Prothena Corp Public Ltd Co (PRTA) September 2026 Conference Transcript

Hi, good morning, and welcome to H.C. Wainwright's 20th Annual Global Investment Conference. Today, we are very pleased to host Gene Keeney, CEO of Prothena, and Mark Johnson, SVP Investor Relations and Corporate Communication, for our fireside chat to discuss Prothena's pipeline and development plans in the next 24 months. So thanks, Gene, and thanks, Mark. Thank you for this. Yeah, and I'm one of the senior biotech analysts here at Wainwright, Ananda Kosh. thanks for joining us today. So maybe we should start with, you know, how has Prothena kind of, you know, we have seen kind of the growth story of Prothena, and then so just wanted to follow up, like, how has Prothena evolved in, you know, in the last 12 months?

Yeah, I think, you know, well, first, thank you for having us. It's always great to be here and to have a chance to discuss the pipeline in the company. I think Prothena today is a very rich company in terms of its pipeline. If you kind of look at where we are, we've got two phase three programs now that are partnered with, we think, excellent partners. Our pracinezumab program targeting alpha-synuclein for Parkinson's disease is currently in a phase three study with our partners at Roche, And, you know, expect to see results from that study in the 2029 period. Also, our phase three program focused on ATTR cardiomyopathy is partnered with Novo. And that program is moving forward also with the 2029 readout. So two phase three programs, I think, in very exciting areas with, I think, you know, broad commercial applicability and I think a strong medical need in both spaces. So we're excited by that. First half of next year, we expect this study to complete on Laponatug, which is our anti-MTBR tau agent that's a phase two studies being run by Bristol-Myers Squibb. And so, again, very exciting in terms of clinical data coming, definitive studies, and I think a very mature pipeline. A little bit earlier in the pipeline, I think we also have some very interesting assets that we're moving forward. Our PRX-12 molecule is a molecule that targets the A-beta protein in the context of Alzheimer's And last year, we showed that following 18 months of subcutaneous treatment once monthly, that we could see very nice reductions of amyloid down to levels well below 20 centeloid. And those are levels that are meaningful, both in the context of what other assets in this space have done, as well as what translates typically through to clinical benefit. The ARIA rates, the RAE rates with that molecule were a little bit higher than we would have liked. And so we've kind of reformulated that using our internal and proprietary transferrin technology and are now moving that back towards the clinic with an eye towards maintaining that profile, that biological effect, but reducing those RAE rates. And so we're excited to see that move forward. And also moving forward with our Cytope technology, which I'm sure we'll talk about. One of the programs that we've talked extensively about is an approach that specifically targets an abnormal form of TDP-43 in a very specific way. This had been a relatively undruggable target heretofore. And so we're excited to be able to develop the technology to expand what we think has been our strength, which is really targeting proteins in a very specific way and expanding the universe of those proteins now to the intracellular space. So that's kind of a new space for us with new technology, and we're very excited to see that move forward as well.

Yeah, and Ananda, just to double down on the Cytope technology. So, you know, I think Protea has been long known as being, you know, really good innovators at coming up with new approaches in the extracellular space for protein dysregulation. And with this CYTOC technology, we now can expand that to intercellular targets that previously weren't really available to anyone in the space before. So very excited about what that can bring to us.

Great. Maybe with that, we can kind of deep dive into some of these programs you mentioned. Let's start with Krasi. Maybe tell us about what were the learnings from the trial so far and what specifically the Paraiso does differently.

Yeah, well, let's start with some of the learnings, and maybe, Mark, you can jump into the current Phase III and some of the ways that those learnings have been incorporated into the Phase III study. I think first, you know, this comes on, you know, the current Phase III studies comes on the heels of two Phase II studies that showed a very consistent benefit across different clinical domains. And I think that's really important as we think about the endpoints that are being used in the phase three study. It's a time to event analysis, looking at motor progression, if you will. And in both of the prior phase two studies, there was a very consistent effect on that endpoint. So really understanding that, understanding how to kind of think about moving that forward and how to power the phase three study was something that, you know, obviously was, you know, derived directly from those phase two studies. I think beyond this time-to-event analysis, now we have up to five years of open-label extension data. In those data sets, I think we've seen consistent benefit, albeit against a propensity-matched control group. Nonetheless, the effects seem to be maintained. They seem to be continuing even across this five-year time period. In fact, in a time-saved analysis, Roche suggested that and showed with their data that, you know, over a five-year period, two years is saved. So that's a meaningful, meaningful effect in patients with Parkinson's disease as we think about progression of disease. So I think, you know, there have been a number of learnings. We can talk a little bit about the biomarkers as well, which I think were also, you know, supportive of these effects. there was some reduction of accumulation of iron in the putamen. We also saw a stabilization, if you will, of neuromelanin in the substantia nigra pars compacta. Both of those effects, I think, are consistent with a disease-modifying approach and obviously supportive of these primary endpoint changes, as we saw. And the final point I'll make is that, you know, somewhere around 75% of the patients in the last phase two trial were taking concomitant L-DOPA treatment, which is the standard of care with respect to symptomatic treatment in Parkinson's disease. And in fact, the effects that we saw in that subpopulation were even greater than the effects across the entirety of the population. And so in the phase three trial, as Mark will get into, we are looking at patients on L-DOPA concomitant treatment. And of course, that's not just important from the biology perspective, it's also important because from a commercial perspective, those are the types of patients you would expect to be encountering, and those are the types of patients you would hope to help.

Yeah, no, absolutely, Gene. And I think, so what Roche has done for the phase three per ESO trial to really, you know, increase the probability success, reduce the noise variance to get a clean readout, really kind of three key things. One, just increasing the size of the patient population going to phase three, which is standard, right? So So from 586 in the phase two to about 900 patients are going to be enrolling in the current trial. The second is what Gene just hit on, which is it's going to be all levodopa-treated patients, right? So on a stable dose of levodopa and then adding presenazimem on top of that. And then the final piece is actually, and we've seen this now with the open label extensions, we've seen this with actually double-blinded data in the phase 2b that went out for two years for the patients that were on for at least two years, there is more separation, especially after the 18-month time point. That's when you really start to see the effects of a disease-modifying therapy, and you can really see the separation from placebo. So all patients will be on the drugs for a minimum of two years, as opposed to 18 months, which was the previous trial. And then you think about the commercial potential. Roche is really excited about this. They've talked about, you know, they have four different buckets where they like to put their candidate programs of where they're going to be for global peak sales. It's either under a billion, one to two billion, two to three billion, or greater than three billion. You know, that's just an open-ended peak sales number. And that's exactly where you would expect President Esmeb to be beaten at. And that's where it is. And for us, it's very exciting because the economics are very attractive, right? We still have $620 million worth of potential milestones that could come our way from this particular program. and then, of course, royalties up to high teens double digits. So very lucrative opportunity for us and looking forward to the results, hopefully, in 2029.

Great. Thanks. You know, talking about biomarkers, like you mentioned about, you know, the iron accumulation and neuromelanine preservations, you know, and also the longitudinal NM change kind of tracking with the MDS-UPDRS, part three. Probably the first biomarker evidence that PRASI, you know, indicating that PRASI kind of touches the underlying pathophysiology of the disease. So are, you know, this iron MRI or neuromelanian MRI and defined and practically defined offset digital measures, are they pre-specified in Paraseo or they're exploratory in subset and how much weight would a positive imaging result carry with the regulators?

Yeah, well, thanks. Yeah, thanks. It's a great question. I think it speaks to how exciting it is to have actually biological data, particularly in a disease like Parkinson's disease tracking, with some of these clinical changes. I think from a regulatory perspective, you know, clearly, you know, in the phase three, the primary thing is the primary thing, right? We want to, we're focused on primary outcome measure, which again is a time to event on motor progression. And I think that's something that we've seen both, you know, from consistency perspective, you've seen that in phase two, you know, clearly, we would expect that Roche has been, you know, have been talking with regulators about these types of endpoints. And I think, you know, not just from a consistency perspective, but also the magnitude of these changes, as I indicated to your time, you know, benefit over five years are meaningful, right? So this is meaningful and consistent. So that's the main thing to focus on. And I think those will be the main things that have to hit in order to see success of this program. Of course, seeing changes that are consistent at the biological level are supportive. Of course, they're meaningful. And I think, you know, that's the way we would think about them. But there's certainly, you know, we wouldn't expect them to be required in terms of any given change. We'd expect the primary outcome measure to be sufficient for a successful trial.

Got it. That brings us to the Koramitag program. You know, so we have seen like stabilizers kind of stop new misfolding and silencers kind of, you know, reduce or cut short the supply, whereas Koramitag clears the amyloid already deposited, you know, completely differentiated approach in the ATTR landscape. The phase two produced around 48% anti-pro BNP reduction, right? And especially on an 84% Tafamides background. So maybe talk about the significance of the data with respect to the ATTR landscape. And if you can comment on, is it an add-on to the standard of care rather than a replacement?

Yeah, well, certainly from a biology perspective, we wouldn't expect it to be competitive with things that are working, you know, further upstream, if you will, the silencers and stabilizers. You know, in essence, if you think about silencers and stabilizers, which are, you know, available today, what they're attempting to do is really decrease the amount of new aberrant protein coming into the system. A karamatog, a depleter mechanism, is differentiated, as you say, in as much as it not only targets what's already there, the resident to amyloid, if you will, which obviously we would expect to be causing dysfunction in the moment, but also anything that's still coming through that system, despite the fact of having stabilizers and silencers on board, it would help in what we've shown in the preclinical setting is it seems to help to prevent that from becoming dysfunctional and further contributing to the amyloid load. And so we think it's a very important differentiated mechanism. It certainly can be complementary to standard of care. And as you say, the phase two data, we thought were very encouraging. You know, they were differentiated from what you see with stabilizers and silencers, or even if you combine the two, as we've seen more recently, in as much as, you know, not only does NT-ProBMP change in a very meaningful way relative to placebo, it also showed over just a one-year period, a decrease from baseline. And, you know, we really haven't seen that with stabilizers or silencers. Moreover, if you look at the six-minute walk changes, which were underpowered, admittedly, but still, I think, directionally meaningful, you saw a separation of the curves as early as that 52-week time point. Again, some of the more recent data looking at the combination of silencers and stabilizers, you really don't start to see any separation until a much later time point. And so I think it's pointing us to the idea that this is a differentiated approach. It's very differentiated from, you know, these things that work a little bit more upstream, and it does, you know, of course target the more resident amyloid as well as the things coming through that system, and so we think, you know, the rationale to continue here and to potentially see greater benefit with the addition of a depleter is something that we're excited to see the readout of, and obviously, as we talked about, Novo is running that phase three trial. We expect those results in the 2029 time frame, but Absolutely.

Well, I just wanted to kind of hop on a little something Gene mentioned, which was the cardio transform results that came out this summer with Eplon Person. And there you're combining a silencer and a stabilizer, right? And we actually wouldn't have expected to see that much more efficacy gain because the similar upstream mechanism of action. And when you look at the data set and compare it to what we showed with Karamatug, a different mechanism of depleter plus the stabilizer, you did see some pretty stark differences, right? Gene had mentioned the NT-ProBMP. If you look at the cardio transform data, it is lower than the placebo group, but it continues to rise, right, over time, which is what you've expected to see from that class. With Calamitog, because it's actually working on the depletion of the resin amyloid, you've actually seen a decrease on improvement in antipropion P levels over that 12-month time point. And then on the six-minute walk test, you know, Gene mentioned it was underpowered, but it did show a meaningful separation of over 13 meters at only 12 months. And when you look at the epilonturcin cardiotransform data, they had a time point of 61 weeks, so very similar time point. There was no separation, right? And it did then start to separate over the two-year period, right? So we would expect a continued separation with kramatug as well. So pretty exciting when you start to compare those results to what is established with the current standard of care treatment.

You know, given the depletion, like the way it behaves differently on top of stabilizers, does that result change anything about how Novo powers monitors the subgroup or anything? Like, has that any significance on those aspects?

Well, you had mentioned it, and I think it bears repeating that, you know, in that phase two study that Mark is referring to, you know, approximately 90% of those patients were already on stabilizers. So I think what you're seeing here is, you know, a differentiation from what stabilizers can bring on their own. You know, so from that perspective, I think we feel pretty confident that, you know, doing this on top of the standard of care, if you will, which tends to be stabilizer treatment at the moment, you know, is a well-founded approach.

Got it. yeah thanks uh the other i think one key question uh with respect to this program is that royalty pharma you know recently paid up to around like 425 million for about three to four percent royalty on you know clear uh clear meter uh like and then that entire evidence is open level uh based right So, you know, with nearly 1 billion in remaining in novel milestones plus tired royalties, like what does these kind of transactions talk about the depleter's landscape?

Yeah, I think that announcement says two things to us about Karamitag, right? First, the potential of success, right? Royalty pharma is very well established. They do very deep diligence, lots of dark calls. They had to obviously, from that data, get very comfortable that there was a high probability success for phase three. So of the $425 million deal, $250 million will be paid out before they see that phase three readout, right? So that just probability success. And then also the fact that they obviously believe that there's huge commercial upside with a depleter mechanism joining the ATTRCM armamentarium, because they're paying for those royalties. So they obviously are putting a lot of money at risk now, with hopefully a big payoff in And then I think what's interesting for us is just recognition for the investor base that, hey, there is another ATTR depleter out there. There's two of us. AstraZeneca has one. We have one. Both of them are successful. We would assume that those are still both multibillion-dollar market opportunities. And the Claramatog data, I believe, is coming. That phase three is coming in 2028. So win, lose, or draw, that could be a catalyst for the Claramatog as well. There are things that we believe are different about caramitug versus caramitug. So if that doesn't work, it necessarily doesn't mean that caramitug wouldn't work. But if it does, it definitely bodes well for the success of caramitug as well.

If you can talk about some of those differences, that would be helpful in terms of…

I mean, at the most basic mechanism level, the way we target the transthyretin protein is a little bit differently. We actually worked with a group that had solved the NMR structure of the homotetramer, which is the normal form of transthyretin, which underlies its normal function, and targeted an area that is only accessible when that normal form falls apart and the protein starts to denature. And what's, you know, moreover, what we've shown in our preclinical studies is that in both soluble abnormal structures as well as the insoluble structures, the deposited amyloid, that epitope remains available to us. So we're able to interact with that, which gives us the opportunity to actually see abnormal material all the way through the system. And so that's actually important. You know, stabilizers stabilize that homotetramer. But at some point, you know, they're still coming apart. And if not cleared rapidly enough, particularly if there's already resident amyloid that's creating a driving force from, you know, a somewhat normally folded structure to an abnormally folded structure, having something there that can actually intervene in that process would be important. And as I said, in our preclinical data, we've shown that Kramitimer, the precursor to that, has that capability. We've not seen that data with the other antibody. It may or may not be true, but that data, at least to our knowledge, doesn't exist.

Great. Thanks. And maybe that kind of brings us to the third program, you know, Moponetag, BMS446. you know isn't target tau 1 completing as you said 1h 2027 with fast track uh designation uh and a sub-q phase one behind it so you know so they are probably going all like all on on this approach uh remind us of the mtbr tau hypothesis you know why the microtubule binding region is essential you know why extracellular you know what magnitude of effect on tau pit spread and clinical decline would make BMS2 kind of commit to phase three? And also, you know, is a commercial frame monotherapy or it's kind of an add-on to anti-inflammatory?

A lot of questions in there, but yes, I'll do one. So, yeah, I mean, I think, so first let's start with tau. Tau is a very complex protein, right? So you have six splice variants, two major isoforms, up to 440 amino acids. How and where you target tau in order to have an, you know, an optimal effect i think was a question that we looked at very early um we chose an approach which was you know a kind of a muscle based approach which was we call empirical epitope mapping which is really to take the tau protein to take it in its different forms and ask questions about its pathological biology so how effectively does it spread from neuron to neuron and seed uh dysfunctional tau you know what does that do downstream in terms of translations toxicity and so on and so forth. And then we simply made, you know, different antibodies that targeted the different areas of tau, different post-translational modifications, whether it be phosphorylation sites or what have you, and asked what gave the most robust and consistent benefit with respect to those biological outcomes, right? And at the end of the day, we really saw nothing that gave us a lot of confidence until we got to the MTBR region. And then, you know, once we started to actually target specific regions within the microtubule binding domains, we started to see very consistent effects. And, you know, admittedly, I think at the time, historically, it wasn't absolutely clear why that might have been the case. But I think the science has really matured around that now. And what we've what we see is, you know, there are groups that have shown very clearly now that these microtubule binding domain regions or fragments of tau containing these MTBR regions binds to, for example, heparin sulfate pernid glycan structures on adjacent neurons and mediate internalization, potentially by translocation into formerly naive cells, seed dysfunctional tau in those cells. And so as we start to think about the propagation of tau spread, you know, the MTBR region seems to be uniquely positioned in that regard. Not only that, but as we look at the biomarker work, and, you know, I think everybody's familiar with the effects of PTAO 181, PTAO 217, and how that not just, you know, speaks to what's happening with respect to tau, but also amyloid beta, which may be upstream of some tau dysregulation. But now what we're seeing is, you know, things like PTAO 243, which are a little bit closer to that MTBR region, seem to be very, very, you know, sensitive indicators of what's happening to tau and tau pen. And so this all starts to make sense if we think about the role of MTBR in tau propagation. And you kind of alluded to this in your comment or your question, but I just want to reiterate, because the approach here is that MTBR may be critical with respect to tau propagation, what we would expect as an a priori kind of expectation in these phase two studies is basically an inhibition of that propagation, right, of tau and tau accumulation, tau spread between areas. That's a very important kind of a priori expectation, but I think, you know, that's something that the BMS study, the phase two study is well-powered to see. You know, they are looking at tau PET as the primary outcome measure, over 300 patients expected in that study. They will be looking at function as well, as secondary and exploratory endpoints, but I would expect to be underpowered on those. And what I'd really be looking for there is what is the relationship between those two variables. Ultimately for us, any data set that I think speaks to the ability to move this into a high probability phase three study would be what we'd be looking for out of the phase two study.

Yeah, and then just to add to that, I think when we look at the landscape of the past, you know, 12 months or so of what data that's been presented, you know, we get encouraged, right, by propranumab data, by even Biogen's data, right, where you're seeing a connection between these biomarkers, you know, the slowing of tau propagation, and, you know, benefits and slowing on cognition, right? So, you know, I think that there's definitely that story is being told, and hopefully we'll add to it in a positive way.

Yeah, and that kind of brings me to the cilia data, you know, the given the recent cilia data at AIC, what was your first thought, you know, with respect to the landscape, you know, and your thoughts on surrounding the biomarker data, the efficacy and safety, the inverted U-shaped response? So I will be very interested to, you know, understand your thought with respect to modality and with respect to your, you know, differentiator approach.

Yeah. Well, so first, I think very encouraged, right? So we're very encouraged. I think it shows, at least in my mind, without any doubt, that tau is a targetable protein. I think they clearly showed an impact on tau PET across their different dose ranges. The relationship between those tau PET changes and the functional outcomes, of course, were encouraging. But as you said, it was a little curious that as you got to the higher doses, you know, you didn't see quite the same level of association between the functional outcomes and the tau PET changes. I think there the question really is, is that a function of the ASO or any RNAi approach targeting normal tau, right? Remember the target here is MAPT with these approaches. You're not just knocking down the abnormal tau, you're knocking down normal tau and tau function as well. And I think the question is, you know, What is the therapeutic window to be able to get to abnormal tau through the normal tau protein? So I think that's an interesting question. There are more RNAi approaches coming. We're going to continue to learn this space. So at a high level, very encouraged by that data. But I think what's left and what's needed in that space is a intracellular approach that specifically targets an abnormal form of Tau where you can leave the normal Tau function alone, I think that might give us an opportunity to continue to hit this system a little bit harder, maybe drive stronger effects, but at the same time leave normal Tau function intact.

Corey, maybe, you know, given the time we have, I really wanted to talk about the Cytop platform.

So, you know, if you can talk about the Cytop platform and where do you see value in the site of a platform that would be helpful yeah well mark kind of introduced this earlier i think you know for us um you know we have spent you know careers thinking about how to target proteins how to specifically regulate those proteins in the context of disease but really because a lot of that work has been using monoclonal antibodies and other approaches that are not really friendly to the inside of cells we've been restricted to these extracellular targets. And I think what our Cytope platform does is it allows us to think about the world of internal targets now and continue to be extremely specific, extremely thoughtful about how to interact with targets. We just talked about leaving normal Tau function intact, but going after abnormal function, this is the type of approach that you could think of. The platform, if you will, at the highest level is a completely differentiated platform. We It basically allows us to bring macromolecules and other molecules into the cell in a way that doesn't appear to disrupt endosomal function. It appears to have high efficiency endosomal escape and allows us to be extremely specific with respect to how we target these proteins. Our prototype program, which is moving forward, is a TDP43 targeting program. our program in the past, you know, TDP-43 is such an important regulator of controlling splice variants and, you know, controlling regulation of, you know, at the nuclear level. And also TDP-43 as it aggregates, you know, is causing a gain of toxic function in the cytosol as well. You can't really target normal TDP-43 activity. It's important for every cell. So what we did was we took an extremely specific approach to an abnormally phosphorylated form of TDP-43. We've shown now in very aggressive mouse models that we can not only remove that phosphate TDP-43 in the brain as well as in the periphery, but in so doing, actually correct splice dysfunction that you see with TDP-43. So it's an example of what I would characterize as a heretofore non-targetable protein where we are now targeting it in a very specific way because of this site to a platform yeah you know the recent jama article talks about like specifically with the tdp-43 i mean it has been a unreadable target right and with the jama neurology i think the paper talks about nearly three million patients across different indications so how do you go about like late or als yeah well look as you say 97 of als patients have tdp-43 dysfunction uh you know it's it's But, you know, to your point, and, you know, there's a recent paper out talking about TAND, which are, you know, TDP-43 disease states. And, you know, some of those are primarily driven by TDP-43, inclusion body myositis, late, you know, some others. But also TDP-43 is an important co-pathology in other disease states, such as Alzheimer's disease, is also something to be considered. When TDP43 is present, for example, in Alzheimer's disease, you tend to have a more aggressive course. You tend to get patients that are experiencing cognitive and functional decline at a greater So it is an important primary mediator in some diseases, as you say, both peripheral and central. And it's a very important co-mediator of disease, which can have real functional impact in some other disease states.

Any final thoughts, like what should we think about as we think about Prithina in the next six, 12 months?

Yeah, well, I think just real quick, because I know we're over time here, but we're expected to end the year with almost $260 million in cash, which gives us the ability and capital resources to get through all of our partner programs and see those phase two next year readouts, as well as the phase three readouts in 2029, as well as continue to invest in this exciting new technology and our X12 TFR technology and bring those closer to the clinic within the next couple of years. So stay tuned on our future clinical development plans, but know that we're well resourced to complete it. Thank you. Thank you very much.