Okay, good morning, everyone, and welcome back to day two of the Cantor Healthcare Conference. My name is Eric Schmidt. I'm one of the analysts at the firm, and it is my distinct pleasure to welcome back to our conference the team from Prothena. We've got the entire senior management team with us today. We've got Gene Kinney, who is Chief Executive Officer, Tran Nguyen, who is CFO and Chief Strategy Officer, and Mark Johnson, who is VP and the head of IR. Thank you guys for being here. We really appreciate it, especially coming off what's been a really eventful last few months for you guys.
Maybe, Gene, you could just give us a quick recap of what has happened, maybe going all the way back to May through June and the restructuring and most recently, just a week ago.
Absolutely. First, Eric, thank you for having us. We really appreciate being here. It's good to be able to spend some time together. Yeah, it's been an eventful 2025 thus far, and we're looking forward to additional events occurring through the rest of this year and into 2026 as well. We had a lot of pipeline updates. We've got good news from some of our partners. Earlier this summer, we heard from Roche around a molecule that we invented by the name prasinezumab, which is a molecule intended for the treatment of Parkinson's disease, where they're moving that into a phase 3 study, and Roche in their communication had indicated that they'd do that by this year.
We also heard from our partners at Novo that they intended to move coramitug, a molecule intended for ATTR cardiomyopathy, into a phase 3 study, also intended to do so, in the near term, so we're excited to see those two programs move forward into phase 3. We did have a phase 3 molecule readout earlier this year as well, which we elected to not move forward, so we did rightsize the company around our go-forward opportunities and our partnership obligations, obviously, on the back end of that news, and we've just very recently talked about our anti-Abeta approach in Alzheimer's disease, which is PRX012. The highlights there, and we can get into the details, are that the molecule showed a lot of positive outcomes in terms of what it was designed to do.
It's a very potent molecule against the amyloid, amyloid structure. We did see pharmacokinetics, anti-drug antibody responses that were in line with the intended product profile of once-monthly subQ drug, but that drug did come with higher than, what we had hoped for in terms of ARIA events, or amyloid-related imaging abnormalities.
One of the things that we talked about as we put that data out was the potential to actually use what's known as a transferrin-based approach with that molecule, now having the foundation of a good understanding of what that antibody does from a clinical perspective, and thinking about mitigating that ARIA event through known biology and what others have described in terms of what transferrin-based approaches bring to that biology around different routes, if you will, of entry into the CNS, bypassing potentially some of those ARIA-creating events. As I said, it's been very eventful from that perspective. We've been very focused as well on shareholder accretive events as well, and thinking about how to continue to make sure that we position ourselves from a financial perspective in a shareholder-friendly way.
Maybe I'll let Tran speak a little bit-
Yeah
... to some of those activities.
I think, just to build off of what Gene is saying, and, you know, over the last few months, it's been able to give us, like, just, operational clarity, right? We're very focused on near-term value creation. Part of that is the $105 million worth of clinical milestones that we have the ability to achieve next year. Some of that is supported by the coramitug moving forward, Novo moving forward to phase 3. The other part of that is our obligation that we're fulfilling in running the phase 1 for X19 in a neurodegenerative indication. So Bristol will take that data next year and make a decision whether to move that antibody into phase 2, and if they do, we'll get a clinical milestone there. And, of course, we want to do that in an accretive way.
We've also announced that we're. You know, because we're Irish, we have to have an EGM, right, to create distributable reserves. Probably never heard of that before. Yeah, I'm not Irish, but I have now. So we have to create that, and then that supports a share repurchase, so again, doing shareholder-friendly, you know, accretive financial activities. And as part of that, too, as we've said on some of the press releases and on some of the calls, is that we, with our reduced operational footprint, those folks not only support the R&D effort obligations with our partner programs, but we're also working very hard to also partner programs out that are unpartnered today.
We can talk more about that, but I think the major thing is that we'd like to get across is just an understanding of our partnership programs, 'cause we do have four of them, and they come with different flavors, and two will be in phase 3. One's in a phase 2 that's reading out in 2027, and of course, X19 that we just discussed, that's in a phase 1.
We'll have plenty of time to talk about the partner programs, but maybe first, before we get there, you did go through a corporate restructuring. What does Prothena look like today in terms of head count, and what resources you are putting forward, say, in R&D and other events, and how does that support this value-creating strategy?
... Yeah, so maybe I can start, and Mark and Tran, you can jump in. So, what we did immediately after we saw the results from the birtamimab trial was to reduce the size of the organization, to really make it right-sized around our ongoing obligations for our partner programs, to think about additional partnership opportunities. We have a number of, obviously, R&D assets, that could be of interest in terms of partnerships. Those folks that are required to do that are what's left in the company, and where we are.
We obviously will always look to make sure that the company is appropriately sized to conduct the activities that are needed to fulfill those obligations to our partner programs, to think about additional shareholder-friendly and shareholder-accretive events, such as additional partnerships and what have you, and that's where we are today. Obviously, we'll continue to assess that as we move forward, as we always do, and so I think that's where we were, and in terms of just kind of where we are from a financial forecast, you know, what we put out-
Yeah
- earlier this year. Yeah?
$300 million at the end of the year, right? And then we'll put out our 2026 guidance, you know, in our fourth quarter call early next year. So but just to reiterate what Gene just said, the folks that are left are to support our obligations under our partner programs, and once those obligations are done, we'll have to reassess and make adjustments.
Okay, and then very high level, what are the sort of value-creating milestones over the next twelve or eighteen months that you think we need to all be paying attention to?
Mm-hmm. Yeah, we've talked about a couple. I mean, we've talked about, obviously, the potential for up to $105 million in milestone payments in 2026. That comes off the heels of our coramitug program with Novo Nordisk and our PRX019 program, which is partnered with Bristol Myers Squibb. So clearly, we wanna make sure that those programs are appropriately staffed and moving forward. That's one of the nearer-term events. Tran made mention of a potential shareholder meeting this year to establish our distributable reserves, which gives us the opportunity then to think about share repurchase. We think from a financial perspective, that could be very friendly to shareholders as well. And then obviously, as the rest of the portfolio continues to move forward, we think there are a lot of exciting opportunities.
We've talked about prasinezumab a little bit, and that molecule moving forward, we can get into more data there, but obviously, there's the coramitug program, and then our additional programs with Bristol Myers Squibb. I don't know, Mark, if you wanna talk a little bit about that?
Let me... Before we-
Yeah
... go to there, well, there's a phase II that reads out later this year that the, we assume will support the phase III, you know, decision that Novo made. So that'll be, you know, fourth quarter at a medical conference. And then, Roche has always been very active in in terms of supporting enrollment in their clinical trials, so they're gonna try to enroll a phase III. I think they're gonna continue to show data from the phase II PADOVA that would support, you know, a phase III success. So we look forward to those data shares at, you know, neurodegenerative medical conferences, too. 27, we have the tau phase II, a robust phase II that reads out. The primary endpoint is tau PET, right? And so we're very excited, for that program, too.
And then, of course, the phase I on X19, when we share that data with Bristol, they'll make their decision. So I'm not saying that they'll share that data broadly, but that's... It's their program, so that's their decision. They own global rights on that. But yeah, I think we have a very exciting near-term value creation milestones, both financially and clinically.
Mm-hmm. And before we get too deep into the partner programs, if you were to return capital to shareholders, it sounds like a share repurchase is the best way, or is it the only way, or what else are you considering?
I think that makes the most sense, right? You're returning capital and also lowering the share count, so I think that's an accretive, we think of that as an accretive, you know, activity. So that's, that's what we're focused on now. But it can take on other flavors, but for now, that's probably the first choice.
Okay. Maybe just a quick recap of the PRX012 data, which just came out a couple of weeks ago. Remind us what you shared. You already mentioned, Gene, that the rates of ARIA were surprisingly elevated, I think, relative to what, you know, we would have hoped, at least. Any sense of why that is and whether it's fixable with the TFR version?
Yeah, so a couple of good questions in that. I mean, obviously, this space, from a competitive perspective, has been heating up, which is great for patients. We've seen a number of molecules, obviously, that are already approved and available to patients. We've seen other approaches in the clinic that are showing, obviously, favorable ARIA rates and continuing to move forward. You know, what was important to us was to really have a good understanding of what the higher potency-based approach and the subcutaneous administration of PRX012 would offer, and in many regards, it was very satisfying. So with respect to kind of some of the more mundane characteristics, things like the PK properties, anti-drug antibody, overall safety, independent of ARIA, it was quite favorable profile.
The reduction of amyloid, which is the targeted biology, was quite robust and very potent at dose levels of 400 milligrams fixed dose, so a flat dose level. So you know, we saw reductions of amyloid at 12 months that were comparable, if not even more potent than some of the agents that are currently available. So it accomplished many of the goals we expected it to accomplish. It was once-monthly subQ in terms of its administration. But as you said, one of the things that did come along was an ARIA rate that was a little bit higher than what we would be comfortable with from a competitive perspective in this space, as it's been developing.
Now, one of the biologics that's being developed in this space, and there's been some interesting publications on this recently, is what is the role of adding blood-brain barrier aided components, like transferrin-based components, to these antibodies? One of the suggestions that's put out there, and there's some recent data on this, is that it potentially moves into the brain, or it enters into the brain through a route that could bypass some of the mechanisms that might be responsible for ARIA. A number of companies are now developing transferrin-based approaches based on that. Given the strong foundational understanding of PRX012 and what that has to offer, you know, we do have some of our own data around a transferrin-based approach with PRX012.
We think that could be an interesting approach to maintain or retain the favorable characteristics that we observe with PRX012, and at the same time, maybe mitigate some of the ARIA liability that we saw with that molecule. Clearly, you know, given where we are today, and some of the other things that we've talked about from a financial perspective, we think doing that through a partnership makes the most sense. And so one of the things we are looking at is whether, in fact, a partnership around that type of approach or even alternative approaches with X12 might be in the cards.
There's some interesting paths from a you know clinical development and regulatory way. You know, trontinemab clearly has taken two phase threes in a very early symptomatic patient population. I think if you were able to establish a subQ, let's say, transferrin with X12, you could also do something like Lilly's doing, where you're combining populations. You can look at the pre-symptomatic space and within early symptomatic space and run one trial for both populations. You can do a time-to-event like they're doing in terms of 18 months on trial and then see who progresses. So I think that's a way to catch up, too. So we see different paths and interesting discussions ahead of us.
What's the timeline to a potential partnership? Is there a window in which you explore and then fill or kill, or how should we think about that?
I think about it in terms of we're trying to do it as soon as we can, but that being said, you know, these discussions can take time. So, you know, we're probably not gonna put a timetable on it, but we're trying to do it as soon as we can.
Meanwhile, very limited internal resources going-
Correct
... to the R&D side of the program.
That's correct.
Correct.
Okay. Well, let's move on to the partnered assets, which, as you say, had some good news over the summer period. Shall we start with prasinezumab?
Sure.
Okay, maybe just on the economics, remind us of what's going on there?
Yeah
... and the considerations that we need to keep in mind as we think about this deal.
Yeah, so the deal with Roche is, the total deal size with milestones was $755 million, and that includes upfronts and clinical milestones, regulatory sales milestones. To date, we've received $135 million, so going forward, there's about $620 million, and that's mostly regulatory sales milestones related to the PD indication. There's also royalties, a very attractive royalty setup. Think about that tiered up to high double-digit teens. And so, you know, Roche has said this is a very large market opportunity for them.
You know, they've put out that this is $4 billion or higher as far as a peak sales opportunity, and if they're able to achieve that, we're gonna be able to realize the value from those milestones and very attractive royalty rates.
Okay, so the news this summer was that Roche is gonna go forward with a phase 3 study based on the phase 2 Padova results that were presented, was it late last year? I can't recall.
Yeah, that's right.
That's right. Mm-hmm.
Are we gonna see another phase 2 look, or just remind us what you guys think is the key or salient points of the phase 2 program?
Yeah. So I think there's two questions in there. The first is, will there be additional data shared? I think we certainly expect that to be the case. Obviously, that will ultimately be up to Roche, but we would expect that they would share additional data as they have. They've been pretty prolific in sharing data, first from the phase 2 Pasadena study, and, you know, at least at the top line, the Padova study results. So just as a reminder, you know, the Pasadena study was an earlier study, also phase 2. In that study, patients were relatively drug naive from a symptomatic perspective, but allowed to start symptomatic treatments if required. In the Padova study, a couple of big differences.
The first is that patients were stably treated with symptomatic treatments, most of which was L-DOPA treatment. And the endpoint was a little bit different. It was a time to progression on a component of the UPDRS scale, the UPDRS Part 3 scale, which measures in large part motor dysfunction. So really looking at a, if you will, a five-point worsening on that scale as an event of progression in that patient population. That is something that, from a post-hoc perspective, was when they went back and took a look at in the Pasadena study, came back to the Padova study in a prospective way, looked at that endpoint. Narrowly missed, I think on the total population, p-value around 0.06 and change.
But the effect size, interestingly, was, you know, relatively consistent to what had been previously, discussed with respect to the previous Pasadena study, so some consistency across those two studies and those different patient populations with Parkinson's disease. You know, one of the things they have looked at in Pasadena and shared as well is longer time course data, so really looking at, what's happening over time relative to what you'd expect in propensity-matched control patients coming from the Michael J. Fox Foundation, PPMI database. And there they saw, you know, going out post four years, in that Pasadena dataset, relatively good stabilization and good separation, from what would be expected in an untreated patient population.
One of the things they mentioned in December when they shared the initial data was they wanted to look a little bit more at that longitudinal data before making a final decision, which they then did in June and announced that in terms of moving that forward to a phase 3 with an intended start date of this year. So yeah, we look forward to seeing more data shared from the Padova study. You know, obviously, we have some of the initial data, which suggests that near miss or narrow miss on the primary and the total population, but of course, when you look at the L-DOPA subgroup, which is the majority of patients in the symptomatic treatment they were on, that effect size gets quite a bit better.
We look forward to seeing additional analyses, additional longitudinal data from Roche as they choose to share that. Maybe a comment about future studies?
Yeah, I mean.
Yeah
... I think they've been vocal, right? They've had a Scrip article where they've been interviewed about what the phase 3 might look like, and to support what Gene's saying, and they've looked at the OLE on, in the PADOVA phase 2b, it required 18 months of treatment on prasinezumab. They might look to extend that, maybe two years. And then, of course, as is customary between phase 2b and phase 3, to increase powering and to reach success, they're gonna enroll more patients than they did in the phase 2b. So those are the two major levers they've already discussed. And if there's any other levers that they wanna pull from understanding of the data set, we would assume they would share that and support that-
Yeah
... with data from the phase 2b.
And I'll just mention, this is, you know, it's an enormous burden in terms of what it is that, you know, prasinezumab tries to address here, which is disease modification in Parkinson's disease. Parkinson's disease is the second-largest neurodegenerative disorder. Globally, it's the fastest-growing in terms of the rate of growth of the disease. And everything that's used to treat this disease today is relatively symptomatic, to address the motor symptoms, but really, none of those have any hope of addressing the underlying progression of the disease, which can be really devastating.
So obviously, prasinezumab targets a protein called alpha-synuclein, which is, you know, thought to be the smoking gun with respect to cause and progression of Parkinson's disease, and does so in a, you know, we think, a relatively sophisticated way, in both where it targets the protein of alpha-synuclein, which is about 140 amino acid protein, and also, built in relatively early into the selection process, a high preference for aggregated forms of alpha-synuclein, which we know are the pathogenic forms, or we believe are the pathogenic forms, relative to non-aggregated forms. So a couple of key characteristics of prasinezumab, which we think gives... you know, has the potential to give it a relatively unique biological profile.
Just sticking with that thought, Gene, there are thoughts to maybe different schools of thought on how to best target alpha-synuclein.
Mm-hmm
... in terms of the epitope. What is the convincing data to support prasinezumab's best mechanism there?
Yeah, so we did a relatively empirical epitope map of alpha-synuclein. So if we kind of think about the complexity of some of these proteins, we talked about A beta earlier, which is 38-42 amino acids in length. You know, alpha-synuclein's about 140-plus amino acids in length, so a little bit more complex, takes on a lot of different shapes. It's considered what's called intrinsically disordered, which just means it has a different shape relative, you know, based on what it binds to. And it's thought to underlie, you know, a pretty diverse set of biologies. You know, so one of the things that we did relatively early was to actually map out that protein, so basically making antibodies to different parts of the protein.
What we found was that there were certain areas which were relatively ineffective if we targeted those areas, most likely because the relevant structures didn't allow for those areas to be interacted with efficiently. But there was an area that was actually quite efficient for us, which was approaching the carboxy terminus of the protein. And in those studies, we actually found much more robust effects, very consistent effects across a number of different biologies that are thought to be driven by abnormal alpha-synuclein toxicity, if you will. And you know, that consistency of biology, that robustness of effect across multiple models, is really what led us to focus on the epitope that PRX002, prasinezumab, targets.
And then, you know, dialing in through a process of really selecting for high avidity antibodies, those things that are gonna be much more efficient at targeting aggregated forms over non-aggregated forms, was an approach to the biology that really allowed us to have additional, we think, efficiency in terms of really targeting the pathogenic forms of the protein.
And then, with that biology in mind, what's the theory behind L-DOPA and why patients on L-DOPA might or might not be better served?
Yeah, I think it's a little hard to say, and I wouldn't be too definitive, but I'd say there's a couple of possibilities, and they're not mutually exclusive, right? I think, just from a patient perspective, patients that feel that they need L-DOPA in the course of treatment may be patients that are progressing. One of the things that was shown by Roche in the Pasadena study results, the earlier phase 2, was that for certain subgroups of patients, including those that needed symptomatic treatments, that progressed a little bit more rapidly, there was a little larger effect size. Now, we have to be careful. Smaller sample sizes, these are subset analyses and what have you.
But that could be as simplistic as indicating that, you know, in order to see a good benefit, you need to see, you know, relatively robust decrement, right, in terms of performance. And so it could be as something as simple as that. Of course, it could also be biological. If we think about what L-DOPA does, right? L-DOPA, when it moves into the brain, it's taken through largely dopamine transporters into vesicles or synaptic terminals, and then through interaction with, you know, dopa decarboxylase and other things, it moves to dopamine, and then that's the effective molecule that's used.
Obviously, from that, you know, the more efficient you are in keeping those terminals functional, the more efficient you may be in allowing L-DOPA to have beneficial effect, and that obviously, would be a pretty positive thing from a neurodegeneration perspective. Is that happening? We saw some evidence of that in animals, but it's hard to say, and we can't say whether that's happening in humans or not. As I said, it could be something, you know, like those two things. They're not necessarily mutually exclusive. And of course, it could be other things that we're not talking about as well.
Last question on prasinezumab. Do we know if Roche is gonna do two separate phase 3s, and when do we think we'll learn more about the trials?
I think right now they describe it as a phase 3 development program, so we'll let them describe that more broadly when they announce... they get closer to initiation. But they wanna start that trial here by year-end, so I'm imagining we're gonna hear that trial design soon enough.
You said, "Trial?" ... Not trials.
Trials, program design.
Okay.
Program.
It wasn't specific to trial.
Program design.
Okay. Well, let's move on to Novo's coramitug. This is another agent upon which your partner made a go into phase III decision this summer. So, maybe just remind us what this product is doing, and again, how it might fit in or why it's differentiated.
Yeah. Well, I'm going to start with the mechanism a little bit. So, coramitug's a monoclonal antibody that targets ATTR. So ATTR and intended for ATTR amyloidosis, and in particular, cardiomyopathy is where there's a significant medical need. Transthyretin, or TTR, is a protein that's made in the liver and the choroid plexus. It's assembled into a unit of four, so it's a homotetramer, so there are four units of transthyretin that get together, and its normal function is to carry different proteins throughout the body, like thyroxine, vitamin A, what have you.
What happens in this disease, we believe, is that as that homotetramer falls apart under normal kinetics, if the monomeric structure isn't adequately cleared, you can start to see a denaturing event or misfolding that then you start to see aggregation, which can aggregate into a toxic form, à la the amyloid. So what a number of companies out there, and you know, we can look to, Pfizer with tafamidis, BridgeBio, Alnylam, Ionis, are focused on is really stopping the entry of transthyretin into this pathological pathway, either by suppressing the de novo synthesis through the silencers, or by stabilizing that tetramer with small molecules with stabilizers. This approach is differentiated there.
What we're looking at really is twofold: one, the resident amyloid that's already built up on organs in patients, and particularly in the heart, and looking to remove that, and then secondarily, to stopping new protein that maybe comes through from those silencing approaches but still is coming into that pathway, to stop that from aggregating in a toxic way. So how do we do that? Well, one of the things that we did was we worked with an academic lab up in Toronto who had solved the structure of the homotetramer, and we looked to areas that held that homotetramer together, that interface region, and targeted those areas with the concept that in fact, when the only time you would be able to see those areas, interact with them, is when the homotetramer was no longer in its normal form.
And so that allowed us to leave the normal form and function of the protein intact, but to go after the abnormal forms, or the misTTR, as we like to call it. With that, we took that molecule obviously into phase I, and then entered into a partnership with Novo Nordisk, and maybe you can talk a little bit more about that.
Yeah. So, actually, what Novo Nordisk did is they purchased the TTR business, right? And so, what we have, just as far as economics, for everyone, is, it's a $1.23 billion deal that is milestone driven, so to for tax-free status, not doing royalties. And so we've already received $100 million to date. We do have, as Gene and Tran described earlier, that is part of the $105 million of clinical milestones. If Novo brings coramitug into phase III, they've already announced that they're doing that, when they hit a pre-specified enrollment target, that will trigger the next clinical milestone. And then the milestones beyond that would be for sales milestones for sale into tiered up to what you would expect.
I know Gene and Tran will probably talk about this, but the market potential here for a new mechanism for the ATTR-CM space, especially one with a depleter mechanism, is quite large. If you look at what tafamidis has been able to do as far as peak sales and Attruby and vutrisiran, what they're projected to do, if comes anywhere close to that, we'd be able to realize all the value of those milestones.
Mark, I think we've estimated the next milestone could be ballpark $50-ish million. Is that something you...?
I think at this point,
Yep, right.
I think what we can say is that's your estimate-
Yeah
... and it's included in the $105 million, and the $105 million is not included in the $300 million that we've guided to the end of the year in cash.
Yeah. And then, not include the $50, the next milestone is not part of the $300 million a year.
Correct.
So that could be a 2026 potential milestone based on enrollment-
Correct
... as you laid out. And then, the remaining $1.2 billion, that is all... the rest of it is all commercial?
Yeah. So once we get to, you know, first sales and commercial tiers. Yeah.
Great.
Yeah. So more medical milestones after-
Gene, the biology here is fascinating, and I hadn't appreciated it, so thanks for walking us through that.
Sure.
What's the evidence that you can actually clear plaque via that mechanism?
Yeah, so obviously, it's a little bit different with ATTR. There aren't a lot of good animal models, so you have to kind of engineer those to a different extent. You have to inject amyloid into animals and those sorts of things. So obviously, you can see all the relevant biology happening from that perspective. We also did run a phase I, where we looked not just at things like global longitudinal strain, which is a cardiac marker, but also in patients with peripheral neuropathy due to ATTR. We looked at neuropathy impairment scores and what have you.
Although the, you know, it's a phase I, so the sample sizes are limited, and I'd say caution is warranted. We did see stabilization and even some, you know, some changes that wouldn't be expected based on the natural course of these diseases, so we were encouraged by those effects. Obviously, the drug, you know, from the phase I was safe, well-tolerated. And so, you know, that really was the foundation on which we were able to speak with our partners over at Novo, and they made the decision to move that into the phase II, so we look forward to seeing their phase II results. Obviously, those phase II results, you know, were the basis of them making a decision to move into phase III, and we look forward to seeing those.
We expect sometime this year.
But you don't know either what we're going to see from the phase II?
Yeah, that's right. So, obviously, that's their program, as Mark described, and they'll, you know, they'll talk about that, when they're ready.
Yeah. Terrific, guys. Thanks for the update. We're out of time.
Eric, thank you.
But very much appreciate the team being here.
Appreciate it. Thank you.
Thank you.