapy.
Sure.
Daratumumab, as you may know, it was approved for AL amyloidosis on an accelerated basis, based largely on the primary basis of approval was hematologic response rate. They have not yet, to my knowledge, shown a clinical outcome associated with that, for example, a survival benefit. They have talked about data out to approximately 12 months, where they have not yet observed a survival benefit. So we think, you know, given that most of the events in these more advanced patients occur relatively quickly. You recall I talked about 8.3 months you know, four to six months, and the fact that, the majority of our observation period in the prior trial was across about nine months. Certainly across that time period, daratumumab has not, in the double-blind, placebo-controlled studies, had any impact on survival, whether or not.
Actually, dara, some of those patients go backwards from-
In the first six months. They noted, in that study, 25 deaths on daratumumab on a background of CyBorD versus 20 on CyBor D itself. So I don't recall if that was statistically meaningful, but sort of from a directional perspective, your point's noted.
It's not obviously helpful.
That's correct.
Yeah, so I was just gonna add that, you know, with the standard of care, so we've seen that now in a double-blind, placebo-controlled trial, right?
Yeah.
ANDROMEDA is a double-blind, placebo-controlled trial, and we now know, at least in the early part of the curve, that actually dara may contribute potentially more events than CyBor D alone.
Yeah.
So clearly, us on top of CyBor D, you know, in a subpopulation of Mayo Stage IV, but stratified at baseline and what the FDA gave us the SPA on, we showed difference early on. And so from that perspective, in terms of blending in with the unmet need, that's really what we're really encouraged and excited for, is that where we showed good differentiation was really early is where dara did not, and actually went the other way, right?
Yeah.
In terms of had more events than even CyBor D alone, so that's all encouraging, so to speak, and I think that tells us to continue to enroll and enrich for the early part of the curve in terms of events, and if you do that, and we are able to confirm what we showed in VITAL, with, you know, with point one, we should have a drug on the market, potentially.
Event-driven study, so probably January is better than December, maybe incrementally or later. But will you be prepared to file an NDA and then build a commercial infrastructure next year, should you get a good readout?
Yes.
Yes.
Yes. No, no, absolutely.
We will be excited for that opportunity.
It should be very exciting.
Yeah, I think, I think, you know, and Mark, you maybe wanna speak a little bit to the commercial opportunity here, but we think this is a very reasonable commercial opportunity for a company like Prothena to take on. We know a lot about this space. The first clinical studies that we started in this space were in 2013. You know, we have some familiarity both with how treatments have evolved in the space, the impact of those treatments, where patients are treated, and so I think we have a pretty good sense of this marketplace and the patient needs here.
Obviously, the AFFIRM trial is squarely focused on the idea that, you know, coming out of this study demonstrating a potential survival benefit on top of standard of care, I think puts treating physicians in a place where they would have a very good understanding of the potential benefit and the use of this agent in a very short period of time. But Mark, why don't you talk a little bit about the commercial opportunity?
We need to hop, 'cause I've consumed too much time.
Oh, sorry.
But I assume this is a heads versus a hands approach to commercialization, and we'll have a chance to talk about that, so.
Yeah.
We will. Lots of planning ongoing already, so.
Yeah.
Very good. Thank you to the audience for your interest. Thank you to Gene and team for joining us.