uniQure N.V. Q1 FY2025 Earnings Call

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. 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. Our first question will come from 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 really look forward to working with Dr. Prasad and really do appreciate his public service. The reality is that no matter who is 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?

Thank you. The plan is to reach an agreement with the FDA and finalize the statistical analysis plan before we lock the database and analyze the data. At that point, we will share the top-line results. We need to be cautious about how much we disclose since the data would not have been reviewed by the FDA yet, but it will be based on the analysis agreed upon 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. Thank you for taking my questions. I appreciate it. Regarding SAP and the different options, could you walk us through your approach in the recent meeting? What were some of the suggestions you made? Also, Matt and Walid, we discussed at a conference earlier this year the advantages and disadvantages of comparing natural history over three years versus two years, particularly concerning survivorship bias. Can you provide an update on your thoughts about that? Lastly, I understand that waiting for the meeting minutes is standard practice. Are you doing this to ensure you fully grasp the meeting's outcome and seek clarifications, or is it simply a precaution to avoid jumping ahead of the FDA? Thank you very much.

Yes, I'll respond to the last question. Regarding the approach to the meeting and whether to focus on two or three years, I'll let Walid handle that. This is standard procedure. It's important to ensure you have complete written responses; it's really that straightforward. Now, Walid, could you address the approach to the meeting and the two versus three years?

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'll address the first question. We'll discuss the path forward when we provide a regulatory update. As mentioned in the prepared remarks, our interactions with the FDA have been very constructive, and we have received clear feedback. We look forward to sharing the regulatory update and feel encouraged about our path forward. Walid, would you like to discuss Cohort 3?

Certainly. To summarize our approach, we believe that AMT-130 is generally safe and well tolerated based on our experience in Cohorts 1 and 2. Notably, there was no perioperative immunosuppression. We did observe some edema and CNS inflammation from the infusion, especially at the high dose, which appeared within days of the procedure. Fortunately, all serious adverse events resolved, either with supportive therapy in two of those cases or after a brief course of steroid therapy in the other two. In cohort 3, we aimed to assess the effects of a triple regimen that included steroids, rituximab, and sirolimus, and we have not seen any drug-related adverse events linked to AMT-130. However, we recorded three serious adverse events associated with immunosuppression: mania, which is a recognized side effect of extended corticosteroid therapy, as well as infection and fever likely resulting from the immunosuppressive regimen. All of these events were resolved with standard care interventions. Overall, we feel that we have made progress in answering our questions and are optimistic about the outcome. Moving forward, we believe that a brief two-week course of corticosteroids administered perioperatively with AMT-130 is likely the best approach. We will confirm this and discuss it with our external advisors, but my current recommendation for immunosuppression would be along those lines.

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 organizations 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 companies, 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.

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 address those points as well. The dataset we provided in July of last year included 21 patients who had reached the two-year mark, based on data from March of last year. During our meeting with the FDA in November, the most recent data we presented was from the June dataset, which included three additional patients at the high dose. In total, they reviewed data from 24 patients at the two-year point, comprising 12 at the high dose and 12 at the low dose. No further data has been shared since that meeting, as our discussions with them regarding the SAP, natural history protocol, and CMC focused specifically on those topics without any data review. They did not see any additional data or data from Cohort 3. Concerning the two-week steroid regimen, for the first Cohorts 1 and 2, no routine perioperative immunosuppression, including steroids, was administered. Therefore, this will be our first use of this regimen. We have chosen it because two weeks of steroids is a common practice in neurosurgery, and its adverse event profile is well understood and considered to be very low. That's our rationale for moving forward with it.

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? Thanks.

I'm going to address both questions. This is Walid again. Regarding the CMC, we have a series of well-considered plans in place. We will share the overall timeline for the BLA submission when we provide a regulatory update at the end of the year. This is not new to us; we are drawing on our significant experience with HEMGENIX. The manufacturing of AMT-130 is taking place in the same facilities and generally by the same team. Much of this experience has been useful in discussions with the FDA. We will give more detailed information during the regulatory update by the end of the second quarter. On the topic of natural history selection, we are evaluating several natural histories and have had discussions with the FDA. We will update you on our findings in the regulatory update. I don’t expect this to significantly change what we have reported so far, especially since our last update in July of last year. We are still moving in the same direction, and I don’t anticipate any change in the outcome.

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, I apologize, I didn't catch the name that was mentioned. I have a couple of questions. Between the CMC meeting and your recent FDA meeting, were there any changes in key personnel? Also, considering the new CBER director, do you think your perspective on developing your current pipeline has changed at all? I just want to confirm that the three-year data will be used for the AMT-130 filing, is that correct? Thank you.

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

I think we're back on, yes.

Oh, great.

Yes, I believe you've raised a few questions. First, regarding the CMC and the personnel we've worked with at the FDA, we haven't seen any significant impact on the review team that we can identify. While there is some public record of resignations, at least 30 individuals have been involved in our interactions, and to our knowledge, there have been no substantial changes. Now, concerning your second question about our other pipeline programs, we remain very optimistic about these initiatives. We expect to generate data from these programs over the next 6 to 12 months, and we are eager to move forward and establish a clinical proof of concept. Additionally, as Walid mentioned, we will provide a more detailed update in conjunction with our regulatory update. In the third quarter, we anticipate having 27 patients at the two-year mark and 24 patients at the three-year mark. It is crucial that the overall data continues to reflect the trends we've observed at both the two and three-year points.

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, etc.? 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, thank you for taking my question and congratulations on your progress. As you consider the long-term strategy for AMT-130, how are you planning to evaluate it in patients with earlier or later-stage disease? Additionally, could you provide any details on the number of physicians in the U.S. who would be qualified to administer AMT-130? Thank you.

Walid, do you want to answer that?

Currently, we are focusing on patients who show early symptoms because we believe this offers the best opportunity to preserve their functions. However, we also need adequate time to assess whether our approach has an effect on the disease's progression. If we treat patients who are still asymptomatic, it will take considerably longer to demonstrate any impact on halting or slowing down the disease. As we progress, there will be considerable interest in exploring the possibility of intervening at earlier or later stages, which are still in the preliminary discussions with regulators to determine the optimal path forward. There is no reason to exclude patients based on their disease stage, but we need to collect data demonstrating that those patients will actually benefit from treatment. I realize this might not fully answer your question, but it's still early in our consideration of this issue, and we need to engage with regulators to better understand how to approach both early and later-stage patients, including establishing treatment endpoints and duration. For patients who are more advanced, we might face challenges related to safely accessing the deeper structures of the brain for therapy administration. This is typically a discussion better addressed by neurosurgeons. I apologize for not providing a clearer response, but this is our current line of thinking. Is there something else? I may have overlooked another aspect of your question.

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

When we examined this, there are over 50 sites that can perform this procedure. It is not very complicated and is currently used for administering chemotherapy through guided administration within the brain using a frame. Neurosurgeons commonly use this approach, so it isn't complex. We need to have centers that can perform this procedure and have access to an MRI. This is important to ensure we maximize the effectiveness of the therapy and avoid taking unnecessary risks. The process is conducted under MRI guidance, allowing us to see exactly where we are injecting and enabling the neurosurgeon to adjust as needed to ensure proper filling of the target structures. These are the two main requirements. There are many centers in the U.S., more than 50, capable of this procedure, which answers 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 the 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 discuss the competitive aspect. From a scientific perspective, I don't believe it's right for us to comment on a competitor's data, particularly when we don't have the complete data set and it's not presented scientifically or published in a peer-reviewed journal. It's quite challenging to make comments on that, and I think it's best that we refrain from doing so. I'll pass 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. Please hold for the next question. The following question comes from Debjit Chattopadhyay at Guggenheim, and it's a follow-up. 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?

We had a discussion with the FDA in November last year and presented a proposal. At that time, the FDA indicated they were not ready to discuss the design of a confirmatory study until they reviewed the data submitted with our Biologics License Application. Currently, the agency is not prepared to engage on this topic. Our understanding is that they might be open to longer-term data from our study, possibly exploring total functional capacity data over a longer duration or even adding another cohort or conducting a completely new independent study, but we believe it would not be placebo-controlled. However, this is somewhat speculative since the agency has not provided clarity on this matter. Importantly, based on our interactions with the FDA, we understand that this confirmatory study does not need to be completed or in progress before we can file for accelerated approval under the BLA. Therefore, we do not anticipate any delays in our timeline.

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.