You for joining us in the room and online, for TD Cowen's 46th Annual Healthcare Conference. I'm Joe Thome, one of the senior biotech analysts here on the team at TD Cowen, and it is my pleasure to have with me today, CEO of uniQure, Matt Kapusta. Thank you for joining us. Obviously, a lot to get through, but, I think we'll start the conversation on a good note. What did we see from the phase III data for Huntington's in AMT-130? If you can take us back, obviously, you know, six months-ish, you know, how are we seeing on patient benefit versus natural history, and kinda what are the highlights of the phase III data from your perspective? Sure. Firstly, thank you for having us, Joe. Yeah at the conference. Yes, in September, we presented data from what we had called our pivotal phase I/II trial, which was in accordance with our statistical analysis plan, where we pooled patients from our phase I/II study in the United States and in Europe. At that point in time, we had 17 patients that we were looking at pooled from the high-dose cohorts of both the U.S. and EU study, of which 12 patients had crossed the three-year mark. We had as a primary endpoint in the study the composite Unified Huntington's Disease Rating Scale, which is essentially a very well validated clinical rating scale that incorporates cognitive, motorial, psychiatric, and behavioral, and functional elements of the disease. That is the disease. Mm-hmm. That is the clinical outcome of the disease. What we did was compare these clinical outcomes of these patients to a methodically and robustly patient-matched external cohort. We derived that cohort from Enroll-HD- Mm-hmm ...which is a natural history, registry that is being conducted by CHDI. Just a bit on that- Mm-hmm ... there are 30,000 participants in this registry. It has been started almost 14 years ago. It is still concurrent, so it is growing every day, and it is clinical grade data that is being captured. What we did is we took eight covariates or what I would consider baseline characteristics that are prognostic factors regarding the progression of the disease, and we matched them based on the treated patients to those that were in Enroll-HD- Mm-hmm ...and we compared them. What we saw was, at three years, a 75% slowing of progression as measured in the composite [audio distortion] year, highly statistically significant. We also demonstrated a statistically significant in disease progression as measured by Total Functional Capacity. That's important because the FDA views that as kind of a full approvable endpoint, whereas the composite was kind of an intermediate clinical endpoint. We showed a 60% decline in disease progression as measured by Total Functional Capacity. We also demonstrated a reduction in Neurofilament light at three years compared to baseline. Why is that important? Because Neurofilament light is an objective measure of neurodegeneration. What's been demonstrated is, on average, over, you know, looking at a larger amount of patients, an increase of somewhere around 10%-15% a year. Mm-hmm. You know, it's variable, it's been generally understood that CSF neurofilament light increases approximately 10%-15% a year. We're expecting probably a 30%, 40% increase, we're showing a decrease from baseline. In addition, there were other clinical outcome measures that all showed evidence of disease slowing. Mm-hmm. That was essentially the synopsis of our data that we presented in September that obviously was, I think, globally embraced by, you know, not only the scientific community, but more importantly, the patient community. Perfect. Obviously, the dialogue with the FDA is ongoing and continues. So if you can't answer some of these questions, obviously we respect that. Can you kinda walk us through the timeline of sort of your interactions with the agency? It seems like they really kinda kicked off at that RMAT meeting in 2024 with sort of the alignment on a potential accelerated approval strategy. You indicated that was in the minutes until obviously your update this morning. If you can kinda walk us through that path and maybe what was the update, this morning and the latest there. Yeah. I think we announced RMAT designation, which is kind of a corollary of Breakthrough Therapy designation in early 2024. Part of the basis of that of granting that was that we had two-year data at the time on a handful of subjects started to see signals of slowing progression. We did some matched analyses and imputing other subjects that would reach the two-year timeframe, and we shared that with the FDA, and they granted RMAT designation. They also asked us to schedule as soon as possible a multidisciplinary meeting with the agency. We did that in November of 2024. As an outcome of that meeting, the FDA specifically agreed that data from the phase I/II study may serve as the primary basis for a BLA submission. They agreed that we could compare the phase I/II data to an external control. Mm-hmm. They agreed that the composite UHDRS would serve as an adequate intermediate clinical endpoint. They requested that we pre-specify a statistical analysis and emphasized that that was going to be important, that we do that as soon as possible before we do any additional analyses. Mm-hmm. We did that. We prepared a statistical analysis plan. We submitted that to the FDA. We had a Type B meeting with the FDA in April of 2025. The FDA provided us comments on the statistical analysis plan. In good faith, we incorporated those comments and ultimately submitted a modified statistical analysis plan before we did any additional analysis and before we locked the database. Then, of course, we presented the data that I just went through in September, and we held a pre-BLA meeting where we shared that data with the FDA. That meeting happened in October. In that meeting, we asked the FDA if they agreed that that data could serve as the primary if they could confirm that the data could serve as the primary basis of BLA submission. They expressed that, as of yet, that they were not comfortable with that. Mm-hmm. The primary reason that they gave was that the phase I/II study was, in their view, a hypothesis-generating study, that we had not pre-specified the statistical analysis related to the three-year data, prior to starting that study- Mm-hmm ... which, you know, per their recent guidance, was a strong recommendation for open-label single-arm studies compared to external controls. Therefore, they viewed that data, which we had analyzed several times, as effectively post hoc analyses that was subject to bias that they could not quantify, and therefore it could not serve as the primary basis of evidence to support a BLA submission. We then, requested a Type A meeting, and we had that Type A meeting on January 30th, and we received final meeting minutes this past Friday. Mm-hmm. Effectively, the FDA reiterated their view that the phase I/II study compared to an external control for all the reasons that I mentioned could not serve as the basis of a BLA submission. In the meeting and in the preliminary comments we received prior because they considered that a post hoc analysis. Mm-hmm they seemed to be very focused on, the 12-month results from the U.S. trial-. Mm-hmm ... which was, of course, pre-specified at the time based on the FDA's strong recommendation. In that study, we did not show any clinical benefit. Mm-hmm. I guess our interpretation is that these are early manifest HD patients. 12 months of follow-up is simply- No ... is simply just not long enough. In fact, the control patients didn't show themselves any signals of progression of disease. Mm-hmm. It would be impossible to... To show that ... you know, to show that. You have to remember that Huntington's is a slow progressing disease, that we're enrolling patients that are, you know, stage 2- Mm-hmm ... and early stage 3, so they are still considered early, and they manifest and progress relatively slowly, which is why you have to really look at 2 - 3 years of data. We don't have, you know, internal randomized control patients to compare to, and that's why we need to rely on this treasure trove of external data. They seem to be, you know, very focused on that, on that 12-month data, and that was some of the other justification they provided. Can you walk us back to why those sham control patients were only followed out to 12 months? Maybe prior guidance from the U.S. and ex-U.S. agencies as to that timeframe. Have those sham patients, are they still out there? Did they receive crossover drug? Kinda where do they look like now? Yeah. This is actually a good question. There were 10 control patients that were blinded for 12 months. Remember, it is, you know, this was a first in man study. Mm-hmm. It is difficult to ask a patient to enroll in a blinded sham-controlled study for three years. It's not only difficult, but many people believe it's unethical to do that. Mm-hmm. In fact, in Europe, they wouldn't allow us to do that in the context of a phase I/II study. That's why we designed it the way we did, understanding that it is a relatively slow progressing disease, and there'd be a limit to what we can learn in that period of time. Of those 10 control patients, when they were unblinded, they were given an opportunity to cross over if they were eligible. Mm. Four of those patients were eligible and six were not. Mm. The four that were eligible received treatment. The six that were not left the study because, you know, you have to be able to participate in other studies or, you know, do whatever you want to do at that point in time if you're not getting treatment. Mm-hmm. It's interesting because one of the things we are evaluating the feasibility of is, despite the fact that they're not in our clinical study, can we access some long-term longitudinal data from those patients that dropped out. Mm ... because many of them may have enrolled, in fact, in Enroll-HD. Mm. That's something that we're looking into, but that's the answer to your question. Okay, perfect. Next steps, it sounds like requesting a Type B meeting with the FDA in the second quarter. I mean, based on the conversation so far, it seems like still hopefully use of an external control would maybe be the company's hope. I guess what will you bring to that meeting? Maybe can you walk us through the potential outcomes of the Type B meeting as best as, I guess, you can? Yeah. I think the focus of that meeting is going to be on the phase III design. Mm-hmm. Just to be very clear, we've always committed to generating confirmatory evidence. whatever the outcomes are, you know, the, you know, we're committed to doing a phase III study. I think that, you know, our view is that the FDA's strong recommendation to do a well-designed, adequately powered, randomized, double-blinded, sham-controlled study, certainly a traditional one that's gonna require, you know, many years or multiple years of follow-up, in our view, doesn't reflect- Mm ... meaningful regulatory flexibility. I think we're gonna be evaluating various different design elements. Mm. Because this is a one-time administered therapy. A sham-controlled procedure, just to be clear, we're not actually introducing a catheter into the brain. Mm Patients are anesthetized for an extended period of time, which does carry risks and has adverse events. We are then immune-suppressing patients-. Mm ... which would then need to be considered, in order to really blind this the appropriate way. I think we want to evaluate how we can best leverage this treasure trove of tens of thousands of clinical grade natural history data in order to provide, you know, scientifically grounded data, but yet, do it in a way that contemplates the feasibility and potential ethical challenges that exist for a slow progressing disease, neurodegenerative disease like Huntington's. Mm. I think that's what we're gonna go in and discuss. you know, I think it would be maybe speculating on what the various outcomes are- Mm ... but, you know, our hope is that we have clarity on what that design would look like or at least a better understanding of that after that meeting. Maybe when we think about the current phase I/II study and the various cohorts, what is the next data update that we should expect? Would you provide, you know, four-year data from the currently patients that you include in the three-year update? There's also that lower striatal volume, cohort 4. I guess, what should we be looking for in terms of data updates as well outside of regulatory stuff? One of the things that we informed the FDA is that we will be updating our statistical analysis plan for the phase I/II studies to incorporate a four-year assessment. Mm ... that I think will be, you know, highly comparable to what we did at three years. That we will be submitting that modification to the FDA for their review and comment, and potentially conducting that analysis in the third quarter of this year. I think, we certainly are going to be doing that internal work. You know, firstly, we have to continue following up these patients. We have a responsibility of doing that. I think, you know, even if that doesn't change the FDA's view about the adequacy of the phase I/II study, it's of strong scientific value. We also believe that, you know, it will further inform the durability of the treatment. Mm. What we believe is that if AMT-130 is going to work over multiple years, the clinical meaningfulness of slowing disease progression is just gonna get larger and larger, at least it should be. Mm. That will be, I think, interesting to look at as well. There is the potential that we'll have some additional data, a little too early that for us to provide guidance. Okay. Perfect. Can you talk a little bit about the safety profile that you saw in the phase I/II data so far? You know, how safe is the administration and kind of when are patients sort of, quote-unquote, "out of the woods" after the, surgery in terms of AEs related to that? Yeah. I mean, you know, what we hear from our neurosurgical investigators is that it's, you know, it is actually remarkably safe and well-tolerated for a neurosurgical procedure. You know, we have not seen any significant adverse events attributed to AMT-130 from patients in those first two cohorts since December of 2022. It's been now more than three years. Most of the safety events are procedure related- Mm-hmm ... and not considered AMT-130 related. There is the potential, idiosyncratic potential for some degree of neuroinflammation. Typically, the signs of neuroinflammation will manifest within days or weeks of the procedure. It's been shown to be highly responsive to immune suppression, which is now gonna be given to patients. Previously, it wasn't given to patients perioperatively, but it is now gonna be given to patients. Those can be detected, they can be monitored, and they are, you know, fully resolvable- Mm-hmm ... you know, within a perioperative period of time. Then beyond that, you know, we just have seen, you know, very little in terms of safety manifestations. Great. Can you talk a little bit about your approach with ex-U.S. regulators, MHRA and EMA, just kind of where things stand with there, any updates we should be expecting from that? Yeah. I think we said on the call, you know, we have been approached on an unsolicited basis by regulators outside the U.S. after we presented, you know, our landmark data in September. We will be engaging in regulatory discussions this year- Mm-hmm ... both in the U.K. and Europe, and potentially in other jurisdictions. We don't know. We need to have those meetings to fully understand what the submission pathway is. Mm-hmm. You know, obviously, we'll be hoping for the potential for expedited review. There's also commercially the ability to explore Expanded Access and Named Patient Use. If we're able to get approval in one of these developed countries, the ability to reference that in other countries. You know, there's been other companies that have done this, that have demonstrated that they can provide significant value to patient communities outside the U.S. and actually generate meaningful revenue for those companies. We're gonna be doing everything we can to bring this therapy to patients as rapidly as we can around the world. Maybe last question on Huntington's before the rest of the pipeline. Obviously, there has been a lot of support from the physician and patient communities after they saw the initial data, and you highlighted that at the beginning. I guess, is there a way that you can best leverage that moving forward? You just mentioned sort of expanded access. Are you getting requests for expanded access in the U.S., or how does that? Yeah. I mean, there, you know, there's always a give and take on expanded access. Mm-hmm. You know, I think when you do that, you really wanna make sure you're adjudicating who gets access... It's very yeah. ... to therapy and who doesn't, and those are some tricky bioethical questions. I think we're getting tremendous enthusiasm from the neurology and neurosurgical community. Our customer-facing teams have been traveling all across the United States, meeting with care groups- Mm-hmm ... at Huntington's disease Treatment Centers of Excellence. There's a substantial amount of enthusiasm for being involved in AMT-130 and advancing the program. You know, look, to the extent that we do initiate a phase III study, I think we're gonna wanna make sure that we're in as many centers as possible to expedite enrollment. I think there's a really good potential for us to do that. Was there a second part of your question? Just in terms of maybe how you can best leverage the patient advocacy support if you haven't kind of crossed all those T's yet. Yeah. No. I mean, the patient community has been. We really applaud and have tremendous gratitude for the energy that the patient community has put forth over the years, but more particularly over the last three or four months to make their voice heard. They are the most important voice in informing and educating and communicating the urgency of the unmet need here and what their perspectives are around things like, you know, blinded sham-controlled studies. They've been involved in letter-writing. They've been involved in meeting with policymakers. They've been involved in petitions. They just recently descended down to Washington, D.C. to hand deliver a petition that had more than 40,000 patient signatures to the FDA. They've been very vocal and, you know, it's been a pleasure to work with them. There's been five major patient advocacy groups in the United States. They've banded together as a coalition because of some of these challenges. You know, we expect that they'll continue to make sure their voice is heard. Great. Maybe we'll move on to AMT-260, the temporal lobe epilepsy program. Obviously, seeing some very interesting early data. Can you just kind of give us a snapshot as to where you're at in that clinical trial? It sounds like we're going to see maybe six-ish patients' worth of data coming up soon. What kind of level set, what the bar is there for seizure reduction? Yeah. We obviously put out, what I view as more of a case study. It was really the first patient that was treated. I think we had five months of follow-up. Most importantly, we didn't see any significant adverse events related to treatment. In that five-month period of time where we can measure seizure frequency, we saw a 92% reduction in seizure frequency compared to baseline seizure frequency. Remember, these are patients that are refractory to anti-seizure medication, and, you know, they have fairly compromised quality of life with multiple seizures that they're experiencing every month. Obviously the whole purpose of this phase I/II study, it's a dose escalation study. We obviously need to gather more evidence from more patients and longer-term follow-up. We've completed dosing of six patients in the first dose cohort. Mm-hmm. We expect to present more data from that cohort in the second quarter, and that will likely have somewhere around I guess a minimum of four months of follow-up and maybe up to one year of follow-up. We've also started enrolling patients in a second dose cohort, and I think we've said that we would expect a complete enrollment of this phase I/II-A study somewhere around the middle of this year. Great. What sort of data from these first cohorts would give you the confidence to move forward into a pivotal registrational trial? Would it basically be just hopefully we can replicate this first patient data? Or kind of what's the minimum amount of information you want to see before maybe going to the regulators? Yeah, I mean, I mean, it's a very different disease than Huntington's- Mm-hmm ...but in some ways it's similar in so much that, you know, you can measure clinical outcomes in terms of frequency of seizures, relatively quickly. Mm-hmm. There is a period of time where, you know, the gene therapy is accumulating, kind of maximum expression... Mm-hmm ...usually in the kind of 1-3 month period. I think you can look at, you know, a minimum probably of a four-month data-. Mm-hmm Begin to start to squint your eyes and get a sense of what you're seeing. you know, I think, again, you have to recognize that many of these patients have really no ability to manage their seizures. Mm-hmm. The ones that have lesions in the dominant hemisphere are really not candidates for resection surgery. I mean, that's really what they have-. Mm-hmm ...available to them is tissue destroying methods. Either you're going to cut out the lesion or you're going to ablate the lesion. What we're hoping is that we can provide a tissue sparing option for these patients. You know, we haven't, I think, set a threshold, but I would imagine, you know, we'll wanna see, you know, a, you know, maybe a 50% or higher reduction in those seizures or total seizures. Of course, we have to look at the severity of seizures. What are the kinds of seizures? If there are seizures that remain, are they, you know, just aura? Are they debilitating seizures? We'll have to look at all of those details in the data that we present. Perfect. Maybe we'll touch on the Fabry program. Can you remind us where that study stands right now, and maybe what can AMT-191 bring that, I guess, standard of care or maybe some competitive approaches maybe can? Yeah. We have, you know, this is a different program. It's an intravenous administered gene therapy like HEMGENIX. In fact, it really leverages the core componentry of HEMGENIX. HEMGENIX is our approved gene therapy for hemophilia B. It leverages IV administered AAV5. I mean, we've explored IV administered AAV5 in, I mean, it's probably 150 patients that have been tested clinically and commercially with, you know, maybe up to a decade of follow-up. In our view, it's, you know, that body of evidence makes it, I think, a really promising delivery vehicle for IV administered liver-directed therapies. We, in our Fabry program, are conducting a dose escalating phase I/II study. We're exploring three different doses. We've treated 11 patients in those doses. We are seeing dose dependent increases in alpha-galactosidase A- Mm-hmm ...which is the enzyme that is deficient in Fabry patients. We now have, I think we announced this on our call today, all 11 patients are now off of enzyme replacement therapy. These were patients that required chronic infusion of enzyme replacement therapy in order to manage their disease and even still were having kind of breakthrough clinical consequences despite being on enzyme replacement therapy. These are patients that are now off of enzyme replacement therapy. Their lyso-Gb3, which is the substrate, has been well managed. You know, we do have to continue to follow these patients longer. There's the potential that we'll dose a few more patients in order to assess long-term outcomes. There is the potential we'll have additional data from this study. We did recently present the data that I just providing an overview on, and we're looking forward to collecting more outcomes and reporting further on that study. Great. Maybe last question just on the cash runway and potential partnerships, I guess to carry out some of the studies that we've touched on so far. I guess what's your appetite? You're in a good funding position right now to run a lot of these things yourself versus looking for a partner, 'cause obviously you mentioned with hemophilia B you've had success in licensing deals as well. How are you thinking about that? Yeah. I think we have demonstrated over the years that we will be very disciplined in spending and making investment decisions. Mm-hmm. You know, we took a lot of medicine over the last several years, you know, despite having a strong balance sheet, that doesn't change our philosophy. You know, I mean, part of our whole strategy is generate data that supports investments. If the data doesn't support investments, you know, we discontinue those investments- Mm-hmm ... and then put our money into investments that we think can maximize shareholder value. We will continue to do that. We have runway that we've guided. While there's a lot of assumptions here, we have runway that we've guided into the second half of 2029. You know, we recognize that as programs get to late-stage development we have to really scrutinize those investments and make sure the ones that can generate value are the mouths that get fed, and we're prepared to make those decisions. On the partnering front, you know, we obviously need to know more data from our existing programs and need to understand, you know, what the ultimate aligned phase III strategy is gonna be for HD. As I said, if we can do a phase III in HD that is feasible and ethical, we will advance this because there's a need there for patients, and this drug works in my mind. If it becomes a funding issue, we'll figure out, you know, the best way to fund it, you know, with the lowest cost of capital that can maximize value for our shareholders. Great. Awesome. Well, thank you for joining us today and, best of luck. Thank you. Thanks, Joe. Appreciate it. Thank you.