uniQure N.V. Q2 FY2025 Earnings Call

Good day, and thank you for standing by. Welcome to the uniQure Second Quarter 2025 Earnings Conference Call. Please be advised that today's conference is being recorded. I would now like to hand the conference over to your speaker today, Chiara Russo, Senior Director of Investor Relations. Please go ahead.

Good morning, and thank you for joining us for uniQure's Second Quarter of 2025 Earnings Call. Earlier this morning, uniQure released its financial results for the second quarter of 2025, and our press release is available on the Investors and Media section of our website at uniqre.com. Our 10-Q was also filed with the SEC earlier this morning. Joining me on the call today are Matt Kapusta, Chief Executive Officer; Dr. Walid Abi-Saab, Chief Medical Officer; and Christian Klemt, Chief Financial Officer. After our formal remarks, we will open up the call for Q&A. Before we begin, please note that we will be making forward-looking statements during this investor call. All statements other than statements of historical facts 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 today's second quarter conference call. The first half of 2025 has been tremendously productive for the company as we advance AMT-130 towards potentially becoming the first disease-modifying therapy for Huntington's disease. Our momentum is strong across four key areas: clinical advancement, regulatory alignment, BLA readiness and commercial launch preparation. We also made advancements across our broader clinical pipeline, including AMT-191 for Fabry disease, AMT-260 for mesial temporal lobe epilepsy and AMT-162 for SOD1-ALS. With pivotal top line data from AMT-130 and initial clinical data from AMT-191 in Fabry, both expected in September, we believe the second half of 2025 is shaping up to be an eventful period for uniQure. Turning to AMT-130. In Q2, we continued to have productive interactions with the FDA, including receipt of breakthrough therapy designation in April and further regulatory alignment. AMT-130 remains the only investigational therapy in Huntington's disease to have either breakthrough therapy designation or Regenerative Medicine Advanced Therapy or RMAT designation granted by the FDA. In June, we achieved alignment with the FDA on both our statistical analysis plan and CMC requirements for a planned BLA submission in the first quarter of 2026. Our primary efficacy analysis will compare the 3-year change in cUHDRS in high-dose patients to a propensity score matched external control arm using data from the ENROLL-HD natural history study. In addition, the FDA agreed that we can leverage our experience from HEMGENIX in validating the AMT-130 manufacturing process and that our process performance qualification can be limited to one such batch, supplemented by additional commercial scale GMP batches. Following FDA guidance, we've made significant progress in preparing for the planned BLA submission. Manufacturing of two-scale pre-PPQ GMP batches is now complete, and we've initiated our formal PPQ campaign. We also recently submitted our final statistical analysis plan to the FDA, which Walid will discuss in more detail shortly. On the commercial planning front, we continue to make disciplined investments in preparation for a potential 2026 launch. In June, we appointed an experienced leader, Kylie O'Keefe, as Chief Customer and Strategy Officer, and our HR team is actively recruiting key roles across medical affairs, market access, commercial operations, and other critical areas. The team is making strong progress on an integrated launch strategy, and we look forward to sharing more details in the future. Now turning to our broader pipeline. In May, we shared encouraging early data from the first patient treated with AMT-260 for mesial temporal lobe epilepsy. Over the first five months of follow-up, the patient experienced a 92% reduction in seizure frequency with no significant adverse events. This early result has sparked strong interest among investigators and the epilepsy community. I'm pleased to say that we have 14 clinical sites in the U.S. that continue to screen patients for this study. During the second quarter, we also continued to advance our Fabry and SOD1-ALS studies and look forward to presenting initial Fabry data at the ICIEM conference in early September. Overall, I'm incredibly proud of the team's execution and dedication towards advancing these important therapies. In the first half of 2025, we delivered on several key goals and remain on track for what we believe could be a transformational second half marked by meaningful data updates, regulatory progress and continued momentum towards the planned BLA submission of AMT-130. I will now turn the call over to Walid to provide a more detailed clinical update.

Thank you, Matt. Good morning, and good afternoon, everyone. During the second quarter of 2025, we continued to make meaningful advancements across our portfolio of clinical stage gene therapies. Let me start with AMT-130. In April, AMT-130 was granted breakthrough therapy designation by the FDA. This recognition, the first in Huntington disease, was based on the Phase I/II data showing the potential to slow disease progression and underscored both the urgent need for effective treatments for Huntington's disease and the potential therapeutic benefits of AMT-130. As you know, our recent FDA interactions have been highly productive. Following two Type B meetings in the first and second quarter, we announced in July alignment with the agency on the statistical analysis plan and CMC requirements for AMT-130. The FDA agreed that the 3-year change in cUHDRS measured against a propensity score adjusted external control constructed using the ENROLL-HD data set could serve as the registrational endpoint for an accelerated approval BLA. The agency also endorsed our CMC strategy, stating that it should be possible to validate the AMT-130 manufacturing process by leveraging prior knowledge and experience from HEMGENIX, uniQure's approved commercial gene therapy for hemophilia B. This approach, supplemented with data from additional full-scale GMP batches and a single successful PPQ run may be sufficient to support process validation for the BLA submission. As Matt just mentioned, we have completed those GMP batches and the PPQ campaign is currently underway. As stated in the press release this morning, we have submitted the final SAP using a propensity score matched external control derived from the ENROLL-HD data set for the primary analysis. A number of additional analyses, including a propensity score weighted external control will be submitted as sensitivity and supplemental analysis. This update reflects an alignment with the FDA's stated preference and recommendation for propensity score matched natural history controls. The FDA will receive both the propensity score matched and propensity score weighted analysis as disclosed previously. Turning now to clinical progress. I'm incredibly pleased to report that the AMT-130 clinical team has successfully completed the June 30 cutoff date for the 3-year data, keeping us on track for the expected September data update. I'm also pleased to announce a fourth cohort in the Phase I/II trial of AMT-130 expected to initiate in the third quarter. This open-label single-arm U.S. study will evaluate safety of the high dose of AMT-130 in at least six patients with lower striatal volumes. Patients who would have previously been excluded based on the criteria of a minimal striatal volume can now be considered potentially expanding access to treatment. We expect to have full enrollment by the fourth quarter of 2025. Finally, in September, we plan to present top line data of our Phase I/II of AMT-130. We currently plan to disclose safety and tolerability data through 36 months follow-up as well as other top line data, including cUHDRS and TFC at both dose levels compared to a propensity score matched natural history control. We also plan on providing CSF, NfL data at both doses compared to baseline at 36 months. Moving on to AMT-260 for mesial temporal epilepsy. In late May, we shared initial data from the first subject in the Gentle Phase I/IIa study at the Epilepsy Therapies and Diagnostics Development Symposium. We observed a 92% reduction in seizure frequency over the first 5 months of follow-up with no serious adverse effects. While additional follow-up on this first trial participant and enrollment of additional participants in this trial are needed, this case study provides an early signal that suggests our miRNA-based grade 2 targeted gene therapy can potentially suppress seizure activity in this type of patients. This early data has generated enthusiasm among investigators and trial sites as well as interest within the broader epilepsy community, which is eager for differentiated novel treatment options. Though trial recruitment remains challenging, I'm very proud to say that additional sites have been activated, and we expect to have additional patients enrolled before the end of the year. Moving to AMT-191 for Fabry disease. The Phase I/IIa clinical trial continues to enroll patients, and we expect to present initial safety and exploratory efficacy data at the 2025 International Congress of Inborn Errors of Metabolism or ICIEM conference on September 5 in Kyoto, Japan. Lastly, I'll touch on AMC-162 for SOD1-ALS. We continue to dose patients in the Phase I/II EPISOD1 clinical trial, and we anticipate sharing the study's initial safety and biomarker data in the first half of 2026. Now I will turn the call over to Christian for a financial update.

Thank you. Good morning. I'll start off by sharing the financial highlights of the second quarter of 2025. Please refer to the earnings press release issued this morning and our quarterly filing for additional details. Revenue for the second quarter was $5.3 million compared to $11.1 million in the same period in 2024. The decrease of $5.8 million in revenue resulted from a $3.4 million increase in license revenue, a decrease of $7.1 million from collaboration revenue and a decrease of $2.1 million from contract manufacturing of HEMGENIX for CSL Behring. As noted in the first quarter, 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 0 for the 3 months ended June 30, 2025, compared to $7.2 million for the same period 2024. Again, following the divestment of the Lexington facility in July of last year, cost of contract manufacturing is recorded net of revenue within other expenses. Research and development expenses were $35.4 million for the 3 months ended June 30, 2025, compared to $33.7 million during the same period in 2024. The $1.7 million increase was related to an increase of $6.3 million in external program spend and the $4 million higher expenses related to an increase in fair value of contingent consideration. This was offset by a decrease of $4.7 million in employee-related expenses, a decrease of $2.1 million in facility expenses and a $1.8 million decrease in costs related to preclinical supplies. Selling, general and administrative expenses were $13.5 million for the 3 months ended June 30, 2025, compared to $15.8 million during the same period in 2024. The $2.3 million decrease was primarily related to a $1.6 million decrease in employee-related expenses and a $0.6 million decrease in professional fees compared to the prior year period. Cash, cash equivalents and investment securities totaled $377 million as of June 30, 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. With this strong balance sheet, we believe uniQure is well positioned to execute its clinical and operational priorities, including the planned commercialization of AMT-130 in the U.S. in 2026. 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 the update, Christian. As you've heard today, our strong execution during the first half of 2025 has positioned us for what we believe will be an exciting and pivotal second half of the year. We've achieved regulatory alignment on an accelerated approval pathway for AMT-130, submitted our final statistical analysis plan, initiated our PPQ campaign and continue to advance key BLA preparation activities. We very much look forward to presenting top line pivotal data anticipated in September, which we expect will support a planned BLA submission in the first quarter of 2026 and if approved, commence a U.S. commercial launch later that year. At the same time, we're progressing our broader pipeline with encouraging early data in mesial temporal lobe epilepsy and initial Fabry data on track for September. Our mission remains clear: to deliver transformative therapies for patients with serious unmet needs. We are focused, well resourced and energized for the opportunities ahead, and we look forward to keeping you updated on our progress in the months to come. With that, we will open the call to take questions from our research analysts. Operator, please proceed.

Our first question comes from Debjit Chattopadhyay with Guggenheim.

I have one and a follow-up as well. So number one, does the FDA expect a minimum threshold for clinical benefit versus the ENROLL-HD or cUHDRS?

Walid, do you want to answer that one?

Sure. In discussions with the FDA, a minimum clinical effect has not been requested nor has it been included in the SAP plan. Having said that, we will be submitting the 3-year data, which we expect that will show a substantial level of evidence that would support accelerated approval after the FDA review.

Appreciate that. And our understanding is that the company has written feedback. So how certain are you that the FDA senior leadership won't run at on what's already been communicated to the company?

Yes, Debjit, obviously, we're watching what's going on in the space. We know what's publicly available in those situations. Each of these situations are very nuanced. All of our interactions with the FDA have been very encouraging and very supportive. And as we've said in the past numerous times, we have very clear and unambiguous feedback with the FDA. In terms of our situation, it is different meaningfully in so much that we're moving forward with clinical outcomes data and long-term clinical outcomes data as opposed to relying on a surrogate biomarker. So we believe this is a robust approach. We're focused on controlling and executing on what we can control, and we're feeling very optimistic about our path forward.

Our next question comes from Joseph Schwartz with Leerink Partners.

This is Jenny on for Joe. Could you walk us through the AMT-130 procedure and what this would look like from a patient's perspective, including your time commitment? And how are you thinking about who would be appropriate for the surgery? And how should we think about the commercial population? Do you think there's a particular subset of patients who are more likely to be early adopters?

Walid, do you want to talk about the procedure?

Sure. The procedure is technically straightforward. Neurosurgeons experienced in treating tumors or performing deep brain stimulation consider it a relatively low complexity procedure. Patients typically undergo an MRI beforehand to plan the trajectory, which the neurosurgeon tailors according to individual anatomical differences. On the surgery day, patients arrive at the hospital in the morning, get admitted to neurosurgery, and using MRI-guided registration, probes are inserted into the brain with direct visualization from the MRI. A hole is drilled in the brain for the catheter, which is introduced. Through careful observation, we can see the infusion of the product, which is combined with gadolinium, an MRI-compatible contrast material. This allows the neurosurgeon to monitor the administration of the therapy in real-time to ensure it reaches the target, which is crucial. The infusion must occur slowly for appropriate diffusion to the targeted structure, and this process takes the most time during the procedure. Since we administer the therapy three times on each side of the brain, it takes several hours, after which the patient wakes up. Generally, they stay for about 24 hours post-surgery and are usually discharged afterward.Patients often recover quickly due to the minimally invasive nature of the procedure and typically return to work within a few days, according to our trial experience. Now, back to you, Matt, for details on the target patient population and commercial considerations.

Yes. The reality is that there are no available disease-modifying therapies for these patients. I believe that the vast majority of eligible patients will become aware of this and will seriously consider the therapy. Our inclusion criteria mainly focus on Stage II and Stage III patients, who are typically early manifest cases. These patients have shown some symptoms and have been genetically tested and confirmed to have Huntington's disease that will definitely progress. This will be our primary focus. Now that there is a treatment option, it is difficult to imagine that most of our patients will not consider and learn about our therapy.

Our next question comes from Paul Matteis with Stifel.

We noticed this morning that you said you're going to be using propensity matched in this analysis, not propensity weighted. Can you just talk about where that comes from? Is that something that the FDA requested? And then specifically, how does that compare to the data that we saw in the last cut in 2024? If it's a different methodology than what we're going to see here? Is this going to be apples and oranges? Is the 80% number for 130 still stand? And then if you don't mind, I just have one follow-up.

Walid, do you want to go and answer that?

Thank you, Paul. We previously mentioned that during our meeting with the FDA, they expressed a preference for propensity score matching. After consulting with our external statistical experts and taking everything into account, we decided to submit a Statistical Analysis Plan that aligns with the FDA's preference, using propensity score matching as the primary endpoint. However, the agency will also receive analyses based on both propensity score matching and propensity score weighting, as indicated before. In constructing the natural history database, we evaluated various methodologies to assess the annual decline over a three-year period for patients. We found that the propensity score methodology, in its different forms, is quite robust, yielding similar estimates of decline after three years across methodologies. Therefore, I don't expect any significant differences in results whether we utilize propensity score matching or weighting. Given the FDA’s preference, we opted for propensity score matching to align more closely with their guidelines, but we will be submitting both analyses.

Okay. That's super helpful. And then, look, I know this is extraordinarily subjective and ultimately, in Huntington's, right, there's nothing. But how are you guys thinking about the bar on disease slowing in this 3-year analysis? And look, again, understanding that Huntington's doesn't have any disease-modifying treatments, I would think you'd want the data to hold up to some degree, right? Just first of all, for the best of the drug and second of all, to be confident in your regulatory alignment. So investors and analysts are trying to draw this line, how would you draw this line?

Yes, we get asked that question frequently, and it's a significant one. As you mentioned, there are currently no options for these patients. Our discussions with several key opinion leaders indicate that anything that could reduce disease progression by 25% to 30% would be quite beneficial and could potentially extend many years of quality life for these patients. From our standpoint, we hope that our data continues to demonstrate any significant slowing of disease progression, which we believe the regulatory agency will find suitable for approval and that patients will view as clinically meaningful. We are confident in our mechanism of action, and having seen the data at the two-year mark, we are optimistic that the three-year data will continue to show substantial improvement that will satisfy both patients and the FDA.

Our next question comes from Joseph Thome with TD Cowen.

I have one question and one follow-up, if I can. I guess just given the back and forth with Sarepta over the course of this week, has that changed at all your thinking on how you're approaching the launch in any way, whether you want to do a stage launch with target number of surgeons, be a little bit more cautious at the beginning or how you're thinking about that? Obviously, so many differences between disease states and age and everything like that. But I guess, are there any learnings that you've taken from the past week? And then second, do you expect there to be a minimal striatal volume on the label? I only asked this because I noticed you're initiating a fourth cohort with smaller striatal volume. So kind of just thinking if that's going to be a formal label expansion or if this would be more of just a use guideline for clinicians in the field?

Yes, I’ll start with the first part, and then you can take the second. Patient safety has always been our top priority, and nothing in the sector will change that perspective. We've always anticipated that at the time of launch, there will be centers of excellence that have the experience to perform the surgical procedure for AMT-130, and we will closely monitor this as we introduce the product. So far, we've treated 45 patients, and we believe that AMT-130 is generally safe and well tolerated. It's worth noting that AMT-130 is administered locally, which significantly reduces systemic exposure compared to gene therapies administered systemically. We have not observed any liver toxicity linked to AMT-130. Additionally, we are using an AAV5 vector that has been previously studied in systemic administration, such as in HEMGENIX, where no significant adverse events were reported. It's crucial to understand these technical differences in administration, but our commitment to patient safety will always remain our highest priority.

On the topic of striatal volume, it's important to reflect on the study's initial design from about six years ago. To ensure patient safety, we aimed for a sufficient striatal volume for administering the product. However, with our accumulated experience from over 45 intraparenchymal administrations and ongoing discussions with our neurosurgeons, we have decided to relax these criteria. We will now rely on the neurosurgeons' clinical judgment to safely access the targeted structure without a specific minimum volume requirement. To advance this evaluation, we need to include patients who were previously excluded due to lower striatal volumes in order to gather safety data. Discussions regarding whether this will be part of the label have yet to occur with the FDA and will take place later in the review process. Generating this data and assessing the safety profile will be essential for our discussions with the agency, but at this moment, it is too early to speculate or provide guidance on what the label might entail.

Our next question comes from Sushila Hernandez with Van Lanschot Kempen.

Also, just a follow-up on the fourth cohort. So what do you hope to expect to see in this patient population? And then second question, what are the next steps for AMT-260? Are you expecting to add more sites?

I suppose I'll address both questions. With the fourth cohort, our immediate goal is to ensure the safety of the procedure we can administer, confirming that our neurosurgeons and the systems in place effectively evaluate the safety of administering AMT-130 to those who might have been excluded from our trial due to lower striatal volume. The infrastructure is established, functioning well, and we are able to monitor them for efficacy. Personally, I don't anticipate any differences once we prove that AMT-130 effectively slows disease progression, and there's no reason for this to differ based on an arbitrary striatal volume cutoff. Regarding AMT-260, as Matt mentioned, we have expanded the number of active sites to 14. Since we shared the positive data from the first patient, there has been considerable activity and a significant increase in patient screenings. We're confident that we will enroll several additional patients in the second half of the year.

Our next question comes from Patrick Trucchio with H.C. Wainwright.

Congratulations on the progress. This is Luis in for Patrick. First question, are there any anticipated differences in the regulatory path to approval in Europe compared to the U.S.? Also, regarding the 130 and 160, how should we approach the planned Phase II portion in terms of patient enrollment? Will we focus on the same disease stage patients or will we also include other patient groups?

Yes. I'll take the first question, and Walid can address the second one. We have not yet met with EMA to seek scientific advice regarding the registration process moving forward. Our current focus is on the U.S. We also expect to present the 3-year data, which we believe will be important information to share with EMA during those scientific advice discussions. We anticipate having those meetings in the near term, and once we do, we will provide an update to the market.

Regarding AMT-260, it's too early to talk about the design of the Phase II study. The purpose of Phase I is to gather insights, which will inform the design of the next trial. We will initially focus on patients with the nondominant disease to establish the risk-benefit profile before expanding to those with dominant disease. A logical next step will be to consider bilateral cases. The unmet need is significant for those with dominant and bilateral conditions since they are less likely to benefit from invasive treatments like laser ablation or resection surgery. This is the direction we are considering for expansion as we progress in the program.

Our next question comes from Eliana Merle with UBS.

This is Jasmine speaking for Ellie. First, can you share what you intend to discuss and learn from the pre-BLA meeting with the FDA in Q4? Will there be an update after this meeting? Secondly, regarding the Huntington’s commercial opportunity, how many sites in the U.S. can perform the administration procedure? Based on the study enrollment criteria, can you provide an estimate of the prevalence of eligible patients in the U.S.?

Yes. I will address the last question first, and then Walid can respond to the first question. Regarding the commercial potential, there are 35,000 patients currently diagnosed with Huntington's disease. Additionally, there are likely three times that number who have the disease but have not been genetically confirmed, as there are currently no treatments for those patients. We believe the majority of diagnosed patients are in Stage II and Stage III, as diagnosis typically occurs after the onset of symptoms. Therefore, we anticipate that many thousands of patients will be eligible for the procedure. Regarding the number of sites that can perform the procedure, it's important to note that this is a standard procedure for a neurosurgeon. There are approximately 50 to 55 sites with the necessary neurosurgical expertise and imaging equipment. We believe we do not need to cover every one of these centers to reach the market. At the launch, we will implement a center of excellence strategy. Now, I'll let Walid address the first part of your question.

Yes. Thank you. So for the pre-BLA meeting, we will be meeting with the FDA, of course, and sharing with them the top line results from our Phase III data and also as well as any updates on CMC activities and discuss with them. There are some elements of the typical technical procedures and tactical questions in logistics that way, whether the data that we have is acceptable to them and whether the totality of the data would support moving forward and submitting the BLA. That's the plan. And as usual, after we have meetings with the regulators, once we receive feedback, we usually have always been communicating back to you guys the outcome of these meetings. So we will do that again.

Our next question comes from Luca Issi with RBC.

Maybe circling back on regulatory. Have you actually met or maybe had some informal conversations with Vinay Prasad? I think many investors argue that the final decision to approve this drug will ultimately come down to the very senior leadership at CBER, similar to Sarepta with Peter Mark. So I was just curious if you already had interactions with him and if you have any insights that you can share there? And then maybe second, can you just maybe clarify whether you think that the ongoing data for Huntington lead to full approval given you're chasing function? Or is it fair for us to assume that this is going to lead to accelerated approval that's still the base case scenario? And if so, if it is accelerated approval, can you maybe talk through how you're thinking about the timing of starting a confirmatory trial?

Our last interaction with the FDA took place in late April. Vinay was appointed and was in charge at that time, although he didn’t attend our meeting. I had the opportunity to attend the CEO listening tour with Dr. Makaryi and Dr. Prasad in Boston, where I met him and learned about his perspectives and approaches. He made it clear that he is very interested in evaluating additional data sets beyond randomized controlled studies. Dr. Prasad, being an epidemiologist, understands the use of external controls and synthetic cohorts to assess therapeutic benefits. Given Dr. Prasad's statements, I am confident he is open and supportive of faster accelerated pathways for cell and gene therapies addressing severe unmet needs like Huntington's disease. Regarding full approval and accelerated approval, our primary goal is to seek accelerated approval. However, the FDA has indicated that the results from the Phase I/II study can support full approval. If any additional evidence is needed for full approval, it can build on what we have already established from the Phase I/II study so far.

Our next question comes from Salveen Richter with Goldman Sachs.

This is Althea on behalf of Salveen. Could you discuss how consistent the 2.5-year data has been compared to the 2-year data we reviewed last year?

Walid?

Yes. Well, we have not conducted any formal analysis on the data since day 1 with the June 30 cutoff of 2024, which served the basis for the November 2024 meeting with the FDA. So we do not have the data that you are describing. The next analysis will be the one at June 30 cutoff of this year, which we will be communicating to you guys in September, the 3-year data cutoff.

Our next question comes from Yanan Zhu with Wells Fargo Securities.

On the topic of propensity matched versus propensity score weighted analysis methodologies, could you comment on whether the data submitted to the FDA for your SAP proposal shows similarities between those two methodologies? Additionally, does the choice of methodology impact the sample size for the external control arm?

Walid, why don't you go ahead and answer those questions?

Thanks, Matt. That's a great question. To clarify, the SAP we submitted to the agency does not include results; it includes methodologies. As we assess the natural history protocol to determine the most suitable database for comparison among ENROLL, TRACK, HD, and PREDICT-HD, we've used various propensity score methodologies to select patients that meet the baseline criteria for our trial and to observe their decline over three years using these methodologies. We have significant confidence in the methodologies, both in propensity score weighting and matching. There are different matching methods available, including optimal, greedy, and full matching. These approaches may yield different sizes for control groups, but generally, the estimates around the scores in cUHDRS or TFC show similar declines after three years, which reassures us that these methodologies will produce comparable results when we subtract the change in our data from the change in the natural history control. However, this analysis comparing our three-year data has not been completed yet. Regarding the size of the external control, propensity score weighting uses all available controls that meet the trial criteria. For ENROLL-HD, this is roughly about 3,000 participants. Matching uses a subset of those patients and comes in various types, such as simple 1:1 matching or matching one patient to multiple controls based on the size of the control group. These methodologies can yield control sizes possibly ranging from 200 to 600, depending on the type of matching used. I apologize if I went into too much detail, but it's a topic I'm passionate about. You can be assured that the estimated changes after three years are generally similar across methodologies, which gives us confidence that the results won’t be materially different when compared to the changes in our patients.

Our next question comes from Sami Corwin with William Blair.

I guess I was curious if the FDA provided any guidance as to what they're looking for with NfL for it to be used as a supportive biomarker, if they're kind of looking to see if levels return to or below baseline, and that will be sufficient or if there will need to be some specific magnitude of reduction beyond baseline shown? And then I had a follow-up. I was curious, we've seen with some other gene therapy trials, one of the key limiting factors for commercialization seems to be the availability of beds as well as hospital staff. And if you think that may be a limiting factor for the launch of AMT-130 as well.

Walid, do you want to answer the first one?

Thanks, Matt. To clarify, we have not discussed the NfL topic with the FDA. We first raised it last November, inquiring if NfL data could support our findings, and the FDA confirmed it could. However, there has been no conversation about the correlation with cUHDRS or what changes should occur from the baseline. The challenge lies in the fact that, when we presented data previously, we relied on two-year data due to available external studies showing longitudinal changes in CSF NfL levels. Unfortunately, we don't have similar data for the three-year mark, which complicates our interpretation of the upcoming data. It's tough to ascertain what constitutes a positive outcome. We understand what deterioration looks like with NfL increases, typically a 15% rise per year in patients. Our two-year data indicated that both doses were below baseline, so we are eager to see our three-year results, but the lack of an external comparator makes it difficult. Returning to your initial question, we haven't had specific discussions with the FDA regarding the expected NfL data, but we are confident that it will continue to support our primary clinical endpoint of cUHDRS.

Yes. And maybe just the second question. We don't think capacity of beds is something that is going to be a significant factor in the launch of our product. I mean, remember, this is not cell therapy where patients have to be preconditioned, spend weeks in the hospital. I've often talked about the last patient we treated earlier this year was admitted to the hospital on a Tuesday morning, completed the procedure on Tuesday and was discharged from the hospital Wednesday morning. So I don't think that's a factor that we think is going to be a material one for our launch.

Our next question comes from Kristen Kluska with Cantor Fitzgerald.

This is Rick Miller standing in for Kristen. We have a question regarding the natural history comparators that might inform the external comparator we could see in the September update. Should we expect to see ENROLL-HD comparators at that time or any other analyses?

Walid?

Thank you. During our meeting with the FDA in November, we discussed how to evaluate the various natural history databases available to us and inquired about including ENROLL-HD due to its extensive database. The FDA encouraged us to include it, and we followed through. In our follow-up meeting in April, we presented our assessments comparing natural history databases for various reasons, which I can elaborate on later. ENROLL-HD was identified as the best fit for comparison. We made that proposal, and the FDA concurred that ENROLL-HD would serve as our comparison. Therefore, the data you will see in September will compare our findings to the ENROLL-HD three-year data using propensity score matching as the primary endpoint. Additionally, we will include several sensitivity analyses, such as propensity score weighting, and submit that to the FDA.

This concludes the question-and-answer session and today's conference call. Thank you for participating. You may now disconnect.