STIFEL 2026 HEALTHCARE CONFERENCE - UNIQURE NV

Awesome. We can go ahead and get started. Thanks, everybody, for coming. Very pleased to be here with Matt Capista from Unicure. You know, very topical time to be meeting with the team. Matt, we'll just kick it over to you. Feel free to introduce yourself. You know any initial comments about Unicre before we just dive into Q&A. Yeah, very excited to have you here. So thanks again. No, thank you very much for having us here. We're delighted to be here. We are wrapping up a year where we've made substantial progress in our lead program in Huntington's disease, and we're full tilt focused on making 2027 our best year and a very impactful year for Huntington patients going forward. So looking forward to getting into the discussion. Terrific. Great. So yeah, you just had some recent news where the BLA for AMT 130 was accepted with priority review. You're also told that there's likely to be an adcom. Just like talk a little bit about that. Is that sort of, you know, in line with your expectations? Generally, any sort of high level comments, then we can dig further. Yeah, I mean, it's totally in line with our expectations. I think we've been interacting with research analysts and investors getting asked these questions now for quite some time. And, you know, we think that, you know, for a first disease modifying treatment for Huntington's, one-time administered gene therapy, our expectations have been all along that we would have an adcom, and quite frankly, we're delighted to have an opportunity to speak about our data in public and to have perspectives from various stakeholders, including the patient community. Terrific. Yeah, no, totally makes sense. And I guess, like, how do you prepare for an adcomm and you know, what types of questions are you expecting for the FDA to be bringing up? And I guess like any sort of other commentary you can provide about, you know you've commented in the past about the rigor of the sensitivity analysis you've done with respect to your data in comparison to several, you know, natural history data sets. Just talk a little bit about that and sort of how you're preparing for the panel overall. Yeah, I won't speculate on, you what kind of questions will be asked. I mean, that will obviously be up to the FDA. But what I can talk about is just an enormous amount of preparation that we're going through. And as I said, this is our base case expectation. We've already started kicking off planning and preparation for the ADCOM months ago. We are engaged with one of the leading preparatory the advisors to help us through this process. You know, it incorporates a tremendous amount of work from all members of our team. It includes numerous mock panels that we go through. So this is pretty standard stuff, but, you know, we obviously are taking this, you know very, very seriously. Yeah, in terms of the data, you You know, we, you know, in our discussions with the FDA, you know, were very clear that one of the benefits that you have in Huntington's is probably some of the most prolific natural history data that exists. So there are multiple different natural history studies, the largest of which is called EnrollHD. Enroll HD, at the time that we did our original analysis back in 2025, had more than 30,000 participants. It is a natural history study. that has been going on for 10 years. CHDI is the sponsor of the study. They've invested a tremendous amount of money in it. It is clinical-grade quality data. You know, this is not just a, you know, slapping data together. I mean, this has, you knows, run almost as a clinical trial. So very high-quality data, very significant amount of subjects. It has been is concurrent, so it is ongoing. It is still accruing patients. And so it was a natural source of data. Having said that, we recognize that in developing an external control, you're making a lot of assumptions. So as part of our pre-specified sensitivity analyses, we sensitized a number of those assumptions. So that includes looking at other sources of data, so we looked at track and predict HD, which is another natural history data set that has about one-tenth the number of patients, but we looked at that. We also looked at different covariates. So when you develop propensity score, you baseline patients and you match patients based on what's called covariates, we use eight. We also looking at four different covariants. There's different ways of matching, different assumptions you can make. We sensitize that. So we've done a lot of work on the natural history. We've shared our methodologies with the FDA along the process, and really since those discussions that we had in 2025, we tried to keep a lot of those the same going forward. So the data that supports our BLA is based on the data That was reviewed with the fda back in 2025 and it's in accordance with the statistical analysis plan that was shared with the Fda back earlier that year as well terrific. And I think that's a good segue just to touch on, you know, this wasn't sort of a straight path with respect to regulatory. You know, FDA had changed their tone under prior leadership. There's now new leadership. Just talk overall just about, you Know, how comfortable you are in general. And generally speaking, you Now, what was sort of the context of the meeting that got the FDA to turn back and, You know. Allow you guys to file. or got you comfortable in at least filing the BLA? Yeah, I mean, what I can do is go through a little bit of the recent history. So we, of course, in January 2026, had our Type A meeting with the FDA after our pre-BLA meeting. And in that meeting, the FDA informed us that the data that we had presented thus far, the 36-month data, could not serve as the primary analysis to support a BLA, and they strongly recommended that we move forward with a double-blinded sham-controlled phase three study. We have all along the way felt that that was not in the best interest of patients with HD who have no disease-modifying treatments available. And we were going to continue to try to interact with the FDA to advance the program. So we had a type B meeting in June of this year. And in that meeting was FDA leadership. And they made it clear to us in that meeting that they do believe that the data that we had presented could support the primary basis of a BLA submission. So it's hard for us to get into the mind's eye of what might have changed. But obviously, we've never given up on this. We're completely committed to this patient population. And we very, very rapidly moved. We really never stopped preparing for the BLA, planning for success. We very quickly turned that into a final BLA submission and just recently last week announced the acceptance. So we're delighted. Terrific. And before that, you know, BLA acceptance, you also recently shared some updated data from AMT-130, both four-year data following up the three-year data from last year, as well as, you know, a couple additional patients, a three- year data set, right? So can you just talk a little bit about that? You know, what were the results there? And can have some follow-ups, too. Yeah. So, as I mentioned, the BLA is based on the September 2025 data. We viewed the data that we presented this past September as being supportive of that primary analysis. And there's a number of reasons why we believe that AMT-130 is continuing to demonstrate durable and persistent effect. firstly when we look at total functional capacity total functional capacity is important to understand is the most important measure for patients for clinicians and it's also an important endpoint for regulators TFC is the primary endpoint of our confirmatory study and the FDA views this as a important measure because it encapsulates the disease and what is most important to patients in terms of their independence. So it measures things like, can a patient hold a full-time job, a part-time job? Can a patient perform the daily chores to support their family? Can a patient manage their finances? These are daily living tasks that measure independence, and they factor in all facets of the disease, including psychiatric, cognitive, behavioral, and motorial. So that is why it is a very important endpoint. When we look at our 48-month data, patients over that four-year period have not lost on average even a tenth of a point of total functional capacity. That compares to untreated patients at 48 months that have lost nearly a full point on total functional – a full point is a significant impact on a patient's life. It could be the difference between a full-time job and a part-time job or, you know, not being able to perform the functions of a father or mother, etc. Secondly, we continue to see meaningful evidence of dose dependency, which is consistent with what you would expect to see if there's real treatment effect. So as an example on CUHDRS, if you look at our high-dose patients, they have more than a point higher, higher being better on a CUHDR scale compared to patients that receive the low dose. And what's interesting about that is there's a lot of debate about adequacy of control. How do you construct an external control? The low dose, which we still believe is minimally infective, is almost like an internal control. So it's a very important comparison, and we continue to see dose-dependent effects there. The one thing I would mention about CUHDRS, you know, it's, I think, a little easy to over-interpret a particular measure in a given year. Just as an example, on CUHGRS, we saw at year one, it favorably went up. In year two, it went down. In your three, it went up in year four, it down. We do not view this as waxing and waning of treatment effect. So it's really beneficial to look at longer periods of time. So as an example, if you look at the first two years change in CUHDRS and you compare that to the second two years, it's nearly identical. So I think the data continues to be supportive. We did begin to see some limitations in the external control that I think impacted some of the statistical analyses. So just as some background, these patients that enroll in natural history studies, as you might imagine, are not treated. So when you establish a natural history external control at baseline and you're starting to now follow patients out to four years, you have a lot of patients that are missing visits and you have patients that ARE discontinuing. At 48 months, we had more than half of the data points were missing from the external control. When we evaluated those patients that had discontinued and we looked at their trends of progression of disease, it was very clear that they were progressing more significantly than those that were remaining in the external control through 48 months. So what does that mean? It means that that kind of effect compounds each year. and by the time you get out to four years, you have a healthier patient population than what you started with. So those are things that are well understood in neurodegenerative natural history studies. We see it in ALS, we see it and other diseases. And, you know, by the time you out to to four-years, it becomes a limitation that is to be expected, you know, when you make that comparison. sense and of course your filing is based around this this three-year data set which is which is highly robust and I think like you make a good point about how you know there's there's going to be some variance you know in these time points especially for a small data set I guess for you know some investors out there that may be you know somewhat skeptical that you know because you're seeing this slight regression or you know a small change you know and in a one-year time point beyond three years, what would you say to them with respect to what has you guys confident before you go before FDA this spring? Yeah, I mean, I would say that we do not agree with that assessment for all the reasons that I mentioned. What I would tell you is that Even if you want to be as conservative and take all the caveats that I mentioned, right, with a big grain of salt, the patient community that has a ferocious disease with no modifying treatments would be clamoring for something that slows disease 44 percent. on total functional capacity, which, as I mentioned, is the most important thing. We see 60% slowing of disease. When we talk to key opinion leaders and we go through the totality of the data set, they tell us to stop. They say, look, what we see in total functional capacity is remarkable. Remember that patients that are diagnosed with Huntington's disease may not live 10 years. We're now looking at a four-year period of time and seeing very little degradation on one of the most important measures. So we really do see this data as compelling and meaningful. We believe the drug is approvable and that we stand by the data and we look forward to getting into it in more detail with the FDA and at the outcome. Great. And for the panel, the FDA, we know that they're going to try to stress test your sort of analyses as much as possible. They just try to torture these data sets. I guess taking a step back, can you just remind us how you instructed or decided upon the comparator group to begin with? I know there was initially some back and forth before you were presenting the three-year analysis on the comparator group for the natural history. Just remind us, you know, what went into the selection there and, you know, what questions specifically in the natural history comparisons that you're expecting from the agency potentially? Yeah, you have to remember, we started this clinical investigation back in 2018, 2019. I mean, it was a long time ago. Back at this period of time, the amount of natural history was a fraction of what's available now. We had conducted a study that had a randomized control, but that was only looking at one year. You know, it's very difficult to recruit Huntington's patients, right, in a blinded study, you know, where you're asking them to either be blinded or to be on standard of care for three plus years. it's very difficult to do, particularly in a first-in-man study. So, you know, when we got to a point where we realized that the progression of disease really required longer-term follow-up, the question became, well, how are we going to develop a comparator? Now, at the time, we started getting more and more patients that were starting to cross the two-year mark, and we saw some really intriguing signals. And that's when we started really debating, you know, how can we leverage and exploit this, you know this treasure trove of natural history data to develop as close of a comparator as possible. Again, thankfully we have the benefit of having tens of thousands of patients at that point in time that were available to us. There are tried and true methodologies that the FDA is aware of that other companies have used to identify a matched cohort as a comparater using baseline characteristics. We had done some preliminary analysis. We shared that with the FDA and that became the basis of our RMAT designation in early 2024. And then we had a more significant discussion with the FDA about the ability to use that as a comparator to support an accelerated approval pathway. And that is when they had aligned with us that that would be considered reasonable, and that CUHDRS can be considered an intermediate clinical endpoint. So that's a little bit of the history of how we developed this. And of course, we did this in concert and collaboration with CHDI and leading KOLs in the HD space and biostatisticians as well to support us. Terrific. And can you just remind us, so of course we have a new leadership at FDA. can you just remind us in terms of you know the consistency of the FDA staff and the interactions that you've had you know with the agency and you know have you had any discussions with the new head of CBER I guess like anything you could say just about the personnel at a high level yeah I think and then we can move on from regulatory yeah I don't I don'T think I'll comment on our interactions with any specific individuals I think maybe what I'll just say is I think we have a constructive and collaborative relationship with the FDA, and obviously we very much look forward to engaging with them as part of the review. Okay, great. And then, so on the confirmatory study design, you touched upon it a little bit in the very beginning. Can you just talk a littlebit about it there in terms of the primary endpoint, you know, how you decided on TFC, how that's going to be powered, And, you know, how you're thinking about enrollment in the light of, you know, potentially having accelerated approval here in the U.S.? Yeah, sure. Happy to. So obviously accelerated approval is conditional approval, right? It's conditioned on conducting a confirmatory study to generate information and data that would support full approval. Um, so, uh, in our June meeting is when we began having discussions with the FDA about, uh, what that design might look like. Um, I think the FDA, uh had agreed that it was reasonable not to incorporate a sham procedure, uh you know, given, given the, you know a number of different factors. Um what they, what they did feel strongly about is they wanted randomized data and what they agreed to is that we can randomize patients to treatment and standard of care, but that would be done in a way that was not blinded to the patients and to the providers. So as you pointed out, total functional capacity is the endpoint that the FDA has aligned on. I think we've known for some time and have talked about indications from the FDA that they were preferential towards total functional capacity for the reasons that we talked about earlier in this conversation. We expect about 200 patients to be in our sample size, and patients treated with AMT-130 will be compared at 36 months to these patients that are randomized in the standard of care to evaluate treatment benefit. So this study is expected to be a global study. So we just nailed down the design with the FDA within the last month or so. We are well down the road of operationalizing the study. We're going to be initially highly focused on recruiting in the United States, but we are also in parallel going to Be activating sites internationally. Obviously, when the product, or if and when the product is approved on an accelerated basis, we would expect, you know, recruitment to be more prominent in sites internationally where the drug is not commercially available. We are 100% committed to the execution of the study and are highly confident that we'll be able to demonstrate that is, you know, meaningfully underway at the time of the PDUFA date and that we can generate that data in a timely manner. Yeah, I guess where do you expect to be, broadly speaking, with respect to enrollment come May 1st? And what makes you confident that that will be sort of acceptable by FDA? They want things to be somewhat far along before granting accelerated approval. Yeah, we do not have, we have not been given, nor have we given externally a hard, specific number. There is draft guidance that the FDA put out in January 2025. It pertains to accelerated approvals broadly. So this is for any sponsor that is pursuing accelerated approval. It does cover confirmatory studies. It doesn't cover the provide the FDA a wide degree of discretion in order to determine what meaningfully or well underway means. What I will say is that the FDA is obviously well aware that we just recently finalized the design, that we're initiating the study. We provided the FDA a preliminary timeline for the study, and we're committed to continuing to give them progress updates. What I can say is we expect to have multiple sites activated, multiple sites that are screening patients, to have patients enrolled in the study, and to be able to support why we think we can complete the study in a timely manner. That's terrific. And then just like thinking ahead to commercial, if you were to be granted accelerated approval, how are you thinking about who the indicated population would be and just initial capacity for administration of AMT-130, some of the dynamics that we should be thinking about, types of centers that would be equipped to sort of, you know, conduct this kind of surgery and administration, plans for hiring and build out of your commercial team, anything that's relevant there would be super helpful to hear. Yeah, so we obviously haven't engaged in labeling discussion, so it's probably premature for me to indicate which specific patients would be on label for AMT130. Obviously, we conducted our phase 1-2 study looking for early manifest patients that are typically classified as stage 2 or stage 3. So these are patients that have been recently diagnosed with some of the clinical symptoms associated with HD and are early, you know, relatively early within their disease course. So, you Know, as we progress further with the FDA, we'll get a better sense of that. From a commercial point of view, you're completely right. This is, you know, there's a supply side of the equation and a demand side of the equation. And the demand side of the equation here, you know, with a tremendous unmet need and really very few options for patients, the demand side of equation is not going to be much of the issue. The issue that we're focused on is on the capacity side, the supply side. We do incorporate, obviously, a precision-targeted surgical delivery of the drug. There's some advantages of that, but it requires a specific catheter system, a ClearPoint catheter systems. There are approximately 100 different sites that are certified on the ClearPoint catheter system, and there are 60 HD centers of excellence across the United States. So we're, of course, looking at the intersection between those two and are heavily focused on those sites that have the functional neurosurgeons and the interoperative capabilities that they can be high-throughput centers. So I think we've talked about that we will have a minimum of 15 sites uh available to do the procedure and likely more we haven't given a specific number if it's 20 25 30 but we are you know heavily focused on making sure that we have uh sites that are motivated to do this they have the capabilities to do this uh and you know we've been over the course of the last uh six plus months been building a a commercial team that incorporates medical, field people, strategic account groups, you know, a whole bunch of different areas that are planning this and focused on implementing this and making sure we're ready for launch. Terrific. And obviously, a lot of the emphasis and focus is on the U.S. market. But of course, you guys were actually making headway in the UK, before things were all clear in the U.S.? I guess, could you just comment a little bit on how things are evolving with the UK market and how you see the commercial potential for 130 in the UK as well? Yeah, so we're very happy that we have a second license application under review with the MHRA for the United Kingdom. That application was just recently validated and that review now is moving forward. So, you know, that process is going to be ongoing in parallel with the FDA review of the BLA. In the United Kingdom, there's approximately 7,000 to 8,000 patients that have been diagnosed with HD. We'd likely expect there's another 35,000-40,000 patience that are pre-symptomatic. You know, it is a meaningful market opportunity there. We're very serious about pursuing that. We likely will pursue that with a distributor model. We're well underway in planning that. We will probably do a parallel discussion with NICE while the marketing application is under review. There's also an innovative medicines fund that we would expect potentially could be available within six months of approval. that's a specially dedicated fund for certain innovative treatments that you can do early patient access. So these are all the things that are currently in motion, and we're looking forward to advancing those discussions as well. Great. Any final comments on 130 or HD? And we have a little bit more than a minute left. Do you want to just give you a second to comment on your early stage pipeline? Do you have some programs that are progressing nicely there? Anything else that you want to say? Yeah, we appreciate the focus is on HD, and we're honestly very excited to advance this and move this forward. We do have some other very interesting programs that are also well under clinical investigation. We have a temporal lobe epilepsy program, which expects to have additional data that will be presented in the first half of next year. There we have 13 patients in a dose-ranging study. We had some encouraging data earlier this year, and we expect to have 12 months of follow-up on the first dose cohort and about six months of follow-ups on the second dose cohort. And then we have another program in Fabry disease, which leverages a lot of our expertise for hemigenics, which is our approved hemophilia B gene therapy. There we have a phase 1, 2 dose- ranging study in three different doses. We expect to have additional data available in the first half of next year, and that will incorporate somewhere between four months and 18 months of follow-up data. Okay, great. We're about up on time. Do you want to just remind the folks of your cash runway? Yeah, so we have approximately $780 million of cash, so we're well-financed to prepare for launch, to advance these other programs, and we expect that that will be sufficient runway to get us into 2030. Great. Thanks so much for joining, Matt. All right. Thank you for having us. Of course. Thank you.