All right, great. Well, thank you again for joining us this morning at the Citizens Life Sciences Conference. Really happy to be joined next by Prothena and Gene Kinney, CEO. Gene, maybe I'll just turn it over to you to give a quick, you know, 30,000-foot like perspective of the company, where we are today, and introduce the rest of the team.
Uh.
Tran and Mark here to
Yeah. Why don't I let Tran and Mark introduce themselves, and I'm happy to jump in and introduce the company a little bit.
Sure. Mark Johnson, Head of Investor Relations and Corp Comms.
Tran Nguyen, CFO.
Great. First just, you know, thank you for having us. It's really a pleasure to be here. Great location, great meeting, so appreciate the invite. Just a little bit about Prothena. We've been around since 2012 as a spin-out from Elan Pharmaceuticals, really focused on diseases that are characterized by dysfunctional proteins. We feel like we have a unique and differentiated approach in terms of how we think about that and how we approach that science, which has resulted in an organic portfolio that is both partnered and unpartnered, which we think is relatively extensive. If you think about now the partnered side of the business, we have multiple phase III programs. We have a partnership with Roche.
This is in Parkinson's disease, where we have a molecule targeting the protein alpha-synuclein that's now moved into phase III studies on the back of, I think, some very interesting and consistent data coming out of two phase II studies that were conducted by Roche. We have a molecule that's moved into phase III, partnered with Novo Nordisk. That program is focused on ATTR cardiomyopathy. This is a disease characterized by transthyretin deposition in the heart, which leads to a progressive restrictive cardiomyopathy, and something that still requires care and significant attention.
We have a number of programs that are partnered with Bristol Myers Squibb. The most advanced of those is a molecule targeting the tau protein and specifically the MTBR region of tau, which we think is a very important region on, you know, a relatively large protein, 440 amino acids, six different splice variants, lots of phosphorylation sites, lots of post-translational modifications, truncations. Where to target that protein, we think, is actually very important. Working with Bristol Myers Squibb, they've fully enrolled now their TargetTau-1 phase II study last year and received a Fast Track designation from FDA. We're excited about that molecule moving forward. The two phase III studies I mentioned, we expect data from those in about the 2029 period.
We expect data from the TargetTau-1 phase II program with Bristol Myers Squibb in the first half of next year, so that's moving right along. We also have a program that Bristol Myers Squibb opted into on a global basis in 2024. This is our PRX-019 molecule. We are completing the phase I study there that we expect to have done the first half of this year. Because they've already opted into global rights, we'll be sharing that data with Bristol Myers Squibb. They'll obviously have to make a portfolio decision on their own as to what to do with that molecule. They have until about the end of the year to make that decision.
Obviously, if they choose to move that forward into a phase II, it would avail us of additional milestone opportunities. We're excited about that opportunity moving forward. Then a little bit deeper into the portfolio, we have some, I think, some interesting molecules that we're moving forward into the later preclinical stages. One of those is a molecule that's based on our clinical understanding of the PRX012 results.
Mm-hmm.
This is an anti-Abeta antibody that we received data from last year. What we've saw with that study is that with a single monthly subcutaneous administration, very good amyloid removal, but ARIA rates one of the key on-target side effects of this class of drugs that were not quite where we wanted them to be with respect to to being a competitive approach. Fortunately for us, there's a known approach in the space where if you add transferrin targeting technology to these types of antibodies, it seems to reduce the ARIA rates. At least that's been the case with competitors' molecules. We brought that back in and reformulated that with the transferrin-based technology, and that's moving forward.
Of course, we might have opportunity to talk about some of our newer technology that we've been developing and now starting to just talk about beginning last year, which we call the CYTOPE technology. Broadly speaking, briefly speaking, you know, it's a technology that we think opens up the world of previously undruggable protein targets within cells, so inside cells, to now targeting them with almost antibody level levels of specificity. We're excited about that. We've exemplified that with the TDP-43 approach. A lot going on.
Yeah.
You know, we're excited about where we are.
I'll say it this way. Very science-focused, pipeline-rich company, so I'm gonna start with the CFO. You've talked about, you know, generating over $100 million in milestones this year from your partner programs, one hit this week. Just walk us through those dynamics of what you think is coming in and what triggers the milestones.
Absolutely. So as you know, just earlier this week, we announced earning the $50 million of clinical milestones for an enrollment achievement from Novo. So that's in the first quarter, but they have 30 days to pay it. That being said, we're also excited for the potential for the $55 million that we earn when Bristol makes a decision to bring PRX019 into phase II. So that'll happen probably by year-end, right? Then we're actually excited too, where we announced a share repurchase program of up to $100 million for 2026. None of this is included in the guidance of ending the year with $255 million.
Again, you can add the 50 now to the 255. It's like 305, and then depending on what happens with the 55, that's an addition. Of course, depending on how many shares we would purchase, that'll be a decrease there. I think we're balancing all of that when you know on a $50 million cash spend this year, as we you know get to clinical data on our partner programs and more preclinical data on our.
Preclinical programs. I mean, the idea of course with CYTOPE and PRX012 transferrin is we continue to have strategic dialogues around that to potentially build a business development deals, and then as we get back to our own proprietary pipeline.
I understand it's Bristol's decision on 19, but how are you looking at the signals that could trigger their decision to move?
I mean, internally, obviously, we're generating the data set that they and we have talked about together. They'll have to review that data set and make a decision. At the end of the day, it's completely their decision. You know, there are factors beyond even, you know, the data itself. I mean, obviously, they have to think about the fit within their portfolio and other things. You know, I think at this point, we'll wait until they make that decision.
It is important to say though, and I think you might be hinting at this a little bit around the edges, you know, because they opted in and that availed us of an $80 million payment back in 2024, it is really up to them in terms of what they wanna share, when they wanna share it, and how they wanna share it. I think the expectation should be probably less to hear from us on that, from that perspective and more to hear from Bristol Myers Squibb when and if they make the decision to do so.
Got it. Then you mentioned timelines, broadly speaking, for the two late-stage partner programs. So what should we think about, like, you know, in terms of data releases, publication? And again, it's Roche and Novo, they get to make the final decisions here.
Yeah.
How much do you expect them to be talking about these programs as we wait for data?
Yeah. Well, you know, I invite Mark to speak to this as well. I'll just say one quick thing, which is, you know, although we can't speak for them, and obviously they have to make their own decisions, I would say generally, you know, in our business, you know, as you're running phase III studies, you are out there talking about data, the data sets that kind of compelled you to both move this forward and, you know, that get people interested and even potentially excited about, you know, opening these studies at their sites in the case of PIs, and enrolling in studies in the case of the volunteers that choose to do so. But maybe Mark, I don't know.
Yeah, absolutely. Next week is AD/PD 2026. Roche has historically presented data, and they are gonna be presenting additional data on the prasinezumab program next week. That includes, there is a presentation where they're gonna talk about the five-year open label extension data from PASADENA and comparing that to the PPMI and talking about the time saved. That's in their abstract. That's pretty exciting. We'll be looking forward to that data set and that share. Another thing that they're gonna be presenting is an additional six months of open label extension data from the PADOVA Phase IIb trial. What we've seen so far is the patients that were double-blind out to two years, that looked really compelling on the progression of MDS-UPDRS Part III.
They're gonna be also looking at additional data with another six months of open-label extension. Both of those presentations will happen.
I think that's a really important point because one of the things that Roche was very clear in saying when they moved prasinezumab into phase III was that a key consideration for them was the longer-term data that they were looking at.
Yeah.
Can you maybe give us just an overview of the data they've seen from the current studies and then that longer term extension data on what we could maybe, you know, think about as benchmarking success when we see the data coming out in a few weeks?
Yeah, absolutely. With phase IIb, the PADOVA trial, what was really exciting is when, especially on the, you know, the 18-month endpoint, you know, they just missed. It was 0.06, right? When they looked at an additional six months, you saw a continued separation, especially on change from baseline, which was this exploratory endpoint on MDS-UPDRS Part III, right? That, of course, correlates to the primary endpoint of the time to event, right? What they're also doing in phase III, so they're extending the time from 18 months - 24 months to improve the probability of success. They're also increasing the powering, so they're going from 586 patients to 900 patients. And then what-
They're enrolling 100%.
Yeah, sorry. Then they're also looking at the levodopa subset of patients, right, which was 75% of the patients in the PADOVA phase IIb. In that patient population, that was also nominally statistically significant. They're just looking at patients who are on stable symptomatic treatment with levodopa, all of this to increase the probability of success for the phase III program.
Yeah.
Okay. Tie this back into Tran again. Can you maybe just remind us of the deal terms with the partnership with Roche?
Oh, actually. Go for it.
Also just at a high level, you know, how do you think about the market opportunity here?
Well, I mean, I'll maybe start with the market opportunity. This is basically from Roche's own.
Yeah
Projections, and you can see that on their earnings calls. They have it at over $3.5 billion of peak sales. It's quite a large. We also have a co-promote, actually right to it. We have an ability to actually have our sales force that they can pay for, so to speak. That'll be interesting too, when that moment arises. In terms of details, maybe I'll let Mark take it. Yeah. The total deal with Roche was $755 million in milestones + royalties. To date, we've received $135 million, so still another $620 million in milestones yet to get. Then also the sales royalties are tiered up to high double-digit teens.
Right. Maybe switching over to Novo and coramitug. They made or they announced the decision to move forward into phase III before we saw the data. We've now seen the data that drove that decision. Just walk us through, and again, honestly, your perspective of
Yeah
Why those data were so compelling.
Maybe I can start, and Mark, you can jump in. Look, I think the data was very interesting. I mean, first, NT-proBNP is an important biomarker in that patient population. I think most in the space feel like that it tracks well with patient outcomes including, but not limited to survival. Here you saw something that started to approach a 50% change at the highest dose level, highly statistically significant. And importantly, you know, I think it's the first time I've seen this, at least, it reduced below baseline. So you actually saw a reduction below where you started on an average basis for patients. So really encouraging from that perspective. They had a co-primary in that phase II.
Of course, it was underpowered, short duration, but a Six-Minute Walk distance. There were trends that pointed to improvement, although it didn't quite reach statistical significance. I think, you know, that was encouraging. I think on top of all of that, you know, there were some exploratory endpoints around echocardiogram changes that spoke to cardiac structural remodeling that were consistent as well. I think it is that totality of package. Plus on top of all of that, about 90% of these patients in aggregate were on standard of care already. This was on top of standard of care, the stabilizers, and what have you.
I think, you know, that was very encouraging from a commercial relevance perspective, showing that this mechanism of deleting existing protein as opposed to just turning off or stabilizing the normal form of the protein is providing some additional benefit. It was really on the strength of that data, I think, that they indicated they made the decision to move to phase III in the CLEOPATRA study. We're excited about that. As I said, we expect that data to come out around 2029 or so based on the ClinicalTrials.gov listing. We'll stay tuned for that. I don't know, Mark, if you wanna add.
Yeah, I would just, you know, you mentioned that they shared it last year, that was at the American Heart Association, so AHA 2025. It was in a late breaker presentation by Luigi Fontana. You know, I think, you know, just doubling down on what Gene said, on the NT-proBNP, not only a large separation from placebo, but actually a reduction from baseline over 12 months.
Yeah
Which is pretty phenomenal.
Yeah.
Yeah.
Yep. Not sure I've seen that before.
Yeah.
Gene, you mentioned before the tau program with Bristol and the specifics around the mechanism, which I think is
Yeah
I agree, really important. Maybe just at a high level, talk about tau, where you think we are today, and how should we start to think about those that data readout and what's success?
Well, look, I think tau, you know, is a very interesting protein, right? It's a large protein, it's up to 440 amino acids in some isoforms, has multiple splice variants, as I mentioned before. It goes through a lot of post-translational modification. So the question of, you know, how do you actually target tau in the appropriate way to affect propagation of disease, it was really a key question for us, and we took an approach which was very empirical. We simply made antibodies to all the different parts of the protein, the different potential splice variants, different potential post-translational modifications.
We simply asked, you know, if we interact with the protein in this way or that way or the other way, what gives us the best, most robust ability to impact the biology in a positive direction? It was through that work that we started to really hone in on the microtubule binding region, the MTBR region. Specifically, there are four repeat regions in that space, or I should say microtubule binding regions in that space. You know, there were specific areas in that that gave us much better biology than other areas. Now, since that time, we've learned why that might be. For example, the MTBR seems to be very important with respect to the biology of propagating from one cell to another cell.
The MTBR region of tau actually binds to, for example, a heparan sulfate proteoglycan that mediates the internalization in a formerly naive cell. Blocking that process, it turns out, makes a lot of sense. We didn't know that at the time, but we know that now. You know, interestingly, when we tested antibodies that targeted different parts of tau, we didn't get that robust biology. What we're seeing now is that, you know, there are antibodies out there in the field that are targeting those latter areas and, you know, maybe not so successful as we'd like them to be. I think we're learning a lot in the field right now. We're learning the difference between targeting the amino terminus.
Right
The proline-rich region. What does that mean with respect to regional PET changes? Those are important lessons to learn. I think we're at the very early stages of learning what an MTBR interacting region does when you target that space. Clearly, Eisai has an approach there. We've been interested in their early data sets. But I think in terms of a robust phase II, we're very, very interested in where Bristol Myers Squibb ends up with this data readout. That'll be first half of next year. As I said, it's a well-powered study, over 300 patients. Primary outcome measure there is change in tau PET. That's gonna give, I think, an ability to really see what happens at the PET level.
They'll be carrying underpowered secondary endpoints, around functional changes. Of course, you know, you wouldn't expect those to be statistically significant.
Right.
The question of how they change in relationship to the tau PET changes, I think, will be very, very interesting.
Got it. Let me just ask, PRX019, do you wanna tell us the mechanism and the target today?
Um-
I know you can't, so I won't even ask.
Okay.
Can you tell us when we could learn more? Again, understanding that Bristol, you know, owns the news flow here, when could we find out about it? 'Cause it does feel like this is already a target they care about.
Well, I mean, look, as we've talked about in 2024, they opted into global rights, that availed us of an $80 million payment, which we've reported on. You know, we obviously have run that phase I study, are running that phase I study. We expect to complete that this year. At which point, you know, what we'll be doing behind the scenes is sharing that information with Bristol Myers Squibb and they'll make their decision. Their decision, I assume, will be multifactorial. It'll be based on the data, but I'm sure it'll be based on other things as well. You know, based on that, I think what you could expect to hear from us is the outcome of that decision.
I think in terms of the actual target, broadly, it's in the neurodegenerative space. I think, you know, we've said publicly that it's a target for which I think we—the collective we, Bristol Myers Squibb and we—feel that we have a unique way of thinking about the application of that target, which is part of the reason that we haven't talked about it publicly. You know, ultimately, it would be up to them to decide how to move that forward. Generically speaking, not with respect to PRX019 specifically, I think, you know, it would be typical as you're thinking about starting to ramp up a phase II study and enrollment and other things that you're gonna wanna start generating, some external feedback around that.
Yeah.
That wouldn't surprise me. Again, I can't speak for Bristol Myers Squibb here. That ultimately is up to them.
Yeah. It is a competitive target, too. They'll take that into account when they make their decision later this year.
Okay, great. Just big picture, the two programs with Bristol, deal economics.
Yeah
You know, how should we think about, you know, again, the value potential of those economics?
Yeah. Great question, Jason. Combined, there was $1.55 billion in potential milestones plus sales royalties tiered for the two programs in total. That included a $100 million upfront payment plus a $50 million equity investment, of which BMS still holds. Specifically for each program, BMS-986446, the anti-tau antibody, we have received to date $135 million in clinical milestone payments. There's another $562.5 million yet to receive. That's more tied to regulatory and sales milestones. Then PRX019, we have received $80 million, which Gene has mentioned. The decision to move forward to phase II could trigger another $55 million
Mm.
Milestone payment by the end of this year potentially. Then of course, on top of that, another $562.5 million yet to get. Both of them have tiered sales royalties that would go up to high teens on a weighted average basis.
You have some really high quality partnerships, right? At the same time, you're spending a lot of this year thinking really carefully about how to, like, reinvest in your own wholly owned pipelines. Just strategically, what are the pushes and pulls on, you know, when you start to write the checks?
Yeah. Careful capital allocation, right? I mean, I think that's key. You know, I mean we talked about them in pieces and parts, but you know, if you kind of put them in aggregate, our partnered opportunities on a non-risk adjusted basis, you're talking about up to $3 billion just in milestones, right?
Yeah.
That's.
Yeah.
That's without the royalties on top of that with success. I think, you know, the question is exactly the right one. How do we keep spend down and continue to avail ourselves of future potential opportunities with the science that we have? That's obviously, you know, very important to us. One of the things I should say very clearly is that everything we just talked about with respect to partnerships came from the Prothena laboratories, right?
Right.
This is all of an organic portfolio that we've used to partner I think in a pretty efficient way. We have further opportunities in front of us. We talked about PRX012 and the transferrin approach. We've talked a little bit about the CYTOPE technology that we've been developing in the laboratories. Clearly we are active in business development discussions around that as well. One of the strategies, for example, with CYTOPE, is to really think about expanding the potential application of that technology into areas where we maybe don't have the expertise, the interest or even the right capital structure to do it ourselves through research collaborations with large pharmaceutical partners. We've already done that, right? We're doing that actively, and we're gonna continue to do that.
We're gonna continue to think about that as a near-term way to think about a very capital-efficient way to expand this science and create more value.
I think.
Sorry. Go, go.
I was gonna say let's talk about CYTOPE.
Mm-hmm.
The platform itself, the technology, and how does it enable you to go after what some would view as undruggable targets?
Yeah. I think the great example here is TDP-43, which is something we've talked about publicly. Broadly speaking, and I think you said it well, it's really about thinking about once formerly undruggable targets, you know, what we consider undruggable in the context of the intracellular space, right? This is what this technology kind of focuses on. TDP-43 is a very important RNA regulating protein that basically is the master switch with respect to exon inclusion or exclusion. When you think about splice variants and normal splice variants, it's a very important protein from that perspective. It's translocated, it's transported between the nucleus and the cytosol.
Mm-hmm.
What you know we know happens in the context of ALS, and TDP-43 dysregulation in ALS is known in about 97% of that population, is that you start to get stabilizing post-translational modifications in the cytosol. You start to get aggregates. They're phosphorylated, other things are kind of included in those aggregates. The question has always been, well, how do you go and you clear a cytosolic aggregate in a specific way that doesn't mess up normal TDP-43 functions. Very difficult problem to think about. You can't really do it with existing technologies. You can't turn off TDP-43. You can't nonspecifically go after it, and you can't just bind to it and hope something good happens. You need to actually have an effector mediated approach where you can actually clear those cytosolic aggregates.
What we've developed with this technology and what we've demonstrated is that we can actually go into cells, and we've done this in human cell lines in vitro, and we've done it in animal models as well, in the brain or in peripheral spaces as well, such as the muscle. We can not only see intracellular localization of our CYTOPE approach.
Mm.
Inside the cytosol, co-localizing with, in this case, a phosphorylated form of TDP-43, which is uniquely kind of aberrant, if you will. In so doing, you can actually get significant clearance of that cytosolic component. Downstream from that, you actually see a normalization of these splice variants, which is really on the loss of function nuclear side of the approach. Really interesting use of this technology to be both specific and intracellular following systemic administration with both CNS and peripheral application.
Great. We're basically out of time, but I wanna squeeze one more in on CYTOPE. Kind of coming out party last year at Neuroscience, what's next for the program? Will we see more this year?
Yeah. The idea is we'll continue to talk about that in the appropriate scientific venues, and we would expect to talk more about that this year. Yep.
Fantastic. Well, Gene, Tran, Mark, really appreciate you being with us, this morning. Thank you.
Appreciate it.
Thanks, Jason.