Good morning, and thank you for joining Guggenheim's Second Annual SMID Cap Biotech Conference. I am Debjit, one of the senior analysts here on the biotechnology team, and joining me from uniQure is CEO Matthew Kapusta. Matt, thank you for your time. Thanks for having us here. Maybe we can just start with a very quick introduction before we jump into the Q&A. Yeah, sure. Matthew Kapusta, CEO of uniQure, just had my decade anniversary with the company. Really excited about how we ended 2024 and looking into a very exciting 2025. We have four clinical programs that we're very enthusiastic about, with a lead program in Huntington's. We had some very favorable feedback from the FDA, which we'll get into in more detail. This is why I and my leadership team and our organization come into work every day, is to bring this very promising one-time-administered gene therapy over the finish line in one of the largest, highest unmet needs in the genetically defined disease area. I'm talking about Huntington's now. Looking forward to getting into more detail some of your questions. Awesome. So first of all, congrats on the regulatory progress last year. When you think about 2025 and the upcoming meeting with the FDA, the prospectively defined cohort from natural history, could you shed some more light on that? How are you thinking about it? Have you sort of nailed down what that's going to look like? Yeah. So I mean, we have spent years now analyzing the natural history data. Fortunately, I mean, just so the audience knows, there's probably close to 30,000 patients that have been followed and have data captured in multiple different registries. So it is one of the most prolific databases within the rare disease space. And obviously, it's very gratifying and exciting to understand that the FDA is going to allow uniQure to rely on that as an external control. So we've been working with CHDI, which captures a lot of this data now for an extended period of time. The FDA is very focused on how you ensure that you're mitigating biases when you are taking what is 30,000 patients of data, and you're now winnowing this down into something that is going to now become your comparator arm. Obviously, biases are less concerning when you have an active or internal control arm where you're going to be concurrently enrolling patients in a randomized and blinded manner. When you're looking at a retrospective historical control, how do you select that control and the biases that could come in? Like, for example, how do you handle data that's missing? What does it mean when somebody drops out of the database? They may drop out of the database because they got sicker. And if you don't have an approach to handling that, you could actually bias your data set either favorably or unfavorably. So we think we have a very good handle on this. I can tell you that in the natural history that we presented back in July, and historically, we made very conservative assumptions. So if you were to, for example, compare our two-year trends in natural history to some of the other data that's been presented by other competitors, you'll see that the rate of decline for what we're comparing to demonstrate therapeutic benefit is much slower in our control. So I think the bottom line is we feel like we're in good shape. I would tell you, I'll feel like we nail it down once we have our next meeting with the FDA. You mentioned 30,000 patients. How big do you think your database has to be to adequately capture or remove biases? Yeah, I don't think it has to be a certain size. I think that it has to be constructed objectively in accordance with an inclusion or exclusion criteria that is rationally supported. So what we presented back in July was, I think we, of course, did the propensity weighting, and we created what's effectively a synthetic cohort that is matched one-to-one with our 21 patients at the time. That synthetic cohort was derived from about 154 patients. That is of adequate size, but the key thing is, the inclusion/exclusion criteria appropriate? I think it's possible that it will grow, but we do not believe that it will be materially different than what we've shown in the past. Got it. And the likely meeting with the agency, is that already on the calendar and at the first quarter event, or is it? Yeah, I think we expect to have a meeting to review CMC and a meeting to discuss the statistical analysis plan in the coming months with the CMC meeting expected before the end of this quarter. Got it. So just CMC is a good segue. So where are you currently, and where do you need to go based on the first meeting that you had? Yeah, so it's important to understand, we've been very transparent with this, that accelerated approval is usually an approach to consider expediting the clinical development pathway in demonstrating therapeutic benefit. The FDA typically does not look at accelerated approval as, "OK, let's accelerate your CMC validation." So I think it's going to be very important that we review with the FDA what are the technical requirements for the BLA submission. Having said that, we're in a very unique position in terms of gene therapy because we actually are using a highly homologous process with the same exact AAV vector as we used with Hemgenix, which is a commercially approved gene therapy. So the FDA has talked a lot about leverageable platforms. One of the things that we're going to be looking for is, do we have to do the same validation of certain processes that are identical with what we've already validated for Hemgenix? So the things to remember are, if you compare the process that we use to manufacture for the clinical study, no material changes to the process, no material changes to the scale. We are not tech transferring the manufacturing out of one facility into the other. It is being manufactured in the same exact facility that is manufacturing today Hemgenix. This is a licensed facility with very strong quality management systems. So I think we feel like we're in a good position, but we obviously want to nail down these things with the FDA in the coming months. Got it. The CMC meeting is coming in first, and then the stats plan or stats alignment later. Do you need the three-year data or the approval discussion? Is that based on the two-year data that was disclosed last year? Yeah, so I think what's important to understand is that the accelerated approval is no doubt going to be on the totality of the data. So we do have to make a decision about what is going to be the primary analysis. And that primary analysis will need to be at a particular dose. It will need to be at a particular amount of follow-up. But no matter what is in the primary analysis, we're going to have to look at the totality of the data. So we have to make a decision. Do we want more patients at two years or maybe slightly less patients at three years? There's pros and cons to that. Obviously, the longer the follow-up, the more you expect the delta between the control and the treatment group. But obviously, the more patients, the more power you get. So there's a trade-off there. But it's not like if we selected two years and we meet an endpoint, but then we saw something untoward at three years, that, that's not going to raise questions from the FDA. So I do think the key thing that we reviewed with the FDA is, here's what data we expect to have in the second half of this year. We expect to have 45 patients treated with AMT-130. We expect to have 33 patients with two years of follow-up, 24 patients with three years of follow-up, and the longest follow-up being five years. And we had asked the FDA, do you think this is adequate to demonstrate therapeutic benefit if we see something consistent with what we're seeing in the data that we submitted to you? And their answer was yes. So you've talked about accelerated approval. What would be a confirmatory study then? So we did go to the FDA in our November meeting, and as part of our briefing submission, we did prepare a synopsis of what we thought a confirmatory study might look like. The FDA felt like that was something that we should discuss at a later point in time. I think given the amazing clarity and lack of ambiguity in the written answers, given the discussion in the actual meeting itself, we interpreted that because one of the things we were concerned about is, hey, look, we understand that in an accelerated approval, you want to see demonstrated commitment to a confirmatory study, so we don't want to be remiss here. We want to get going on it if we need to. The FDA said, let's talk about that later, and we interpreted that to be all options are on the table. All options could mean that it's a new study. We don't think any new study would be blinded or internally controlled. It would be open label. But it could include a new study. But we also think it could include a scenario where long-term outcomes from the existing study may be adequate to support full approval. So I mean, we didn't get into that discussion, but our view is that all those options are on the table. Got it. So if the next meeting is on the CMC, how are you planning to disclose any updates? Or would you hold off until you have the subsequent meeting on the stats plan and the cohort size, et cetera? Yeah, I mean, I think they're going to be within weeks of each other. So I think once we have meaningful material clarity, we'll provide an update. We would expect that we would provide that update in the first half of this year, and that update would also include an expectation for what we think the timing is for submitting a BLA. The choice of primary endpoint, is that UHDRS plus NfL, or do you choose? No. The primary endpoint we expect would be the Composite Unified Huntington's Disease Rating Scale. Why is that sort of intermediate? Yeah, so it's interesting. We've been asked this. This is really an FDA terminology. So the FDA came out a couple of months ago with draft guidance. And this is actually a really important aspect about how I think the FDA is looking at accelerated approval and maybe some of the differences between companies that are approaching this. The FDA generally considers two different primary endpoints for accelerated approval. One is something that we've talked about forever, which is surrogate biomarkers. And those are things like, I don't know, it could be mutant huntingtin. It could be GLA levels for Fabry or something else. The second is what's considered intermediate clinical endpoint, which is actually a clinical outcome. It is not a biomarker. It is a clinical outcome that the FDA feels is reasonably likely to predict what they feel is a gold standard for demonstrating therapeutic benefit. Take Fabry as an example because this is a little bit easier. eGFR would be an intermediate clinical endpoint for kidney function or cardiac events. An intermediate means that the FDA, I think, generally looks at Total Functional Capacity as being the strongest evidence of therapeutic benefit in Huntington's. What they're saying is that they believe that the Composite Unified Huntington's Disease Rating Scale is reasonably likely to predict meaningful changes in Total Functional Capacity. I do think that when they think about accelerated approval and what would provide adequate evidence, I do think that they look at intermediate clinical endpoints differently than biomarkers. Because for biomarkers, the question is, how do I know that this is correlated with therapeutic effect? We dealt with this in hemophilia where even with Factor IX, they said, you need to present the evidence where you correlate bleeding events to Factor IX activity. You find yourself in this catch-22 where you're trying to look for accelerated approval, but you also need to demonstrate correlation with clinical outcomes. I do think intermediate clinical endpoints are stronger in that way. You don't expect FDA to revert back to any imaging studies? They understand interstitial delivery does complicate imaging. Oh, I mean, yeah, I mean, I don't think so. I mean, I think we have six years of preclinical and nonclinical data in five different diseased animal models that show beautiful correlation. Where we have vector DNA, we see microRNA. Where we see microRNA, we see messenger RNA suppression. And where we see messenger RNA suppression, we see protein degradation. I mean, that is clear in all of our models. And I think they understand that the direct delivery into the brain just makes it complicated to measure that distally or systemically. Got it. Now, the ongoing cohort with higher immunosuppression, how important is that to the overall package? And then if you were to choose a dose, would you lean towards the higher dose? Yeah, I think so the purpose of that cohort three is really to define and optimize the immunosuppression regimen. And that detail of the immunosuppression regimen will need to go into the BLA submission. We do not think it is integral in the dose selection because we believe that the adverse event profile is manageable. I mean, nearly all of the SAEs related to treatment were really infusion reactions. They all manifested within weeks of the procedure. They reacted beautifully to steroids. In fact, in some cases, they didn't even require steroids. So we're not seeing any long-term perturbations. So we believe that the high dose has a manageable safety profile. And we don't really need to see the third cohort in order to make a dose selection. But we do want to see that data in order to define exactly what the immunosuppression regimen will be. So if everything goes according to plan or it's sort of the ideal outcome, do you think uniQure will be in a position to file a BLA this year? Or this is more of an early 2026 event? Yeah, I think we'll know more after we meet with the FDA, with the clinical meeting and the CMC meeting. I can tell you that right today, we think that the CMC activities are probably going to be the longer pole in the tent, not because they're risky, but the reality is we were not investing last year in preparing for process validation and PPQ until we established the regulatory pathway with the FDA, and we were just obviously fell off our chair when we had such a fantastic meeting in November, and so now we're getting started on that. We would expect that at the very least, once we start PPQ, that it could take up to PPQ being process validation, that it could take six months to complete, and we potentially could start that around the middle of the year. So we'll provide more specific guidance on the timing of it. But I can tell you that we're not waiting for anything. And we are pulling out all the stops and aggressively moving forward to be in a position to put a BLA on file ASAP. Got it. So given the size of the opportunity, both here and globally, do you think you need to find a partner or you want to go it alone? We do not feel like we need to find a partner, I mean, particularly in the U.S. I mean, I think we have to think about the investment required and the return on that investment outside the U.S. But we do not feel that, given the size of the opportunity that we need, a partner. And right now, that's not what we're looking for in the United States. And we feel that we did, of course, decide to partner hemophilia. We viewed that as obviously a very different opportunity. That was a mature opportunity where there was an embedded treatment regimen. It's an area that is dominated by large pharma companies with a more moderate unmet need. So we partnered that. And obviously, I think looking back, we made the right decision here. We see this as a blockbuster opportunity, potentially larger than DMD, larger than SMA, and one where we think we can capture a substantial amount of the value ourselves in the United States. Got it. Then in the last few minutes on the pipeline, both the Fabry and the what was the second program now? SOD1-ALS and temporal epilepsy. The SOD1-ALS and the Fabry both are in the higher dose cohorts now or the second dose cohort. Why those two indications? Because that's been sort of a back and forth in the investment community given the size of the opportunities. Yeah, so it's interesting. So Fabry is a. We believe there's an unmet need in Fabry. We recognize that not everything is going to be Huntington's. But what Fabry represents is an opportunity to leverage so much of what we developed already for Hemgenix. So we have used AAV5 in more than 80 patients. And then probably commercially, it's more than if you add that, it's more than 100 patients with 10 years of follow-up. We think it has got very strong immunological and safety data. We don't have adverse events related to treatment. We demonstrated that we can treat patients irrespective of pre-existing neutralizing antibodies. So we can treat nearly all patients with disease. And so we see lower risks in some areas, understanding that it is a more moderate unmet need. But our goal with both Fabry and ALS is to be better than be best in class. Where we cannot be first to market, we want to be best in class. And we think we have the potential to do that. The one other thing I would mention about ALS is that it is a small prevalence. But it's also because of how dire the unmet need is. If you actually look, I mean, there are probably 300 patients a year diagnosed with SOD1-ALS. So in a weird way, hemophilia has a larger prevalence. But once you get through that prevalence, it's pretty much done. But for ALS, it's more like a chronic or traditional medicine where there's going to be people being diagnosed and treated every year. And in that way, it's actually an interesting market. Got it. And for Fabry, historically, there's been a challenge with response rates because for liver-directed gene therapies, you don't get a very uniform expression profile. So how are you thinking about that when you think about assuming eGFR is the endpoint that FDA has actually agreed upon? Yeah, so that's a good point. One of the things that's interesting with Fabry is you have a much wider therapeutic window. So you can be at multiple levels of% of normal. And there's really no deleterious impact. And so our goal is to get to a dose and to use a highly potent liver promoter to overshoot on GLA expression so that even at the low end of that window, the hope is that you're in a very therapeutic level of expression of GLA. And hopefully, that translates into eGFR. Got it. And the last minute, thoughts on TLE? TLE, I mean, I love the opportunity because it's tremendous. There are hundreds of thousands of patients with TLE that are resistant to multiple anti-seizure medicines. We think making great progress now getting through these initial sentinel patients. The big issue is that the FDA required us to have a much more narrow inclusion criteria for the first three patients. We've got the first one treated, and we do have feedback from the FDA that we can now relax. We don't have to treat the next two with the narrow criteria. We can open that up. So we need to implement that protocol change in the sites, and we would expect to be making progress in the coming months. Awesome. Thank you so much. Good luck this year. Thanks, Debjit. Looking forward to this. Appreciate the invite. Thank you.