Morning, everyone. So my name is Rudy, biotech research analyst from Leerink Partners, and glad today to host a fireside chat with, Dr. Gene Kinney, CEO of Prothena, and Mark Johnson, Head of IR. So thanks for joining us today. Would you like to kickstart with maybe a brief introduction of the company, so?
Great. Well, first, Rudy, thank you very much for having us. We appreciate the opportunity to be here with you today and to be able to talk a little bit about Prothena. So maybe a little bit about the company for those that haven't followed Prothena. We are a company that spun out of Elan Pharmaceuticals, actually, in December of 2012, with a focus on dysregulated proteins. So just thinking about misfolded proteins and their contribution to disease. Obviously, for those that know the history of Elan, you'll know that a lot of that work really started around a study of the amyloid beta protein in the context of Alzheimer's disease, and the very first immunotherapy experiments in that space.
But then really expanded into other protein-based diseases, which include other central nervous system disorders such as Parkinson's disease and others, as well as peripheral indications like ATTR amyloidosis and AL amyloidosis. And I think that really brings us forward then to the current pipeline, which has a number of molecules in active clinical development, ranging from Phase III studies with our molecule birtamimab, which is focused on AL amyloidosis. We have prasinezumab, which is partnered actually with our partners at Roche for the potential treatment of Parkinson's disease.
We can talk about NNC6019, which is partnered with Novo, and that's a molecule for the potential treatment of ATTR amyloidosis that's currently in a Phase II study with Novo Nordisk. And then, of course, our wholly owned Alzheimer's portfolio, which includes PRX012, which is an amyloid beta-targeting molecule, as well as PRX123. Actually, it's an active vaccine that's designed to generate titers to both amyloid beta and to tau. And interestingly, we just received the IND clearance on that at the end of 2023 with Fast Track, and so that's now moving into the clinical space. And of course, I'd be remiss if I didn't also mention our tau molecule, PRX005, which is partnered with our friends over at Bristol Myers Squibb.
And they've announced that they'll be initiating a Phase II with that molecule this year. So again, on the theme of Alzheimer's disease. Just one other note across our portfolio, you know, about half of our programs are partnered. We have excellent relationships with Roche, with Novo Nordisk, as I've mentioned, with Bristol Myers Squibb, and about half of our molecules are independent, including our Phase III asset, birtamimab, as well as PRX123 and PRX012, in the clinical space for Alzheimer's disease. And I think just a final note in terms of overview of the company, maybe around the finances, Mark, if you want to just update on that.
Yeah, absolutely. Thank you, Gene. My pleasure. So we ended the year with $621 million in cash. We just put out guidance that based on the midpoint of our expense ranges, we expect to end 2024 with around $405 million in cash. And as Gene just mentioned, we have several clinical trial readouts coming over the next 15 or so months. So we are well-positioned for successful clinical readouts with our current cash balance.
Cool. Yeah, thanks for the introduction. So maybe you can start with PRX012 and your Alzheimer's portfolio. Apparently, investors are still laser-focused on this program, so maybe you can talk about the market dynamics of anti-A beta products in Alzheimer's, and the initial launch of Biogen's Leqembi has been gradual so far, as expected. So maybe talk about your the implication to your program.
Yeah, well, I think so there's a couple of, I think, pieces built into that. I think first is just really the transition in the Alzheimer's treatment space, moving from treatments that we had in hand, which were largely around symptomatic benefit for patients, but really did nothing to address the underlying disease pathophysiology or the progression of disease, to now a place where we have seen, on an approval basis, the accelerated approval of aducanumab, and then, of course, with lecanemab and the full approval subsequently of lecanemab. I think it's an exciting time for patients and caregivers in terms of thinking about that transition.
Moving from symptomatic treatments to having now treatments that arguably are disease-modifying in their action, is a pretty big step as we think about the treatment armamentarium that physicians have to help their patients kind of move through a diagnosis of Alzheimer's disease. And if we look to other areas of medicine, it's typically just the beginning, right? As we think about this space, for example, we at Prothena look forward to a period not only where we start to optimize these types of treatments, and we can talk about that in the context of PRX012, but also as we think forward to where the field is likely to go and start thinking about combination approaches, adding to the anti-amyloid approach, other approaches, for example, targeting tau and other things, to further increase the efficacy profile.
And also, particularly important in central nervous system diseases, moving the treatment paradigm back to the pre-symptomatic space. You know, we don't, we don't treat HIV when AIDS is, has happened. We treat it when we can detect the HIV. And so the idea of treating when the biology is relevant, but yet maybe even before the symptoms are starting to become manifest, is something that's quite attractive as well. So when we think about that in the context of the Prothena portfolio, we can talk about PRX012. PRX012, for example, was specifically and systematically designed to provide a benefit for patients in terms of treatment and access.
As we think about treatment burden and the idea of spending a day in IV infusion centers, and doing that on a regular basis, we felt some time ago that with what we believed to be this first class of disease-modifying agents, particularly agents that target the N-terminus of the amyloid beta protein, that moving to a place where access was something that patients could think about, and really providing an opportunity for once-monthly subcutaneous treatment, would be a significant advantage as we thought about a best-in-class presentation here. So PRX012 was designed very much with that idea in mind. We really optimized around things like potency, bioavailability, you know, really brought all the lessons that we'd learned over decades of experience in this space to bear.
Made literally hundreds of antibodies to develop the right biological profile, and ultimately, PRX012 was at the top of those characteristics and moved forward into clinical trials. We've indicated in January that in an initial multiple-dose cohort, where patients were treated for six months, once monthly subcutaneously, that we saw indications of amyloid reduction with therapeutic index that was certainly permissive to continue to explore a fulsome dose range, so in terms of exposure-response relationship, and we're conducting that study as we speak. And so we're very excited to be able to further update around details of those results when it's appropriate to do so. The vaccine we talked about earlier is another component of that in terms of the offering.
As we think about PRX123 and the potential to think about treatment choices even in the pre-symptomatic stage, we think a vaccine would be a very good offering in that space. So we look forward to initiating the first-in-human studies with our active vaccine at the appropriate time. And once we do that, you know, we would look to then position that, either into the treatment setting or potentially into the pre-symptomatic treatment setting, or potentially both. And so we think that those are important offerings, as we put those together. In terms of the market dynamics, it's, you know, I will say for us, it is not all unexpected in terms of how these current offerings have been taken up.
We obviously expect that a medical infrastructure and other things needs to catch up with the current treatments and the approaches. One of the reasons we developed PRX012 with the characteristics we did, was to actually think very much about the treatment burden in a moment of diagnosis for an Alzheimer's patient. If you think about an Alzheimer's patient receiving that type of diagnosis, you know, you'll understand that Alzheimer's disease today remains a 100% fatal disease. And obviously, as you think about the burden that is incurred by any given patient or their family or caregivers in a moment of diagnosis, one of the things we want to try and do is remove treatment burden in that moment.
We think a once-monthly subcutaneous offering has the potential to do that, provided that we can think about a best-in-class that incorporates both convenience and access on one hand, but also an appropriate therapeutic index on the other. So, so that really is the goal in terms of the target presentation for PRX012, and obviously, as we conduct our Phase I trials, that's what we're looking for.
Yep, that makes a lot of sense. So a lot happened during the past couple of weeks, like apparently, Roche presented additional data for trontinemab B rain Shuttle product. So shows the high dose had good data regarding Aβ reduction, and they have low ARIA rates. And also, we learned last week that FDA is holding AdCom for its, for donanemab. So curious about yourselves, about the market dynamics. Now, you have Biogen, Lilly, also Roche in the market, and how should we think about positioning?
Yeah, I think. Well, again, I think as you think about best-in-class in this approach, you know, we think three factors are very important, right? Certainly, convenience, which I think speaks to access and to treatment burden. We obviously think efficacy is clearly very important. And then, of course, safety is also very important. Probably in that order, all being very important, but probably in that order. And so, clearly, you know, we believe that, from that perspective, PRX012 has the potential for a differentiated value proposition in the space, and, you know, we look forward to demonstrating that in our clinical trials. I think in terms of, you know, other companies and what they're doing, you know, this field is moving rapidly, as you would expect and hope it would.
I think from a scientific perspective, we're learning things both on the clinical science side, as well as the basic biology of both from an efficacy perspective as well as from a safety perspective. One of the things that we're very encouraged by in the field is we're starting to see now a little bit of a shift where we're talking about AEs and ARIA as an event as opposed to an AE, which we think is appropriate, given that most ARIA events tend to be asymptomatic and radiographic in nature.
And so I think, you know, starting to have more nuanced conversations is a good thing, and I think having companies out there, like some of the ones you mentioned, Eisai, Eli Lilly, Roche, talking about these issues is good for the field, and I think will stimulate research, in very important areas. You know, we've talked about ARIA, we've talked about efficacy, we've talked about Brain Shuttle. I think the other place that we can think about is blood-based biomarkers, where there's just been an enormous amount of work being done around things like, phosphorylated tau fragments, p-tau 181, p-tau 217 in the blood. What that means with respect to tracking amyloid changes in the brains of patients and how well those blood-based biomarkers actually track.
And I think having additional offerings in the space and additional companies in the space stimulating such research is positive to the field. At the end of the day, you know, there are 6.5 million people with Alzheimer's disease in the U.S., somewhere around 55 million with dementia across the globe. And obviously, the most common form of dementia is Alzheimer's disease. So we think, obviously, having the appropriate types of therapeutics for the appropriate patient populations is critically important.
Yep, yep. So let's talk about the Phase I/II study of PRX012. So you mentioned that current data supported for one-time monthly dose. So what we learned so far, and what give you the confidence?
Yeah, so thank you for the question. So as you kinda indicate, the Phase I study, there's two components to it. There's a single-dose component, and a multiple-dose component. The multiple-dose component contemplates once-monthly subcutaneous injections for six months. That's a double-blind, placebo-controlled portion of the study, at which point, eligible patients can move into an open-label extension for an additional six months of subcutaneous treatment. Again, once-monthly subcutaneous. What we indicated in a press release in January was that after having evaluated the first or single cohort, at a 70 mg dose level, so 70 mg once monthly, in our Phase I study, that we felt that the data to date had supported the once-monthly subcutaneous presentation.
We felt that there was encouraging signals of activity in terms of amyloid reduction, and we felt that the ARIA, at least in that context, and overall, the AE rates were both consistent with placebo and certainly permissive to continue to do what we had planned to do and what we intend to do, which is to fully explore the exposure-response relationship across a number of dose levels. So we're actively exploring dose levels between 45 mg-400 mg once monthly. And we will, of course, come back and update the street with respect to timing and/or more detailed data analysis when we feel like there's a substantive update to provide.
Cool. So maybe just talk about your overall strategy. So what would be the next step, and is, do you think that accelerated approval is still on the table, maybe?
Yeah, well, I think, it's a good question, and I think, you know, in terms of our strategy with the PRX012 program, obviously, you know... I'll state something that I hope is obvious, which is we'd hope to bring that offering to patients on a timeline that's appropriate relative to the data that we collect. I think, you know, one of the things that we've indicated in our Phase I study is that we wanna make sure we're being systematic in our evaluation so that we can select the best or optimized dose level or levels, in a case that we may choose to bring more than one dose level forward, for a subsequent registration-directed trial. And so really, that encompasses a couple of things.
It encompasses having a high level of confidence in our target profile, which would include, again, the convenience, access, burden aspect, as well as the therapeutic index. And obviously, having a high confidence in that so we know what dose levels to take forward into a registration-directed trial would be absolutely important. And I think, you know, it... Yeah, so I'll leave it at that. I think that's really what we want to get out of this Phase I. We wanna make sure we have that high level of confidence, so we can make the right next investment decisions. This is a wholly owned asset, and we want to be thoughtful about capital allocation, and we wanna make sure we're spending that money wisely, and doing so with a high level of confidence.
Yep, makes a lot of sense. So, let's switch gears to a different topic. So prasinezumab in Parkinson's disease. So maybe same thing here, you can start talking about the treatment landscape of Parkinson's disease and your current thoughts on anti-alpha-syn for treating Parkinson's.
Yeah. So alpha-synuclein, as a protein, for those that haven't followed the field, is kind of the smoking gun with respect to cause and progression of Parkinson's disease. We know that genetic mutations or changes that lead to overproduction or higher aggregation states of the alpha-synuclein protein tend to lead to Parkinson's disease, and sometimes with an earlier onset from an age perspective. And so, you know, targeting that protein in a very systematic way was something that we were quite interested in doing. And in prasinezumab, we developed a molecule that is highly preferential to the more aggregated forms of alpha-synuclein. We think that's important because it is those aggregated forms that are the culprits, if you will, with respect to cell-to-cell transmissibility of alpha-synuclein in the brain.
So as you think about progression of Alzheimer's disease, there's a couple of ways to think about it. One is in a very localized region, like the substantia nigra, that contain the dopamine cells that are lost in Parkinson's disease. There certainly is, over the years, a loss of those dopamine cells, which continues. But there are other brain areas that also become involved. So as we think about the onset of alpha-synuclein-based pathology that leads to Parkinson's disease, it actually starts in brain areas away from the substantia nigra, away from the basal ganglia, and it seems to move between interconnected areas of the brain, establishing pathology in those other areas as the disease progresses.
So as we think about disease modification in the context of Parkinson's disease, we can think not only about kind of dampening the fire in a specific area, but also stopping the spread between areas. And one of the things that we were very encouraged about in the preclinical space with prasinezumab, is that it was one of the best molecules we had looked at in terms of stopping or dampening that cell-to-cell transmissibility of that protein. So we had moved that molecule through Phase I, ended, with a relationship, developing a relationship with Roche, which has really been very productive over the years. With Roche, took that molecule into a Phase II study called the PASADENA study, and on the basis of that study, have now subsequently moved into a Phase IIB PADOVA study.
So you had mentioned that Roche had presented some data. They did so last week at the AD/PD conference, again yesterday, on an internal, or I should say, a neurology kind of R&D day call that they did yesterday. And in both cases, they talked about a 4-year follow-up period for that, those Pasadena results. So it showed somewhat we would consider to be very encouraging data in the context of those presentations. So I'll go back to a reminder, because these data were presented some time ago, that, you know, the initial study design was a 12-month study, where patients were either receiving prasinezumab at one of two doses or a placebo.
And in that initial study period, depending on what endpoint you looked at and how it was evaluated, so for example, on the MDS-UPDRS Part III, which looks at the motor dysfunction in Parkinson's disease, so things like tremor, bradykinesia, slowness of movement, and other things. If you centrally evaluated those readouts, there was up to a 35% slowing of disease progression for patients on prasinezumab relative to placebo in that first year. Now, at the end of the first year, patients were able to do a couple of things. First, they were able to move into an open-label extension, where they received prasinezumab. And second, we had discouraged, or not actively discouraged, but we encouraged patients to resist taking L-DOPA, the symptomatic treatment for Parkinson's disease, in the first year, if they didn't need it.
The reason for that is because we know that that has an impact on this outcome measure, this UPDRS Part III. So, you know, we wanted to get as clean a look in that first year as possible. As patients moved into the open-label extension, they began taking these, this L-DOPA as well. And the relevance of that is that the majority of patients with Parkinson's disease do take these L-DOPA treatments. So it about, you know, more or less quadruples the patient population that you're talking about as you think about concomitant L-DOPA usage. Nonetheless, what was shown at AD/PD, and again, yesterday, was really a four-year follow-up in these patients, where they had quite a favorable response over that long period.
And what Roche had done was to do a baseline match of a non-concurrent control group from the Michael J. Fox Foundation PPMI Initiative, where they looked at what you might expect in terms of normal progression in patients. And if we focus on that MDS-UPDRS Part III, what they showed was over that 4-year period, there was approximately a 65%-- up to a 65% slowing of progression if you evaluated patients in their off state, meaning at, at the nadir of when, you know, they hadn't taken L-DOPA for some period of time. And so they were looking at a period where L-DOPA would have a minimum symptomatic benefit. Interestingly, if they looked in the on state, after patients took their L-DOPA intervention, there was up to a 118% slowing of progression.
In other words, they actually did a little bit better numerically than they started at, and we found that really intriguing from a science perspective. You know, it generates some hypotheses about what might be going on around preservation of dopamine neurons, but those are to be fully explored, of course. And then finally, what they also showed, because you couldn't really see this in the short timeframe, was on something called the MDS-UPDRS Part II, which is really more about activity of daily living due to motor function and how patients are doing from that perspective.
What you actually see is that there's not much there in the first year in terms of progression, but as you get out to four years, again, relative to this concurrent PPMI control dataset, you saw an effect with the prasinezumab-treated patients that approximated about 40% slowing of reduction over that time period. So across these multiple clinical domains, you know, seeing very consistent data relative to this non-concurrent control group, I think very intriguing, and obviously certainly suggests that the data needs to be followed up on, which brings us back to the PADOVA study, which is ongoing. That was... Remind me, how many patients in that study?
586.
Thank you, 586. I keep wanting to say 585. 586 patients in the PADOVA study randomized 1:1 to receive either prasinezumab or placebo. Roche announced at the end of first quarter last year, that study was fully enrolled. Little bit different study. These patients are all okay to take levodopa from the beginning, and it's also a little bit different in terms of how the endpoint was constructed for this study. It's a time to event study looking at worsening of this MDS-UPDRS Part III as, as represented by a five-point worsening on that scale. So because it is time to event, the end of that study is a little bit less exact, but I think Roche said as recently as yesterday on their call, that they expect to see those data by the second half of this year. So we're, we're very excited to see those data, and we're, we're excited to see that data readout.
Yeah. Yeah. So, maybe remind us, the regulatory pathway here will be next, and also regarding the Roche deal term, like will be the milestone and royalties.
Yeah. So maybe I can start on the regulatory, and Mark, you can talk about the deal terms. So I think from a regulatory perspective, obviously, we have high confidence that Roche is very sophisticated when it comes to regulatory discussions and will be as appropriately as aggressive as the data warrants and dictates. I think what they did say on their call yesterday was that, you know, they are in dialogue with the regulatory authorities, both around the most appropriate endpoints. They do consider the PADOVA study to be a high-integrity study, and certainly, under the right context, could be supportive of filing. But I think what they said yesterday, very specifically, was they expect. Their baseline assumption is that an additional Phase III study would be needed, right?
So I think that's where they came out yesterday, and obviously, as one would always hope and expect, dependent upon the data from PADOVA, I would expect our partners to have additional conversations with regulators around that for the most appropriate path forward. But maybe, Mark, you wanna talk about deal terms? Yeah.
Yeah, so, the total deal terms with upfront and milestones is $755 million, of which we've been paid $135 million to date. So remaining milestone payments are mostly around, regulatory and first sale, and then tiered U.S. and ex-U.S. sales milestones, and then we do have royalties on top of that, that go up to double-digit teens, and we also do have a U.S. co-promote option.
Cool. So, very interesting program. Hopefully, we have data by the second half of the year.
We're eagerly awaiting the results.
Yeah, yeah, finally.
Eager to see. Yeah.
We only have a couple of minutes, so maybe we can start talking about birtamimab.
Sure.
You can talk about the unmet need and, maybe the positioning of this product.
Yeah. So, birtamimab is targeted for a disease known as AL amyloidosis, which is a protein dysregulation disease in the periphery. The offending protein, if you will, in this case, is light chain. This typically comes from a plasma cell clone, so in some ways is somewhat related to multiple myeloma. And as is the case in a number of these peripheral amyloid diseases, the current standard of care really focuses on the protein production, so on the, you know, targeting the plasma cells that are actually making the protein, and obviously, those are primarily multiple myeloma therapies that are repositioned to this disease. As we see it, the limitation of those approaches is that they don't have impact on the more advanced patients in particular.
Those more advanced patients, you know, clearly you would expect the resident amyloid, the protein that's already been made, that's already deposited in critical organs like the heart, you know, is driving the majority of dysfunction in those patients and ultimately leads, we believe, to mortality in those patients, particularly from a cardiac perspective. What birtamimab is uniquely designed to do is to target that resident amyloid for removal, and to also disrupt the aggregation process, and thereby prevent some of the soluble aggregates from having whatever toxic influence they may have in and of themselves. In prior trials, we've shown, for example, in what was called our VITAL trial, a potential benefit in that patient population.
So as we think about severity of this disease, Mayo Stage IV, so there's I, II, III , IV , at diagnosis, tends to be your more advanced patients. And in that patient population, you know, depending on the literature that you read, the median survival is reported to be anywhere from 4-6 months post-diagnosis. In a prior study, where we had actually looked at a broad population of AL amyloidosis and specifically focused in on the Mayo Stage IV patients, what we found was that on best standard of care, the median survival in our study was around 8.8 months. And then for the patients that received best standard of care and birtamimab, the median survival was not met.
In fact, we observed a hazard ratio on all-cause mortality of 0.413, so almost a 60% relative risk benefit. And on top of that, across other clinical domains, like six-minute walk test, a patient-reported outcome known as Short Form 36, we saw clinically meaningful effects, in terms of effect size in that patient population as well, which were also nominally statistically significant. So, very encouraging data from that perspective. We entered into, I think, very robust discussions with the FDA around these data and ended with, a study that we call AFFIRM-AL, which is our, confirmatory study in these Mayo Stage IV patients, which is now under a SPA agreement with the FDA, where, success is determined at an alpha of 0.10.
So really pretty unprecedented in terms of that alpha level, around the SPA agreement, but we're very excited to be conducting that study. We're continuing to enroll that study. One of the things we did, at the end of last year was based on, basically achieving a pre-specified number of events. So all-cause mortality is our primary outcome. We estimated when that study might conclude, and we guided to a range of anywhere between 4Q this year to 2Q next year, in terms of expecting to meet the final event, which defines the end of that study. We also said in January, when we issued out a press release, that we had an interim analysis built in, which at the time was still in front of us.
That interim analysis, it only contemplates stopping for overwhelming efficacy. There's no futility component to that. But importantly, as we've always guided, we expect, because we didn't spend a lot of terminal alpha on that interim, it's a high bar to win at the interim from an efficacy perspective, that the expectation should be that we'll get to the end of that study. We want to win at the end of this study and get this treatment to patients. So obviously, we will not be updating on that interim analysis when or if that occurred, unless obviously we stop for overwhelming efficacy.
Cool. Super helpful, but we're running out of time. Maybe lastly, I still want to ask, what would you be with, has been mostly underappreciated by investors? Anything else that you want to highlight for last minute?
Well, I think I'd just say, you know, in general, it's a very exciting time for the company. We have, as Mark mentioned earlier, the capital to get to a number of value inflection points over the next 12-18 months across the entirety of our portfolio. We think, you know, the birtamimab is a wholly owned asset. You know, one of the things I didn't mention is somewhere around 75% of these patients, we estimate are treated at around 500 specialty centers across the globe. So this is a very efficient call point from a commercial perspective. You know, we expect that we'll commercialize this, ourselves, and so we're, we're very excited about that, and we'll have that data on the timeframe that I talked about.
We'll also have data over the next 12-18 months to talk about around PRX012, our wholly owned Alzheimer's anti-beta asset. We'll be obviously talking about the timing to start the initial studies with our vaccine. We'll get data from our partners on prasinezumab and on NNC6019, our anti-ATTR program from Novo Nordisk, in the next 12-18 months. And obviously, we expect our partners, as they've indicated publicly at Bristol Myers Squibb, to initiate studies with the tau molecule, this year in terms of Phase II. And then, of course, we're busy in the discovery labs as well, continuing to think about next-generation approaches. So it's an exciting time. We have the capital structure to see all of these exciting, I think, potentially transformational milestones across the entirety of our, I think, pretty rich portfolio.
Totally. Great. Cool. Well, very interesting discussion. All right, and thanks, everyone, for joining us today.
Thank you, Rudy. Appreciate it.
Thank you, Rudy.