uniQure N.V. (QURE) Q1 2025 Earnings Report, Transcript and Summary

Good day and thank you for standing by. Welcome to the uniQure First Quarter 2025 Earnings Conference Call. At this time all participants are in a listen-only mode. After the speakers' presentation, there will be a question-and-answer session. [Operator Instructions] Please be advised that today's conference is being recorded. I would now like to turn the conference over to your speaker for today, Chiara Russo, Senior Director of Investor Relations. Please go ahead. Thank you.

Good morning and thank you for joining us for uniQure's inaugural quarterly earnings call. Earlier this morning, uniQure released its financial results for the first quarter of 2025. The press release is available on the Investors and Media section of our website at uniqure.com and our 10-Q will be filed with the SEC later today. Joining me on the call this morning are Matt Kapusta, Chief Executive Officer; Dr. Walid Abi-Saab, Chief Medical Officer; and Christian Klemt, our Chief Financial Officer. After our formal remarks, we'll open up the call for Q&A. Please note that we'll be making forward-looking statements during this investor call. All statements other than statements 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 these 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.

Thanks, Chiara, and good morning, everyone. Thank you for joining our call today. I'm very pleased to share with you our first quarter 2025 financial results and provide an update on the progress of our four clinical stage gene therapy programs. As we continue to advance our pipeline and drive AMT-130 closer to a planned BLA submission, we are commencing quarterly earnings calls to provide regular updates on our progress. I'm joined today by Dr. Walid Abi-Saab, our Chief Medical Officer; and Christian Klemt, our Chief Financial Officer, who will each provide updates on their respective areas. I'd like to begin by reflecting on what has been a truly remarkable last 12 months for uniQure and why we believe 2025 has the potential to be a transformational year for the company with multiple important value-driving milestones ahead. Last July, we presented compelling two-year data from our Huntington's program, demonstrating AMT-130's potential to meaningfully slow disease progression. Then in November, we announced alignment with the FDA on key elements of an accelerated approval pathway, which include the use of a natural history external control and cUHDRS as a registrational intermediate clinical endpoint. In 2025, we continue to make strong progress with AMT-130. In April, the FDA granted breakthrough therapy designation, underscoring both the urgent need in Huntington's disease and the strength of our clinical data. In recent weeks, we've had multiple productive interactions with the FDA focused on preparing for a planned BLA submission, and we look forward to providing a detailed regulatory update later this quarter after we receive formal meeting minutes. We're also making good progress towards initiating CMC process validation, another important step in support of the planned BLA submission. In addition to the strong progress made with our Huntington's program, we've also expanded our clinical pipeline with the initiation of three additional clinical studies in refractory temporal lobe epilepsy, or TLE, Fabry disease and SOD1-ALS. In the quarter, we continue to advance enrollment in both our Fabry and SOD1-ALS studies, and we look forward to presenting initial Fabry data in the second half of 2025. We completed enrollment of the first two dose cohorts in our SOD1-ALS trial and currently have several patients screening for our TLE clinical study. We also expect to share preliminary results from the first patient dosed in the TLE study at an upcoming scientific meeting later this month. Lastly, uniQure continues to be in a strong financial position with more than $400 million of cash on hand as of March 31. Last year, we significantly reduced our cash burn with the divestiture of our GMP manufacturing facility and organizational restructuring. We further strengthened our balance sheet with the completion of a targeted $80 million follow-on offering earlier this year. Together, these actions provide us the financial flexibility to advance our pipeline, including the planned BLA submission and launch of AMT-130 and support key data readouts from our other clinical programs. Overall, I'm incredibly proud of the progress our team made in the first quarter. We delivered on our key objectives and remain on track to meet the strategic goals outlined for 2025. Our continued focus and disciplined execution position us well for what we expect will be a transformative year for uniQure. I'll now turn the call over to Walid to provide a more detailed clinical update. Walid?

Thank you, Matt. Good morning and good afternoon, everyone. During the first quarter of 2025, we made meaningful progress across our pipeline of clinical stage gene therapies. Let me start with AMT-130. AMT-130 for the treatment of Huntington's disease has made significant gains over the last 12 months, beginning in May of last year with the granting of the Regenerative Medicine Advanced Therapy, or RMAT designation by the FDA, the first for Huntington's disease. In July, we announced positive long-term follow-up data on AMT-130, supporting dose-dependent slowing of Huntington's disease progression. In November, we successfully aligned with the FDA on key elements for an accelerated approval pathway, including the use of the composite Unified Huntington's Disease Rating Scale, or cUHDRS, a functional measure as an intermediate clinical endpoint. In February of this year, we completed enrollment of all 12 patients in the third cohort of the Phase 1/2 trial, and I'll be reviewing the short-term safety data with you in just a moment. In April, AMT-130 was granted breakthrough therapy designation by the FDA, further underscoring the potential promise of this program and the urgent need for disease-modifying treatments for this devastating condition. Most importantly, we believe our interactions with the FDA in both the first and second quarters of this year have been productive. We expect to provide a more comprehensive regulatory update, including guidance on the planned BLA submission later this quarter and additional clinical data in the third quarter of this year. Now I'd like to move on to Cohort 3. Based on our experiences from Cohort 1 and 2, which did not include prophylactic immunosuppression, we believe AMT-130 is generally safe and well tolerated at both doses. Cohort 3, which completed enrollment in February, was designed to evaluate the impact of prophylactic immunosuppression regimen consisting of dexamethasone, sirolimus and rituximab. This cohort includes 12 patients blinded and randomized to receive either the high or low dose of AMT-130. Key observations from Cohort 3 are as follows: AMT-130 continues to be generally well tolerated at both doses with no treatment-related serious adverse events reported. There were three serious adverse events related to immunosuppression, which were observed, mania, MRSA infection from an abrasion and fever, all of which resolved fully with standard of care interventions. Perioperative changes in CSF NfL were consistent with previously reported observations reinforcing their association with the surgical procedure. Based on these results, we believe a short two-week course of steroids represents an appropriate and optimized immunosuppression strategy to accompany AMT-130. We view this as a favorable outcome and plan to review this data with external advisers in the near future. Importantly, we do not anticipate any impact on the potential timing of a BLA submission. Moving on to mesial temporal lobe epilepsy, the team remains focused on driving patient enrollment in the Phase 1/2 trial of AMT-260. Following the implementation of FDA-cleared protocol amendments to broaden eligibility, the trial now has 12 active clinical sites with more expected to be activated throughout the year. We plan to present a case study for the first dose patients, including initial safety and exploratory efficacy data at the Epilepsy Therapies and Diagnostics Development Symposium on Thursday, May 29. In Fabry disease, we announced a favorable safety review by the independent data monitoring committee and have now treated a total of four patients in the Phase 1/2 study. We expect to share initial patient data in the second half of this year. Similarly, in the Phase 1/2 study of AMT-162 in SOD1-ALS, following the review of the initial safety data, the IDMC recommended proceeding with enrollment in the second cohort, the team has now completed enrollment in the second cohort and expects to initiate enrollment in the third cohort in the third quarter of this year. Now I will turn the call over to Christian for a financial update. Christian?

Thank you, Walid. I'll start off by sharing the financial highlights for the first quarter of 2025. Please refer to the earnings press release issued this morning and our quarterly filing for additional details. Revenue for the first quarter was $1.6 million compared to $8.5 million in the same period 2024. The decrease of $6.9 million in revenue was mainly from a decrease of $3.3 million of collaboration revenue and a decrease of $4 million in contract manufacturing revenue. Following the divestment of the Lexington facility in July 2024, revenue from contract manufacturing is recorded net of cost within other expenses. Cost of contract manufacturing revenues were nil in the first quarter compared to $9.1 million for the same period in 2024. Again, following the divestment of the Lexington facility in July 2024, cost of contract manufacturing is recorded net of revenue within other expenses. Research and development expenses were $36.1 million in the quarter compared to $40.7 million during the same period in 2024. The majority of the cost reduction was related to a decrease in employee-related expenses and facility expenses. This was partially offset by a $5.8 million increase in external program spend, primarily related to the submission of a BLA for our Huntington's program. Selling, general and administrative expenses were $10.9 million in the quarter compared to $13.9 million during the same period in 2024. The decrease was again primarily due to a reduction of employee-related expenses. Cash, cash equivalents and investment securities totaled $409 million as of March 31, 2025, compared to $367.5 million as of December 31, 2024. The increase is primarily related to the net proceeds of $80.5 million from our first quarter follow-on offering. This strong balance sheet provides uniQure with the resources for clinical and operational strategy, including the planned U.S. launch of AMT-130. We expect cash, cash equivalents and investment securities will be sufficient to fund operations into the second half of 2027. I'll now turn the call back over to Matt.

Thanks for that update, Christian. As you've heard today, we believe 2025 will be a transformative year for uniQure. We continue to advance a robust pipeline of gene therapies and expect to present data from all of our clinical programs in the next 12 months. We look forward to continuing our productive engagement with the FDA on AMT-130 and expect to update you on our recent interactions, including the expected timing of a BLA submission later this quarter once we receive formal meeting minutes. In addition, we expect to share new data in the third quarter from our ongoing Phase 1/2 study to further support the planned BLA submission. We're extremely excited about the opportunities ahead of uniQure and remain focused on delivering innovative therapies that can improve the lives of the patients we serve. We look forward to keeping you updated on our continued progress. With that, we will open the call to take questions from our research analysts. Operator, please proceed.

Thank you. [Operator Instructions] And our first question will come from the line of Luca Issi of RBC. Your line is open.

Great. Thanks so much for taking my question and congrats on all the progress. Maybe one for either Matt or Walid on the new CBER head. Obviously, Ultragenyx is a company with a long history in rare disease, is on record saying that Dr. Prasad may not be the right guy for the job. I guess two questions. One, would you agree with Ultragenyx? And two, maybe bigger picture, how confident are you that all the productive conversations that you have had so far with CBER on Huntington will not be flipped upside down by the new leadership? Any thoughts there? I much appreciate it. Thank you.

Yes. Thanks, Luca. First, let me just state that, honestly, I very much look forward to working with Dr. Prasad and really do appreciate his public service. The reality is that no matter who's the Director of CBER, we believe strongly in our data, and we believe in the end that this is going to carry the day. I also want to point out something really important in terms of the reliance on surrogate biomarkers, which has been something that I think has come up over the last couple of days. You have to keep in mind that this is not our approach with AMT-130. We're going to be seeking accelerated approval based on three-plus years of clinical outcomes and utilizing a clinical measure as a primary endpoint. So honestly, I believe that this is a key differentiator for AMT-130, and I remain really encouraged about our path forward.

Got it. Thanks so much.

Thank you. One moment for the next question. And the next question will be coming from the line of Debjit Chattopadhyay of Guggenheim. Your line is open.

Hi, good morning. Thanks for indulging me with on two questions. So number one, how confident are you on the three-year follow-up data on the cUHDRS? And what would you consider as a good outcome? And I have a follow-up.

Walid, do you want to answer that one?

Sure. As you know, we've been monitoring these patients for a long time. We have not been doing any additional analysis on the data. But it's very clear when we submitted to the FDA included data two years from these patients, but we also have some other patients on the low dose that have been treated even much longer than that. We have no indication at all that we lose any of the efficacy over time. As a result, we believe that the dose-dependent reduction in cUHDRS that we observed at the two-year data will be maintained when we evaluate the three-year data. So we feel very confident about our results going forward.

Got it. Appreciate that. And the last question, will the third quarter update include propensity match scoring based on the agreed-upon SAP? Or will that analysis be withheld for the BLA submission only? Thank you and congrats.

Walid, do you want to answer that one?

Yes. Thank you. Yes. So the plan is to essentially agree with the FDA on -- and finalize the statistical analysis plan before we lock the database and analyze the data. And at that point, we will be sharing the top line results of these data. As you know, we have to be careful the degree to which we share from the data because the data would have been not yet reviewed by the FDA, but it will be the analysis that we would have agreed to with the FDA.

Thank you. One moment for the next question. And the next question will come from the line of Paul Matteis of Stifel. Your line is open

Hi, good morning. Thanks for taking my questions. I appreciate it. As it relates to the SAP and the different sort of permutations there, I was wondering if you can kind of walk through your approach to this recent meeting. What are the different things you suggested? So that's one. Two, Matt and Walid, we talked at a conference earlier this year as it relates to the pros and cons of three-year versus two-year natural history comparisons with survivorship bias and things like that. So maybe you can just kind of give us an update on where your head is at? And then three, just in terms of waiting for the meeting minutes, and as I understand that, that is -- that's the best practice. But are you waiting for the minutes to make sure you fully understand how the meeting went down and that you want to clarify things? Or is this more good housekeeping to not get in front of the FDA? Thanks so much.

Yes. I'll just answer the last one. And then in terms of the approach to the meeting or two versus three years, I'll give that to Walid. This is good housekeeping. This is just an appropriate thing to do best practice is to make sure you have the complete written responses. So that -- it's really that simple. And then on the approach to the meeting and two versus three years, Walid, why don't you address those?

Sure. I mean, look, this has been an ongoing study. We have people who have been also treated for up to four years. The overwhelming majority of patients would have three-year data. And the assessment is to look at the totality of the data. So we must look at the most relevant data sets, and that's the three-year because that's where the majority of patients are. Of course, we will be looking at the two years. We will be providing the four-year data, but the primary analysis will be based on the three-year data. And the reason for this is that you want to be able to continue to see the promising effects that we've seen at two years are continuing to be manifested at three years and beyond. And so we cannot just look at the earlier part and ignore where the majority of the data are. That's really simply what this is about.

Thank you. And our next question will be coming from the line of Patrick Trucchio of H.C. Wainwright. Your line is open.

Thanks. Good morning. Just a clarification on now that you've held the Type B meetings on both CMC and the SAP for AMT-130, would you anticipate any additional regulatory interactions ahead of the BLA filing? And then separately, regarding the Cohort 3 update, I'm wondering if you can elaborate on the three immunosuppression-related SAEs reported in Cohort 3? And what changes, if any, were made to the protocols or perioperative management?

Yes. I mean, I can -- I'll address maybe the first question. We'll talk about the path forward when we provide a regulatory update. But I think as we stated in the prepared remarks, we've had very constructive interactions with the FDA. We've previously gotten very clear feedback. We obviously look forward to providing the regulatory update, and we feel very encouraged about our path forward. Walid, do you want to address the Cohort 3?

Yes, sure. So maybe I can take a step back a little bit and kind of summarize why we did this. So starting with this, that we believe that AMT-130 is generally safe and well tolerated based on our experience in Cohorts 1 and 2. In that context, there was no perioperative immunosuppression. And what we saw that was some edema and CNS inflammation from the infusion, particularly at the high dose, which manifested within several days of the procedure. But all of these serious adverse events resolved with either supportive therapy in two out of those four cases and the other two resolved after a short course of steroid therapy. Now in cohort 3, we set out to evaluate the effects of a triple regimen, as I said, including steroids, rituximab and sirolimus. And we have not observed any drug-related adverse events attributable to AMT-130. We have observed three serious adverse events related to immunosuppression, mania, which is a well-known adverse event of prolonged corticosteroid therapy and infection and fever, which probably are related to the triple regimen of immunosuppression. And all of these events fully resolved with standard of care interventions. So overall, we have, to some degree, answered our question. We're quite -- we believe we have a good outcome here. We think the optimal way going forward is most likely going to be a short two-week course of corticosteroids that would be given perioperatively with AMT-130. We will be double checking these and discussing with our external advisers. But if you ask me today, my opinion, that would be the -- my advice going forward with immunosuppression.

Terrific. Thanks so much.

Sure.

Thank you. And our next question will be coming from the line of Joseph Schwartz of Leerink Partners. Your line is open.

Hi. This is Jenny on for Joe. Thank you for taking our questions. Just another one on Prasad. We've heard some strong and somewhat contradictory opinions about patient advocacy groups from him. We've heard him say that the patient voice is probably the most important one at the table, but then we've also heard him express concerns about these groups that take funding from pharmaceutical companies, especially if they've been vocal about lowering regulatory standards for approval. In Huntington's, we're aware of the Huntington's Disease Society of America. What kind of relationship do you have with them? Do you know if they've interacted with the FDA? And also, I would just love to hear your thoughts about the HD community in general since we know at least some of them were kind of hesitant about expediting development after tominersen and branaplam. Thank you.

Walid, do you want to address that?

Sure. Thanks, Matt. We've been having very long history working with CHDI and a number of other patient advocacy organization working in Huntington's disease. Honestly, we would not be here today, not us, not other ones in the field if there was no deep commitment from the patients, from the patient advocates and also from all the experts to generate these very elaborate and very sophisticated natural history that really gave us the understanding of the course of the disease regardless of the stage of Huntington's disease, so that we can truly compare our trials, I think compared to that. So without them, honestly, we will not be here today. These patient organization I find them to be extremely balanced. They work with all organizations. They work with regulators. They work with various pharma and biotech company, and they make their data available to be used in a scientifically valid manner. I have never seen them favor one group versus the other. I think they're really well respected. And actually, last year, in the late October or early November timeframe, there was a very important meeting that was held by the FDA that invited the patient organization and heard from a number of them. I think that speaks to the respect that they have for them and they're really equitable balance in the way they conduct themselves. So I really feel very fortunate that we have the relationship with them. I don't feel them to be biased at all. And honestly, without them, we would not be here today, not us and not other companies that you've seen recently, who have used the natural history data.

Thank you.

Thank you. One moment. Our next question will be coming from the line of Salveen Richter of Goldman Sachs. Your line is open.

Hi. This is Lydia on for Salveen and thanks so much for taking our questions and congrats on all the progress. Maybe just on the third cohort of AMT-130, do you plan to include these data in the potential BLA filing, even though I think you've noted you don't believe they'll be necessary for the filing? Thanks so much.

Yes. Thank you. Matt, I assume I'm responding to this. I'm going to go. Yes, thank you for this question. Yes, of course, at the time of submitting the BLA, all data from all the patients that we have for as long as we have them as of the cutoff will be included in the data. So as such, the 12 patients in Cohort 3 will be part of the totality of the data for the FDA to review.

Thanks so much.

Thank you. Next question will be coming from the line of Joseph Thome of TD Cowen. Your line is open.

Hi there. Good morning. Thank you for taking my question and congrats on the progress. Just to clarify, what's the latest data set that the FDA has seen in terms of the data cut versus what's been publicly released? And have they seen any of that Cohort 3 data with the updated immunosuppression regimen? And maybe just to be clear, the two-week immunosuppression with steroid that you're suggesting, is this identical to what the initial patients received in the study?

So Matt, I'll take those two as well. So the data set that we shared with you back in July of 2024 last year included 21 patients, who have crossed the two-year time point. That was based on a data cut of March of 2024. When we met with the FDA in November that is the most recent data that we shared with them, which was based on the June of last year cut, which included three more patients at the high dose. So in total, they saw data from 24 patients at two years, two at the high -- 12 at the high dose and 12 at the low dose. There has been no additional data shared with them since then since our meetings with them regarding SAP and the natural history protocol and CMC were about those specific topics without any review of data. So they did not see any additional data. They did not see any data from Cohort 3. Regarding the two-week steroids, so for first Cohorts 1 and 2, there were no systematic perioperative immunosuppression given, including steroids. So this will be the first time that we would be using this regimen. The reason why we're choosing it is because two weeks of steroids is very commonly used in neurosurgical procedures. Two weeks of steroid therapy is also -- the adverse event profile of that immunosuppression is well understood and considered to be very low. So that's why we're choosing it going forward.

Great, thank you.

Sure.

Thank you. And our next question will be coming from the line of Ellie Merle of UBS. Your line is open.

Hi, guys. Thanks for taking the question. Just curious if you can update us on the latest in terms of the CMC work and specifically, how long you think the CMC requirements will take in order to complete, in order to be ready for filing since I think in the past, you've said the timing of the filing would be more driven by when you'd be able to complete the CMC requirements. And then just a second question. Just in terms of the selection of the natural history comparator and the composition of that, I guess, after you met with the FDA and discussed the SAP plan, how confident are you that the natural history will look similar to the natural history that you've used before and when you presented the data, so just in terms of the composition of that. Thanks.

Okay. I'm going to be answering both questions. So this is Walid again. So on the CMC, there are a series of well-agreed and thought through plans for this. We will be sharing with you the overall time line for BLA submission when we provide a regulatory update at the end of the year. All of this is not new to us. As we've said before, we're leveraging the significant experience we have with HEMGENIX. We're manufacturing AMT-130 in the same place by generally the same people. And a lot of this has been leveraged in discussing with the FDA. So we'll provide more granular information on this when we provide the regulatory update by the end of this -- in the second quarter. On the selection of natural history, I think we've discussed that we're evaluating a number of natural histories. We've had that discussion with the FDA. We have -- we will be updating you again as part of the regulatory update as to where we landed on this. I do not anticipate for this to have any significant difference on what we have been reporting so far or at least last time we reported it to you back in July of last year. So I think we're still going in the same direction. I don't expect any difference in the outcome. Thank you.

Thanks.

Thank you. Our next question will be coming from the line of Uy Ear of Mizuho. Your line is open.

Hello.

Yes, hi.

Hi. Yes, sorry, I didn't hear whose name was announced, sorry. Yes. So a couple of questions from us. Between the CMC meeting and your recent meeting with the FDA, were there any changes in the key personnel? And secondly, given the new CBER director, are you -- I know it's early. Are you thinking that -- have your thoughts on developing your current pipeline changed in any way? And just wanted to make sure, so it's the three-year data that will be used for AMT-130 filing, is that right? Thanks.

Okay. Very good. Matt, are you back on?

I think we're back on, yes.

Oh, great.

Yes. So I think you've asked a few questions here. So the first one was around the CMC and the personnel that we've interacted with at the FDA. We've had no material impact on anybody that is part of the review team that we obviously can see. There's some public record of people that have resigned. There has been at least 30 people that have been involved in our various interactions, and there has been no material changes that we're aware of. Just in terms of your second question about the other pipeline programs, we continue to be very encouraged about the programs that we have. We're going to be generating data across those programs over the course of the next 6 to 12 months, and we're very excited to do that. And obviously are hoping that we're able to determine a path forward and to establish a clinical proof of concept. And then just in terms of the two to three year data, I think as Walid mentioned, we'll provide -- we'll obviously provide a more detailed update when we provide our regulatory update. I think what Walid is pointing out is that in the third quarter, we're going to have 27 patients at two years and 24 patients at three years. So no matter what we look at, it's going to be very important that the totality of the data continue to reflect the trends that we continue to see both at two years and three years.

Thank you.

Thank you. And our next question will be coming from the line of Suzanne Van Voorthuizen of VLK. Thank you. Your line is open.

Hi, team. This is Suzanne from Kempen. Thanks for taking my questions. I know the focus is very much on the data and the BLA, but can you elaborate a bit on your preliminary thinking on the commercial plans and the rollout, the focus on centers, what you consider key target groups, et cetera? And secondly, can you share your current thinking on a potential filing in Europe and/or thoughts on the partnership ex U.S.? Thank you.

Okay. So we will talk in more detail going forward about the commercial strategy. What I can tell you is we're very excited about the potential here in Huntington's. Obviously, there's no disease-modifying treatments that are available for these patients. And we believe that being able to demonstrate meaningful slowing of disease progression would be a transformational leap forward for this community. Just in terms of prevalence, it's probably one of the largest genetically defined diseases. And we honestly believe that we have a very good shot at being not only first to market, but best-in-class. So we're really excited about that. We're right now focused on regulatory interactions with the United States. And now that we've established an accelerated path forward, we'll be engaging with regulators in Europe, and we'll talk more about that. We are preparing for commercialization. As I said, we're very excited about this opportunity. No doubt, strategics are excited about this opportunity as well. This is a needle-moving area for both large biotechs and large pharma companies. So there's certainly a lot of strategic interest in Huntington's. And in the end, we're always going to do what's in the best interest of our shareholders.

Thank you. One moment for the next question. And the next question is coming from the line of Sami Corwin of William Blair. Your line is open.

Hi, there. Thanks for taking my question and congrats on the progress. I guess as you kind of think about the longer-term strategy for AMT-130, how are you thinking about potentially evaluating it in patients with earlier stage or later-stage disease? And then I was also curious if you could give us -- provide any color, I guess, on the number of physicians in the U.S. who would be capable of performing the administration necessary for AMT-130? Thank you.

Walid, do you want to answer that?

So right now, as you know, in this first trial, we evaluated patients who are early manifest because we believe that this is the best chance to maximize the functions to preserve as much functions as possible, but also at the same time that we need to have enough time to evaluate them to see whether there is an impact on the course of disease. If you take people much earlier at a presymptomatic stage, then it's going to take you much, much longer to be able to show evidence of stopping or slowing disease progression. As we now move forward with this, of course, there will be great interest to try and figure out whether you can intervene earlier or later. And those are really early stages right now that we need to be discussing those with the regulators to see what would be the best path going forward. There's no good reason to believe that you should be excluding patients depending on their stage of the disease. At the same time, we need to be able to generate data to convince us that actually those people are set to benefit from it. So I know I'm not giving you a real answer, but this is really early days in our thinking about it, and we need to engage with the regulators to have a much better idea about how we would be approaching for both patients, those who are earlier and presymptomatic and what would be the endpoint in that case and how long we should treat them and those who are maybe further advanced. There, I would imagine the limitation would be about being able to reach the deep structures of the brain where we need to inject our therapy in a safe manner. In other words, there's not enough -- not significant atrophy that happen such that we will be a bit unsafe to be able to get there. But that usually is a discussion that the neurosurgeon will be able to have. So I know it's not a very clean question to -- answer to your question, but this is our thinking as of today. Was there something else? I'm sorry, I might have missed another piece of your question.

Yes. Yes. How many physicians in the U.S. could be capable of performing the administration procedure?

Right. So when we looked at this, there are upwards of 50 sites who can do this. And really, this is not a very complicated procedure. I mean, this is something that is being used right now for administering chemotherapy using sort of essentially a guided administration intraparenchymally in the brain using a frame. This is used commonly by neurosurgeon and they should be -- it's not very complicated. So essentially, in our case, we need to have centers that essentially can do that, but also we'll have access to an MRI because, as you know, we do this to maximize the chances that we don't cut corners. This is one and done. So we need to make sure that whoever is getting that therapy is getting the most out of it. So we're not going -- navigating blind. We'll do it under MRI guidance. We will look exactly where we're injecting and the neurosurgeon can adjust the course and make sure that these structures are appropriately filled. So those are really the two conditions. But when we look, there's plenty of centers in the U.S., I said more than 50 that can do it. And yes, I think that's my answer to your question.

Sounds good. Thanks.

Thank you. And the next question will be coming from the line of Yanan Zhu of Wells Fargo. Your line is open.

Great. Thanks for taking our questions and for the very helpful call. So maybe a couple of follow-up questions on topics already discussed on the length of follow-up for the data in the filing package and also the control arm. On the length of follow-up, I think based on what I heard, it's maybe a discussion between two or three years or that might be the range. I just wanted to ask, could you confirm this is not going to be even longer follow-up than a three-year follow-up for the filing? And on the external control, it sounds like there shouldn't be much surprise compared with what you have been thinking or what you have reported. But just wanted to confirm that in terms of the natural history study that you are looking forward to using is the same like TRACK-HD in that study and not a different study like Enroll-HD or perhaps it doesn't matter. Yes, please help with those questions. Thanks.

Sure. On the first question, we have already discussed this last November with the FDA and agreed that the data cutoff of end of June of this year, 2025, will be the data cutoff and we will use the totality of the data to support a BLA submission. At that time, we will have, as Matt said, 27 patients with two years of follow-up, 24 patients with three years of follow-up, eight patients with four years and actually one patient with five years. But the totality of the data will be received. The primary analysis will be done on the three-year data because that's where the majority of the patients that is going to generate meaningful understanding of the rate of progression of the disease. Regarding external control, also, we communicated that last time when we met with the FDA, we were asked to evaluate systematically all the available natural history protocols. And Enroll-HD is one of the largest ones, TRACK and PREDICT-HD, we've used previously because they control the striatal volume. But now we've gone through this and systematically evaluated this. We've had discussions with the FDA and agreed on the one that we will be using as a primary. This will be part of our feedback to you when we provide the regulatory feedback. Again, I think, you also answered your question in the question itself. We said it doesn't matter. Honestly, I don't think it does matter that much between those. The results between Enroll TRACK and PREDICT in terms of the course of the disease provided that you do the appropriate matching to your patient population generates virtually the same rate of decline that you see. Incidentally, if I may, you have seen probably recently data from PTC, where they've used external control used compared to natural history. In that case, it was Enroll-HD. They looked at the rate of decline in cUHDRS after two years, and it came out at 1.1. If you recall, that's very close to the data that we shared with you last year in July, where we used TRACK and PREDICT, and we came out to virtually the same number. So that should give you and us confidence that, in general, if you do the appropriate matching of your patient population, you're going to end up in the same place after two years or in our case three years.

Yes, indeed, that is what we saw. So thank you for clarifying all of that. Maybe as a quick follow-up, would the team care to share your view on PTC's data and the drug as a potential competitive consideration? Thanks.

Well, perhaps Matt can speak about the competitive piece of it. From a scientific point of view, I do not think it's appropriate for us to comment on a competitor's data, especially when it's not -- we don't see the full data set. It's not in a scientific presentation or a peer-reviewed publication. It's very difficult to do that, and I don't think it's appropriate for us to comment on that. Turn it over to you, Matt.

Yes. Well, I mean, I would just focus on our data. I think our data that we presented last year showed an approximately 80% slowing of disease progression based on the composite UHDRS. We're very comfortable with our bioavailability of our drug because we can see real-time the filling of the structures when it's administered. And we're also very comfortable with our target, right, which not only suppresses the full-length mutant Huntingtin protein, but also the short, highly toxic exon 1 fragment, which certainly provides differentiation. So I mean, we're focused on our data, really encouraged by it and also believe that our administration in our target makes us potentially best-in-class.

Got it. Thanks and congrats on the progress.

Thank you.

Thank you. [Operator Instructions] One moment for the next question. And the next question will be coming from the line of Debjit Chattopadhyay of Guggenheim, and it's a follow-up. Here you go. Your line is open.

Hi. Thanks for letting me back in again. Just another follow-up for me. Has there been a discussion on what a future confirmatory study could look like? Or would you not need one since cUHDRS is not a surrogate endpoint?

Walid?

So we have discussed with the FDA back in November last year. And we -- actually, at the time, we had a proposal in place. The FDA said we're not prepared to discuss what would the confirmatory study would look like until we have a chance to review the data that you submit to us as part of the BLA submission that we agreed to with them. So at this point, the agency is not ready to discuss this. Our interpretation is that it can be as optimistic as maybe more longer-term data from this study, maybe looking at total functional capacity data from our study at a longer time point, maybe adding another cohort to our study or a completely new independent study, but it would not be placebo-controlled in our opinion. But again, to some degree, this is speculation on our part because the agency did not want to discuss that. What we know for sure is that this will not be -- or it's not expected based on what the agency has told us so far to have to be completed and done and about to start or halfway conducted before we can file for BLA for accelerated approval. So we don't think it's going to slow us down at all. And that was clear from our interaction with the FDA.

Thank you.

At this time, I'm not showing any more questions in the queue and I'll turn the call back to Matt Kapusta for closing remarks. Please go ahead.

Thank you very much, operator. Really appreciate everybody dialing into the call. We look forward to providing additional updates very shortly. Thank you so much.

This does conclude today's conference call. Thank you all for joining. You may now disconnect.