Good day, and thank you for standing by. Welcome to the AMT-130 Huntington's Disease Program Update conference call. At this time, all participants are in a listen-only mode. After the speaker's presentation, there will be a question-and-answer session. To ask a question during the session, you will need to press star one one on your telephones. You will then hear an automated message advising that your hand is raised. To withdraw your question, please press star one one again. Please be advised that today's conference is being recorded. I would now like to hand the conference over to your speaker today, Maria Cantor, Chief Corporate Affairs Officer. Please go ahead. Good morning, and thank you for joining us. This morning, uniQure announced updated interim data on 29 patients treated with AMT-130 in our ongoing Huntington's disease phase I/II clinical trials that are taking place in the U.S., Europe, and the U.K. The update consists of data on clinical measures, exploratory biomarkers, and safety and tolerability, as well as the anticipated regulatory next steps. Joining me for this investor event and webcast are Matt Kapusta, our Chief Executive Officer, Dr. Walid Abi-Saab, our Chief Medical Officer, and Dr. Victor Sung, Professor of Neurology at the University of Alabama at Birmingham, the Director of its Huntington's Disease Clinic, and a clinical investigator in the AMT-130 U.S. trial. The slides included in this morning's webcast will be available on the investor page of uniQure's website shortly after the conclusion of the investor call. Please know that we'll be making forward-looking statements during this call, and all statements other than those of historical fact are forward-looking statements. They are based on management's beliefs and assumptions and on information available to management only as of the date of this conference call. Our actual results could differ materially from those anticipated in these forward-looking statements for many reasons, including, without limitation, the factors described in uniQure's most recent SEC filings. Given these risks, you should not place undue reliance on those forward-looking statements, and we assume no obligation to update these statements, even if new information becomes available in the future. Now, let me introduce Matt Kapusta, uniQure's CEO. Thank you, Maria, and good morning, everyone. We are really delighted to share with you today exciting data from our U.S. and EU phase I/II studies of AMT-130 and Huntington's disease. For the first time in a clinical setting, we have demonstrated statistically significant dose-dependent slowing of disease progression and reduction of a key marker of neurodegeneration in Huntington's disease patients at 24 months. We and key opinion leaders in the HD field we have recently spoken to believe these long-term data provide very encouraging and compelling evidence of AMT-130's disease-modifying potential. These results also follow our recent announcement of the FDA's first-ever RMAT designation in Huntington's disease, and we very much look forward to engaging with the FDA later this year to discuss the potential for expedited clinical development of AMT-130. Huntington's disease is one of the most prevalent monogenic disorders, affecting approximately 70,000 people in the U.S. and Europe alone, with hundreds of thousands of others at risk of inheriting the disease. While Huntington's was one of the earliest rare diseases to be genetically characterized, there continue to be no disease-modifying treatments available for these patients. In personally talking to many patients living with HD and their loved ones, the heartbreak and devastation are immediately clear. The onset of symptoms generally occurs between 30-50 years of age, a time typically dedicated to raising children and building careers. Yet, the progression of the disease is almost tortuously slow, with symptoms gradually worsening over the next 10-25 years, ultimately robbing people of their jobs, relationships, mobility, and the ability to care for themselves. Our vision for AMT-130 is to delay or slow the advancement of this horrible disease, and by doing so, give time back to patients and their families. We at uniQure believe AMT-130 has the potential to be not only a first-in-class treatment for Huntington's disease, but also a best-in-class therapy with several important differentiating features. First, AMT-130 is a one-time administered therapy with potentially lasting effects. Remember, Huntington's is a lifelong disorder with disease burden detectable decades before the onset of symptoms. Therapeutic intervention as early as possible is critical to preserve function. As such, providing patients a one-and-done therapeutic option with durable effect can offer patients meaningful advantages compared to repeated lumbar punctures for the remainder of a patient's life. Moreover, in early clinical trials like ours, patients that receive AMT-130 can be followed for years and compared to robust natural history datasets to support clinical benefit. Second, as a one-time therapy, AMT-130 can be delivered directly to the brain, ensuring therapeutic bioavailability in key regions where there is known pathology. Drug delivery to the brain has vexed the industry for decades, yet it's absolutely essential for achieving clinical efficacy in Huntington's disease. During the administration of AMT-130, the filling of critical brain structures is observed in real time under contrast-enhanced MRI. Moreover, in multiple animal species, large and small, and including disease models, we have demonstrated meaningful cortical spread with a high correlation between levels of vector DNA and the suppression of both messenger RNA and mutant huntingtin protein in the range of 25%-75%. And lastly, AMT-130 leverages our proprietary miQURE gene silencing technology and was specifically designed to target the first exon of the huntingtin gene. In doing so, AMT-130 has been demonstrated to suppress not only the full-length mutant huntingtin protein, but also the highly toxic exon 1 splice isoform. We believe no other current therapeutic candidate specifically targets this highly toxic fragment. With that, let me turn the call over to Dr. Walid Abi-Saab, who will discuss the updated results, including new statistical analyses and next steps for the program in more detail. Walid? Thank you, Matt. Good morning. Good afternoon, everybody. I'm here. I'm very, very excited to share with you this important update on our Huntington's disease program. Let me start by thanking the patients, their caregivers, and the larger Huntington's disease community, without whom none of this would have been possible. We have made significant progress since our last update. Now we have patients followed up to 3 years, the longest interventional study in Huntington's disease to date. More importantly, perhaps, now that the majority of our patients have reached the 2-year mark, we were able to conduct post-hoc analyses, demonstrating a statistically significant dose-dependent slowing of disease progression in patients treated with AMT-130, as well as exploratory biomarker evidence demonstrating a reduction in neurodegeneration. AMT-130 continues to be well-tolerated, with a manageable safety profile, with no new drug-related serious adverse event reported since the last update. Most importantly, with the recent RMAT designation, we will be discussing with the FDA in the second half of the year the development path towards a potential accelerated approval. In the next few slides, I will talk you through the clinical measures and the comparison to an external cohort. The key efficacy endpoint in our studies is the Composite Unified Huntington’s Disease Rating Scale, or cUHDRS for short. It's a composite score based on measurements of the key affected areas in Huntington’s disease. Specifically, function, as measured by the total functional capacity, which assesses impairment in occupation, ability to manage finances, daily chores, and the rest. Motor function, as measured by the total motor score, which assesses abnormal movements and rigidity. Cognition, which is very important to patients. Cognition is measured by two tests of attention, processing speed, and working memory. Recently, an independent study in patients with early Huntington's disease concluded that the cUHDRS is the most sensitive measure of progression of the disease. cUHDRS best characterizes the clinical progression and provides an opportunity to improve efficiency of clinical trials relative to individual measures, meaning it has a stronger signal-to-noise ratio compared to individual components, and consequently, a signal could be picked up on this scale before it becomes apparent on individual scales. We are thrilled to have received an RMAT designation for AMT-130, as it is the first Huntington's disease compound in development to receive such a distinction. More importantly, RMAT designation will allow for more frequent interactions and discussions with regulators on the requirements for an accelerated approval. The data that supported the RMAT application were those we shared last December, with only 8 patients having reached the 2-year mark, which is a much less mature data set than what we will be showing you today. To evaluate the effects of AMT-130 by comparing to a natural history cohort, we used propensity score methodology, a standard approach when comparing clinical trial data to an external cohort. Those analyses provided evidence of potential benefit of AMT-130 and led the FDA to grant us RMAT designation. With this update, we continue to build on what was presented to the agency now that we have 21 patients who have completed 24 months of follow-up. Since our update in December 2023, we have expanded our natural history cohort beyond the initial TRACK-HD/TRACK-HD-ON study to include the PREDICT-HD study as well. Thanks to our ongoing collaboration with CHDI, we have access to these studies and to their databases. We have selected these studies because, first, they prospectively collect data longitudinally, they employ consistent and regular rater training similar to clinical trial settings, and both include clinical as well as imaging endpoints, which are key inclusion criteria in our studies. Starting with approximately 2,000 patients from both natural history studies, we applied the clinical and imaging criteria from our studies and selected those patients for whom we have baseline, plus 2 or more years of follow-up data available. Using these criteria, we ended up with a total of 154 patients from both studies. Similar to the RMAT application, in the statistical analyses we are sharing with you for the first time today, we used the propensity score methodology to compare outcomes for AMT-130 treated patients versus natural history external cohort at the two-year mark. Propensity score weighting is a standard statistical approach commonly used for these analyses, as they're designed to reduce selection bias when comparing to an external cohort. This methodology has been used in support of a number of regulatory submissions to date.... We used 8 baseline characteristics for the propensity score weighting to generate an external group that is nearly identical to the 21 AMT-130 treated patients who have completed 2 years of follow-up. With the majority of our patients having reached the important 2-year time point, we could now conduct, for the first time, robust post hoc statistical analyses, yielding nominal p-values to better understand the potential efficacy of AMT-130 in Huntington’s disease. Here we show how well-matched the AMT-130 treated patients are to the propensity score weighted external control. As you see, on virtually all key baseline characteristics, the two groups look virtually identical. As you can see on this graph, AMT-130 shows dose-dependent and statistically significant difference from the external cohort on cUHDRS after 24 months. This is one of the two most important graphs you will see in this presentation. The external cohort is depicted in gray, whereas the low and high dose of AMT-130 are shown in purple and blue or teal, respectively. While the external cohort declined from baseline by 1 point after 2 years, the AMT-130 treated patients declined by 0.7 and 0.2 points for the low and high dose, respectively. These results suggest an 80% reduction in the rate of disease progression by AMT-130 at the high dose, as measured by the sensitive composite score relative to a well-matched external cohort. Reaching statistical significance with such a small sample size is impressive and reflects the large observed effect size. If these effects are maintained over time, AMT-130 has the potential to be a groundbreaking treatment for Huntington’s disease patients. Here, we show the time course for the cUHDRS over a 2-year period for both dose levels of AMT-130. We also include the external cohort to provide context for the AMT-130 data. As you can see, AMT-130 shows sustained favorable effects over the 2-year period relative to the natural history group. In addition, we can also see consistent dose-dependent effects over the duration. Here we show the 4 components of the cUHDRS over the 2-year period, across both doses and external control group. Naturally, we see more variability when we look at these individual scales compared to the composite endpoint, confirming the utility of the composite score in reducing the variability and improving the signal-to-noise ratio, as has been demonstrated in recent studies. For example, the low dose appears to have significant fluctuation on the TMS score and be no better than the external control on the SDMT, but it does on TFC and the Stroop Test. Nonetheless, when we look at the totality of the data, the high dose in particular, appears to perform better than the control across most of those measures. Moving on to neuro, neurodegeneration. Neurofilament light chain is an important biomarker of neurodegeneration. It is released from damaged neurons and is reliably measured in both CSF and plasma. It is very sensitive in measuring toxicity to neurons, whether from neurodegeneration, like in Huntington's disease or ALS, from neuroinflammation, like in multiple sclerosis, or any type of toxicity, like drug-related toxicity, as was recently shown in recent trials in Huntington's disease. As such, long-term trends in CSF neurofilament light chain is viewed by Huntington's disease expert as not just a safety measure, but potentially one of the best characterized biomarker of neuro, neurodegeneration activity. Importantly, a reduction in NfL levels was used as a surrogate biomarker supporting the recent accelerated approval of a treatment of ALS. In this slide, we show the time course of NfL. Sorry, I had to look at the slide. In this slide, we show the time course of CSF NfL over a two-year period. The low and high dose are depicted on the graph in the same purple and teal color, respectively. As we have previously reported, we see an immediate spike in CSF NfL following surgery, and probably because of it, and treatment with AMT-130, and then a gradual return to baseline. The increase is believed to be related to the surgical procedure because it is not dose-dependent. Consistent with the known pharmacokinetics of CSF NfL levels, the return to baseline takes several months. However, we're very pleased to see that two years after treatment, both doses of AMT-130 have CSF levels below baseline, a result that has never been seen before in a clinical trial setting, therapeutic setting in Huntington's disease. As you can see in the graph inset, which zooms in on the data between month 12 and 24, the trends clearly continue downward for both doses. This would be the second most important graph that we're showing you today. The reductions in NfL below baseline in AMT-treated patients is very relevant, considering the increase one would expect in untreated patients as their Huntington's disease progresses. Recently, an independent study called HD-CSF measured NfL levels in the cerebrospinal fluid longitudinally in 71 patients at the start of the study, and then two years later. They found that CSF NfL levels inevitably increase as the disease progresses, and these findings suggest that neuronal damage accelerates as the disease progresses. In fact, when we analyzed data from 19 out of those 71 subjects in the HD-CSF trial and select those who met our clinical and MRI inclusion criteria, we found that their NfL levels after two years increased by 26% relative to their baseline, as shown in the gray bar on the left side of this graph. In contrast, the 21 patients who received the AMT-130 in our studies had a statistically significant reduction of 11% relative to their baseline after two years, as shown in the orange on the right-hand side of the graph. These data suggest that consistent with this mechanism of action, AMT-130 reduces neurodegeneration in Huntington's disease. Furthermore, these observations appear to be consistent with the favorable clinical data suggesting disease slowing. Next slide. Safety and tolerability are the primary endpoints in this phase I/II study. In this update... If you can turn to the next slide, please. Thank you. In this update, we have no new AMT-130 related serious adverse events to report, and AMT-130 remains generally well tolerated with a manageable safety profile. I'll pause for a minute so people—if you can go back to the slide for a second, please, just to give people a chance to look at this. This is a slide they've seen before. It hasn't changed, but I wanna give people a chance to do that. All right, let's move on to conclusion, please. I'm extremely pleased with the results of this interim analysis to date. AMT-130 continues to be generally well tolerated with a manageable safety profile, with up to three years of clinical observation. This is the longest study evaluating a potentially disease-modifying therapy in Huntington's disease. As Huntington's disease is a slow-progressing disease, longitudinal study of two or more years are necessary to show treatment effects in patients at early stages of their disease. With the majority of patients in our studies having reached two years of treatment, our data are starting to look promising, with consistent clinical and biomarker data pointing out to potential beneficial effects of AMT-130, relative to well-matched external control groups. Consistent with this mechanism of action, AMT-130 demonstrated a dose-dependent effect on a clinical composite score designed to sensitively measure disease progression in early Huntington's disease. Furthermore, CSF NfL levels are significantly reduced below baseline, suggesting a reduction in the ongoing neurodegeneration. These are clearly different to what is expected if patients were left untreated. The totality of evidence presented today suggests that one-time treatment with AMT-130 reduces the progression of Huntington's disease over a 2-year period. If this treatment is maintained over time, this therapy has the potential to be groundbreaking in the treatment of this devastating disease. In the second half of this year, we will work closely with the FDA to clarify the regulatory path towards further development of AMT-130 and potential for accelerated approval. We will complete enrollment of cohort 3, which consists of up to 12 patients and is aimed to evaluate the effects of immune suppression on perioperative safety. We aim to provide an initial safety update from cohort 3 in the first half of 2025. We will also provide a 3-year analysis similar to this current one by mid-2025. With this, I conclude my part of the presentation, and I now have the pleasure to introduce Dr. Victor Sung, who has graciously agreed to provide his thoughts on the data update and firsthand experience with AMT-130. Victor? Thank you, Walid, and good morning, everyone. First, let me provide some context for my commentary today. I'm a professor of neurology at the University of Alabama at Birmingham, the director of our UAB Huntington's Disease Clinic. I'm also on the steering committee for AMT-130. More importantly for this conversation, I'm also a site PI for AMT-130 and have four high-dose patients who've received AMT-130 under my care. Before I touch on my personal experience with AMT-130, I wanted to highlight several points which I believe make this data particularly compelling. My biggest takeaways are the statistically significant improvement of cUHDRS at 24 months, which is a time interval at which the disease should have clearly worsened clinically. This is clinically important because cUHDRS, as Walid mentioned, contains motor, functional, and cognitive components to them, which are all the key parts of the disease that patients recognize and find impactful. The other thing, the next thing is the high dose being 0.2 from baseline at the 24-month mark on cUHDRS, means that this group is essentially unchanged from a motor and cognitive standpoint from baseline, which is both impressive and unprecedented. For the CSF NfL data, while this has traditionally been a safety biomarker, I'm really excited about this data. It's significant and noteworthy that it's the first ever treatment in HD to show CSF NfL falling below baseline at any point, during a treatment trial, so that's pretty significant. The natural history cohort had a 26% increase in CSF NfL-... in the two-year timeframe, which is in line with the about 10%-15% inexorable increases that we generally quote to our patients, that NfL will worsen, over time, year by year. But the AMT-130 patients had an 11% decrease, over a two-year time point, which really shouldn't happen and can only be attributed to AMT-130. To me, this is even more impressive considering the 400% increase seen initially due to the instrumentation, and from that big increase initially falling to 11% below baseline at the two-year standpoint is really incredibly exciting. And this is the first study to show both statistically significant improvement in a functional outcome and lowering of NfL to below baseline levels in HD, and that combination really incredibly exciting. Mutant huntingtin levels in gene therapy are hard to interpret because of the way that projections to cortex and the changes are delayed, when you have a therapy that's injected into the basal ganglia. Similarly, volumetric MRI data is hard to interpret in a therapy where we instrument the basal ganglia, and the resulting neuroinflammation there will make volumetric data hard to interpret and even more emphasizes the significance of the NfL and the functional data presented today. My experience with AMT-130 is really colored by my four treated patients, who I've followed for years now, and who have done generally well. In particular, I have one patient who had gathered his family at the time of diagnosis to tell them all the grave news about his diagnosis and that he would ultimately follow the path of the parent he inherited HD from. He told me this story and that there were lots of tears at that gathering. But then this patient had the opportunity to participate in the AMT-130 trial, and now, roughly three years after study entry, they're still working full-time at an age that their parent, who they had inherited the HD from, had already died. That patient's family member said: "Wait, I thought you said that you were going to follow the path of your parent." They're kind of all waiting for that other shoe to drop, and they really attribute the subject's continued stability to AMT-130. So that's just a positive success story that I've experienced personally. With that, I'll pass it back to Matt, and I believe we will take some questions. Thanks, Victor. Operator, you can open the line up now for Q&A. Thank you. Certainly. As a reminder, to ask a question, please press star one one on your telephone and wait for your name to be announced. To withdraw your question, please press star one one again. Please stand by while we compile our Q&A roster. One moment for our first question, which will come from Ry Forseth of Guggenheim Securities, LLC. Your line is open. Hey, everyone. This is Ry from Debjit's team at Guggenheim. Congratulations on the data. Looking forward, what data or operational factors drove your decision to target a, a mid-2025, month 36 update relative to maybe a month 30 update? Yeah. Thank you. This is Walid. Well, we believe the most useful way to compare our data right now as the study is progressing and patients are, at this stage, coming maybe twice a year for their evaluation, is to compare them to the external control. And since the external control natural history visits are annual, the next meaningful update after the second year will be the third-year data. And so we believe that by this time next year we hope that we can build and expand on the data that we've shown you today with looking at a further progression of the disease or essentially slowing of the progression of the disease with AMT-130. That's truly what's driving that decision. Thank you. One moment for our next question. Our next question will be coming from Paul Matteis of Stifel. Your line is open. Hey, thanks so much for taking the questions and for the update this morning. A couple. So one is, I guess, what is your level of confidence right now that you can conduct a natural history control study? Two, do you think that this study is well suited to be expanded into one that could have a natural history control, or is that a different trial altogether in your mind or in your potential proposal? And then three, I mean, certainly the cUHDRS data is interesting. You know, was this the endpoint that at the outset you had proposed to be the most sensitive for this type of therapy? I guess I had been under the impression that something like TMS or something that's more biased towards motor symptomatology might be the best measure for this mechanism, given deep brain delivery. So, just curious in your thought process there, and, yeah, thanks so much. Thanks a lot. So two questions, tackle them in order. First, the natural history. I think it's clearly now the case that we're gonna be relying more and more, as our patients continue to invest in therapy, on comparing to an external natural history cohort. So our objective is to build this natural history, to make it more robust by including—you know, additional databases that we could have access to by working collaboratively with CHDI, among others. But more importantly, when we meet with the FDA, we want to incorporate also their input on how to best construct these external natural history cohorts to be able to robustly compare to our therapy. So more to come as we have more information on this. Regarding the endpoint, the cUHDRS has been shown by an independent study that it has the best signal-to-noise ratio. If you look in our own data, you see that there are, you know, some differences between each component score. Sometimes when you look at patient-level data, you also see a difference within the same patient, where they might have gone maybe a little bit worse on, in one visit compared to the previous one on one of these subscales, but better on another one. That's truly where is the power of a cUHDRS, especially when you're dealing with smaller trials, to take these individual variability and combine them to a composite score that is better designed to measure sensitively these changes. And actually, they successfully were able to show it in recent trials in HD, how they can quickly detect changes. In that case, it happened to be worsening of symptoms in HD. So in terms of a priori choosing this at the beginning, look, this was a phase I trial. At the beginning, when we started the primary endpoint, and I think I mentioned this in my presentation, is always gonna be safety and tolerability. That's the first thing we think about. But of course, this is a gene therapy, one-and-done therapy, where we continue to follow patients for years after therapy. We measure important endpoints, clinical endpoints, which these components are key. cUHDRS is the main one, with its own subcomponents, as well as the biomarker data, NfL and others. Those were the decisions that we made at the beginning. So I do believe that while TMS could, in one case, show positive results and in some cases will not, or changes between visits, cUHDRS is much more stable, particularly when you have smaller number of subjects. Yeah, just two quick points, Paul. One is we have a high degree of confidence that cUHDRS potentially could be an approvable endpoint, at least in certain geographies. It's less clear about a particular individual component or domain of the score. The second is, if you really talk to Huntington's patients, obviously, the motor symptoms are important, but so are the behavioral and cognitive symptoms. So, you know, I do think looking at a composite makes a lot of sense. Yeah, thanks so much. One moment for our next question. Our next question will come from Joseph Schwartz of Leerink Partners. Your line is open. Great, thank you, and, let me add my congrats, on the data. A couple questions. First, could you walk us through your thinking when it comes to the development scenarios that you might face going forward? How much would you be willing to undertake on your own versus, if you would require a partner for continued advancement? Yeah. Hey, Joe, thanks for the question. You know, we are very willing to take this program forward, particularly under an expedited scenario. Obviously, to the extent that the regulatory agencies require a very significant, expensive, long-term phase III study, that is something that we clearly would have to discuss potential partnering or other scenarios. You know, I think we've been pretty clear that, you know, if we're gonna be looking at $hundreds of millions in 5-6 years of a phase III study, you know, that is something that is likely gonna be beyond our means, at least today. But I really do believe, particularly under RMAT designation, that there is a lot of support for an expedited clinical development pathway, particularly in Huntington's disease. I think with the ability to collect long-term outcomes from an early clinical study in conjunction with a potentially surrogate biomarker like CSF NfL, I really do think and encouraged for having discussions with the FDA later this year to discuss those faster pathways. That's helpful. Thanks. And then can you talk about the clinical relevance of these changes in cUHDRS? How does the clinical impact that you're detecting compare to any minimally clinically relevant differences that have been established to date? Yeah, thank you. I'll take that question. The field has been very active in this space. Actually, most recently, there's a paper that came out in 2023 by CHDI, with the lead author Jamie Hamilton, depicting what would be a clinically meaningful worsening on each of the cUHDRS and the subscale, for a given stage of the disease. And actually, we've used this particular analysis to compare our data to, and what we were able to see is that the high dose has a 60% odds of reducing the odds of worsening, for patients who are treated with a high dose compared to the natural history cohort. So we believe this is very clinically meaningful data, and powerful. Thank you. One moment for our next question. Our next question will be coming from Ellie Merle of UBS. Your line is open. Hey, guys. Thanks for taking the question, and congrats on the data. Just for the NfL data, it looks like the low dose is doing slightly better than the high dose, but in the cUHDRS data, that ... the high dose is performing better than the low dose. I guess, how should we interpret this, and how are you thinking about the dose response more broadly? Thanks. Yeah, thanks, Abby. Great question. If you recall, when you look at our time course, we've had, although a similar spike between the low dose and the high dose, which we attribute to the actual effect of the surgery itself, the return to baseline over time took longer at the high dose than at the low dose, and we believe those have been confounded by some of the inflammation that we've observed a bit with the high dose. And those were corroborated in individual cases when we look at individual time points where they have a spike in inflammation and the response to therapy for that. So I do believe that the two-year period is long enough after the intervention and after these effects to start to see a return to baseline. We're very pleased with the fact that we have a return below baseline for the high dose. If I were to predict, my predictions would be that in the 3-year, the high dose should have a larger reduction from baseline than the low dose on NfL. So the bottom line, we believe the high dose data are confounded by the inflammation, which the longer we go away from the intervention, the less we see those effects of the confounding factors. Hmm. Great, thanks. One moment for our next question. Our next question will be coming from Joseph Thome of TD Cowen. Your line is open. Hi there. Good morning. Thank you for taking my questions, and congrats on the update. Maybe one for Dr. Sung. I guess, in terms of implementing this therapy broader into your patient population, should it be approved, I guess, what additional data would you like to see versus what we're seeing today, maybe to make you comfortable with the therapy, if anything, or if the profile right now enough to kind of get you to use it more broadly if it were approved today? And then maybe second, for the company, a little bit of a follow-up to the prior question, but I know in your fiscal year 2023 press release, you did indicate a partner before phase III. I guess, how have partnership discussions been progressing, if at all? And if there is that accelerated pathway, do you think you could go forward with an approval and a launch, internally, or would you still want a partner for commercialization as well? Thank you. Thank you for the question. I'll start first. So I think in general, this profile is very strong with cUHDRS, which I'm very familiar with and comfortable with, both the components and as a composite. And the NfL data is also extremely compelling. So generally, I feel comfortable with it for my patients. As it stands, the one thing that I think I would love to see are, you know, since it's really appearing that the high dose is more impactful overall functionally, and that's where we saw more inflammation. But in the plans for the next cohort, there are plans with a new immunosuppression protocol to kind of suppress that inflammation. And I'd like to see the data on that and how successful that immunosuppression plan is for the actual implementation of the therapy. Otherwise, overall, the profile, I'm pretty satisfied with. Thanks, Victor. Yeah, and regarding your second question on partnering, right now, we are focused on initiating our interactions with the FDA under RMAT. We expect an RMAT kickoff meeting, a multidisciplinary meeting, where we can engage with them meaningfully and frequently to understand the path forward. As I mentioned in one of the prior questions, I do believe, and particularly with more focused operations and preservation of capital initiatives that we recently announced, that we do have the ability to take this forward under an expedited pathway. And, you know, based on the feedback that we get from the FDA, we'll make an appropriate determination if a partner is required. Great. Thank you both very much. One moment for our next question. Our next question will be coming from Salveen Richter of Goldman Sachs. Your line's open. Good morning. Thank you for taking my questions. Two questions from me. Could you speak to the variability that are seen across patients per dose cohort compared to natural history? And then help us understand, as you meet with the FDA later this year, just frame expectations as what you would view as a positive outcome. Okay. So, on the, on the variability, again, I think, we're what we're dealing with are, you know, endpoints that measure cognition, motor symptoms, and Total Functional Capacity is a, is a scale where, it's an integer, based scale, so essentially, it's a scale from 0 to 13, with 13 being normal. So a people can only have a reduction of 1 or 2 or more on that scale, and, and those sometimes could be affected by somebody, you know, losing a job or somebody having a breakup with a partner and things like that. So when you do smaller studies like this, as is necessary in gene therapy, the variability is, on individual scales, will become much more prominent, and that's why the whole cUHDRS was developed specifically to improve that signal-to-noise ratio and reduce that individual variability into a composite score and allow us to draw better conclusions, you know, on our data. And for the second question on the FDA? Yeah, I mean, on the second question, Salveen, I mean, really, well, this is the beginning of what's gonna likely be a series of meetings under RMAT. To kick us off, to set a plan going forward with the FDA, we'll be in a position to raise certain questions and begin the dialogue. And we're, we're committed to providing an update, at the very least, procedural update on what to expect going forward. And once we align with the FDA on a path forward, that's when we'll, we'll provide more detail. Thank you. Our next question will be coming from Luca Issi of RBC Capital. Your line is open. Oh, great. Thanks so much for taking my question, and congrats on the data. Maybe, Matt, appreciate a difficult question to answer, but in your head, what's the likelihood that this data, as is, is sufficient for accelerated approval? Is that number above or below 15%? And then maybe second question on the subgroup, appreciate small N, but any subgroup where the benefit is more pronounced here? I know Roche is focused on patients with low age and low CAP, so wondering if what you're seeing is consistent with what they are seeing. Again, appreciate different, different molecules there, but any call there, much appreciated. Thanks so much. Yeah. Hey, Luca, thanks for the questions. I'll let Walid answer the second question. Yeah, on the first question, it's very hard for me to handicap and provide a probability that based on this data alone, you know, we could get accelerated approval. In my heart, you know, I really am encouraged and really believe that we're seeing a potential therapeutic and clinical benefit here at AMT-130, particularly given the trends that we're seeing over a two-year period. I mean, you heard Dr. Sung talk about, you know, at two years, you really would expect to see this disease progress, and we're generally seeing stability across numerous clinical measures that are supported by the CSF NfL data. The most important thing is not what's in my heart, right? It's in the minds of the FDA, and the great thing is that, you know, we're, you know, we're under RMAT, and, you know, we expect in the relatively near term to begin very significant interactions with them about potentially accelerated approval. Walid, do you wanna answer the second question? Yeah, no, when, I mean, it's a, it's a great question. Subgroup, we always have that tendency to wanna look at this. Honestly, I think this is, these are small numbers, and frankly, I've been there before. Sometimes you can be, you know, misguided by, by looking at this, so I really would caution us from being able to draw conclusions from that. So, I'm sorry, I will not, I will not venture to answer this concretely. Super helpful. Thanks so much. Our next question will be coming from Kristen Kluska of Cantor Fitzgerald. Your line is open, Kristen. Hi, everyone. Congrats on these data. So you mentioned before some of the parallels with ALS, and you and a few of your peers in the space are all meeting with the regulatory agencies around the same time. So, you know, curious what you think their level of flexibility will be to avoid multiyear long trials, as shown in the past, and follow more of a similar course to an ALS, especially considering there are some components of these diseases that overlap? It's an excellent question. It's clearly promising the fact that ALS... In ALS, which is a neurodegenerative disease, faster progressing, at least in the case of SOD1, than Huntington's disease, clear reductions in NfL levels were supportive of an accelerated approval. Again, it's difficult to guess how the FDA would react, but I think we believe that our data, the way they are coming from a clinical perspective, where they're pointing out in the cUHDRS a dose-dependent effect. When you look at the NfL, you clearly see for the first time in a clinical setting, a clinical therapeutic setting, I should say, a reduction from baseline in NfL, a biomarker that's linked to neurodegeneration. We believe those are compelling evidence in support of each other, and we're really looking forward to have our discussion with the FDA in our upcoming Type B meeting, which we will do in the fourth quarter this year, to discuss exactly what you're asking about. It would be difficult to guess how they would respond, but I think FDA has been very open and publicly speaking to support you know advancing programs like Huntington's disease therapies with advanced therapies like ours, and we look forward to have these discussions with them. And as soon as we have clarity on the outcomes, we'll be sharing it with you. Yeah, and Kristin, one other thing. I can tell you that in the ALS analogy, you know, the voice of the patient, you know, was very important and continues to be very important for the FDA, and we've been engaging significantly with these patient advocacy groups. And, you know, this is a group that is really willing to step up in a big way, like the ALS community has. And I think that's going to be important going forward, that they have independent and direct interactions with the agency, and they're very willing to do so. Thank you. ... One moment for our next question. Our next question will be coming from Sami Corwin of William Blair. Your line is open. Hi, this is Caleb, calling for Sami Corwin. Congrats on the data, and thanks for taking our question. We wanted to know if you guys did analysis of the mutant huntingtin levels at 24 months, and as well, if you looked at any volumetric imaging analysis. Then another question, have you guys considered a pivotal trial or another cohort in less advanced disease patients? Thanks. Okay, so let me tackle them one by one. So the mutant huntingtin, we've, as we discussed last time in December, with that assay, we are essentially batching the analysis on a one year at a time for subjects. So in other words, in order to limit the variability in the assay, we're batching each time a subject has one year of data, we will send it for analysis. And we, we said that by this time, we will not have enough data at two years to warrant showing the data, which is the case. Having said that, we've also discussed, we had Professor Wild on the phone with us last time, about the fact that by virtue of the way we treat with the AMT-130, injecting in deep structures of the brain, which represent less than 5% of the total volume of the brain, and where we measure, which is in the lumbar area, in CSF, we would not expect to have these changes apparent. Now, that's not the case for other therapies that are given systematically or therapies that are injected directly into the CSF, intracerebrally, because mHTT is essentially secreted everywhere, and the components that you'll be measuring in the lumbar puncture could be coming from anywhere, but not necessarily from the deep structures of the brain, which are extremely important to us and others in the treatment of HD. So again, we believe that in our case, you know, measuring mHTT is not necessarily relevant, by virtue of the way we provide treatment and where we measure the CSF levels. Turning to the volumetric, we've discussed this again in last December, and Professor Wild was with us, and he has conducted his PhD studies specifically on volumetric measuring in Huntington's disease. What he said at the time is that the changes that we're seeing, especially in the context of a brain that has underwent surgery, would not be out of the ordinary and would not make any sense when you take into consideration the clinical and NfL benefit that were seen at the time, suggesting that these changes that were seen were not clinically meaningful. When we looked at this data at this time, they're fairly consistent with what we've seen before. The other bit that I want to share is that when we look at the data in the second year compared to the data at the first year, you see a slowing down of that initial reduction that is seen, and that is suggestive that the initial reduction that we see in the first year is driven mostly by the surgery. Lastly, on the pivotal trial, I think I noted pivotal trial, but I missed exactly what was your question. Less advanced- Sorry, yes. Less advanced. Yeah, great question. This is definitely the next step, but first you need to demonstrate that you actually are gonna be effective in the patients in the early stages of the disease, where you have a positive risk benefit. And after talking with the agency, the plan would definitely be to expand to earlier stage patients so that you can essentially prevent them from actually getting the disease. So that will make a natural consequence to it, but that will have to wait until we have discussions with the FDA. Thanks so much. One moment for our next question. Our next question will be coming from Patrick Trucchio of H.C. Wainwright. Your line is open. Morning. Thank you so much, and congratulations on the data. This is Luis for Patrick. I wanted to discuss a little bit the selection process that you used for the natural history cohort. So you expanded it to better evaluate efficacy. You had TRACK-HD and ON, then you have PREDICT-HD. My fear here is that the FDA will or might consider that this, although the characteristics are matched, are well matched across the groups and your study, that not all of these will be seen eye to eye just because they're external, it's an external study. So I'm wondering what else, what other characteristics could you consider for this comparison? On a second question, I was wondering if you could tell us a little bit about target engagement and the huntington protein method detection that you've been using and whether that is being detected at standard levels? Yeah, so I can take those quickly. So let me be clear, the-- with external controls, actually, the gold standard is to do a propensity-based analysis. And there have been numerous examples where a propensity-based analysis has been accepted for regulatory submissions. So this is not unprecedented. The 154 patients we selected, I want to be very clear, there was no subjectivity whatsoever. These are patients that met the study criteria, and then the weighting exercise is really done through a regression analysis. So this is, you know, a very robust statistical approach that is done in order to ensure that the comparisons have reduced bias, and reduction of any effect of confounding variables. So it's a very well understood and previously utilized analysis. With respect to mutant huntingtin, I think we, I think we answered this question earlier. We did not. We're doing this now on an annual basis to reduce variability. Given the fact that we administer this directly into the deep brain, it is obviously more complicated to measure this indirectly in cerebrospinal fluid taken from the lower lumbar. What I can tell you is, in multiple animal species, both large and small, and in diseased models, we have validated the mechanism of action. We have a very high degree of confidence given that where we administer this, we can see under real-time MRI, the filling of the structures, that we are getting suppression of mutant huntingtin in the brain where it matters. May I add one thing? Just to say that for the RMAT application, it was precisely those patients that were used in the application from both natural history cohorts and used the propensity score methodology to analyze the data in various different ways to support the case for potential, you know, therapeutic benefit. And it was based on that that the FDA granted us the RMAT. So, I think that, to me, goes a long way to show that this is an acceptable way to do it. Furthermore, while the FDA does not have a specific guidance on this, they have posters on their website by their own statisticians, advocating for using propensity score methodology as the best way to evaluate external control. That's useful. Thank you so much for the follow-up. Thank you. Our next question will be coming from Uy Ear of Mizuho. I'm sorry, Mizuho, your line is open. Hey, guys. Yeah, thanks for taking our questions. I was wondering if there is anything that you can sort of, you know, there's an imbalance, I guess, between the number of patients in the natural history and in the two dose cohorts. Just wondering if there's any way to, if there's any method to account for the imbalance in the number of patients. The reason I'm asking this is because, you know, at 2 years, when you previously showed the data for with 6 patients, the change in the lower dose was something like -0.2, and now it's -0.7, and the high dose, it was +0.7, and now it's, you know, -0.2. Just, you know, wondering whether there's any, if the number of the imbalance in the number of patients might have an effect on the analysis? Thanks. Yeah, thank you for the question. Actually, the external control has no influence at all on the data that we have in our own trial. What you're describing are the fact of, you know, what we reported previously were from a subset of these patients. And when the larger cohort now joined them, then you're having the effects of the total group. So specifically for the low dose, now, the total cohort of 12 patients have data available at 24 months. From the high dose, 9 out of the 17 patients have been treated, have data at 24 months. So I think this is what's causing these changes that you've described between the previous update and this current update. The fact that the natural history... I'm sorry, go ahead. Yeah. What I was sort of referring to, you know, you indicated one, with respect to the statistical analysis. I'm sorry, I didn't understand what you said. I was just wondering if, you know, having the, the fact that you have larger numbers of patients than the, natural, you know, and the propensity- Right sort of reduces the variability and it led to a statistical, you know, yeah, there's less variability. But in the other group, I guess, with fewer patients, there could be greater variability, and I was just wondering if the imbalance in that could have either contributed or to the, the- I see. So your question is more statistical in nature, but- Yeah ... but the reality is that the propensity score weighting actually does not. It uses all the information of the 154 patients to essentially generate a group that would be closely matched. And if you look at that table, that group that's closely matched, it's almost like the best way to describe it is a synthetic group of 21 patients made to contribute from these 154, with these people contributing differently to how close they match our subjects. Yeah, I think going into a lot more detail about the statistical methodology of that is beyond the scope of this call, but this is a tried and true analysis that actually has been used in regulatory submissions. Actually, there's one example where, when a company presented their data, the FDA did not like the analysis, but they went and did their own propensity score weighting analysis and ultimately approved that drug. So I think this methodology is sound, and I'm happy to take discussion offline if you want to go into a bit more details about it. Okay, thank you. Our last question will be coming from Yanan Zhu of Wells Fargo. Your line is open. Hi, great. Thanks for the update and for taking our questions. So first, I was wondering about your confidence level that at 30 months, the cUHDRS comparison will still hold, in terms of the p value, compared to placebo. I was wondering, also, since you probably have six patients of data for low dose for the 30-month data point, based on what you reported, you know, previously, the number of patients at 24 months. So I was wondering, do you think the trend will hold, at least for that low dose, and it at 30 months? And then I have a question on the neurofilament light chain. Thanks. Yeah, no, thank you for this. I think for the 30 months at the low dose, we only have 2 patients. At the high dose, we have 6 patients now up to 36 months. When we look at the data, you know, they're consistent, but again, it's really a subset. I mean, this is like less almost a third of the total site. So I do believe that when we have the total cohort reaching the 36 months, we will have data that are positive. I'm really very heartened by what we see. I'm confident with the data, because again, it's consistent across both a biomarker and clinical endpoint. But the data that we have today is also consistent with what we're seeing right now, but we didn't show it because it's not important for the primary analysis that we're sharing with you today. Great. Thanks. So, NfL and also accelerated approval potential, I was wondering, what is the benefit that could come from such strategy? Does it provide for a shorter study, or does it have a greater signal to noise ratio compared with the cUHDRS, you know, the traditional functional endpoint? Of course, if you could obtain the accelerated approval path now, based on existing data, this would be a moot point. But, since it's not clear whether that's possible, you know, if you have to conduct a new study, what is the benefit of this NfL potential NfL path? Thanks. Yeah, I mean, at the very least, it's highly supportive of the clinical outcomes data that we have. I mean, the neurofilament light chain is a very well-characterized marker for the rate of neurodegenerative activity. And as we've shown, and has been studied, it is highly associated with the clinical severity of the disease. So I think at the very least, it's supportive, and at, you know, at, the greatest, or the most, potentially can serve as a surrogate biomarker for, you know, based on, extended follow-up from a phase 1/2 study. You mean not a new study based on the existing study, the current study? Well, I'm sorry, what was the question? Sorry, I thought you were saying this surrogate marker from the phase 1/2 study could be a surrogate. Is that what it... Sorry, I was just wondering, is this surrogate endpoint? Does it have to be a new study from a new study with like 2-year follow-up, or are you thinking about the current study as a surrogate? Well, I'm thinking about the current study, but all of this is gonna depend on our discussions with the regulators. So, it, it's hard to surmise. But I think having this data from long-term follow-up of patients from a Phase 1/2 study in a way that I think you know, even Victor himself, you know, characterized as being remarkable to see, I think, I think that's gonna be compelling evidence that we're looking forward to discussing with the FDA. Got it. Very helpful. Thank you. I would now like to turn the call back to Matt Kapusta for closing remarks. Okay, thank you everyone for joining us today on the call. I'd like to give a special thanks to Dr. Sung for his participation on today's call and our Phase 1/2 study, the uniQure team for their unwavering dedication to our mission, and of course, the Huntington's disease community for your support and partnership over the years. We look forward to providing additional program updates in the future. Thank you, and have a great day. This concludes today's conference call. Thank you for participating. You may now disconnect.