uniQure N.V. (QURE) Q2 2025 Earnings Report, Transcript and Summary

Good day, and thank you for standing by. Welcome to the uniQure Second Quarter 2025 Earnings Conference Call. [Operator Instructions] 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 uniqure.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 one-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 2-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. Walid?

Thank you, Matt. Good morning, and good afternoon, everyone. During the second quarter of 2025, we continue 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 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. Christian?

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 first (sic) [ 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.

[Operator Instructions] 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 really one that is not complicated technically. I mean, if you speak to neurosurgeons who have done any neurosurgical administration to treat tumors or any deep brain stimulation, this is really a fairly low complexity procedure, at least that's how the neurosurgeons describe it to us. Patients usually get an MRI at a time so that we can plan the trajectory. The neurosurgeon will plan the trajectory based on the MRI because, of course, there are specific anatomical differences for each patient that the surgeon needs to take into consideration. And on the day of the surgery, the patients come in to the hospital in the morning and then they get admitted to neurosurgery and using MRI-guided registration, the -- essentially probes are inserted in the brain under direct visualization of the MRI and the infusion -- there will be drilling of a hole in the brain through which the catheter is infused is introduced. And then through direct visualization, we observe the infusion of the product, which is mixed with the contrast material that is MRI-compatible, gadolinium. And that way, the neurosurgeon can observe live as they're administering the therapy that it's actually reaching its target. That's a very important aspect in what we do. Now the infusion has to occur at a slow rate to make sure that the product diffuses appropriately to the right structure. And that actually is what consumes most of the time. So a lot of the time during the procedure, which has to be done six times because we administer three times on each side of the brain is what it takes actually most of the time. And usually, that takes a number of hours at the end of which essentially the patient wakes up. And usually, they stay like 24 hours, I believe, and then they will be discharged. And often, they tend to recover very quickly because, again, it's a very minimal -- how should I say -- very minimally invasive from the perspective of the size of the probe that are introduced and often patients within a few days, they get back to work. At least that's been our experience in our trial. And I'll go back to you, Matt, for details on the target patient population and the commercial question.

Yes. I mean I think the reality is there's nothing for these patients. There's no disease-modifying therapy. And so I believe that the overwhelming majority of patients that are eligible are going to become informed about it and I think seriously consider therapy. In terms of our inclusion criteria, we're largely looking at Stage II and Stage III patients, which are typically patients that are considered early manifest. So they have developed some form of symptomology, and they've been tested and confirmed genetically that they have Huntington's disease that will become 100% penetrant. So that's definitely going to be our focus. And I think it's going to be -- as I said, it's going to be something that now that there is at least a treatment option that it's hard to imagine that all or a majority of all our patients are going to seriously consider and become informed 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?

Yes. Thanks, Paul. Yes, we've indicated previously when we reported back after meeting with the FDA that the FDA's stated preference was for propensity score matching. We've also consulted with our external statistical experts -- and when we took all of these into consideration, we decided to submit the SAP that's aligned with the FDA preference using propensity score matching as the primary endpoint. Having said that, the agency will also continue to receive both the propensity score matching and the propensity score weighting analysis just as we stated before. Now in constructing the natural history database as we were evaluating the most appropriate natural history database to use, we had to construct the annual decline over a period of 3 years of patients using a variety of methodologies, propensity score weighting matching, exact matching, a number of these. And using the enrolled database, we found that the propensity score methodology in whichever form is quite robust, leading very similar estimate of decline after 3 years regardless of the methodologies. So to answer your question, I will not expect that the results will be materially different if we use propensity score matching propensity score reading. And considering the FDA's preference, we decided to go that route to be more aligned with them. But we will be submitting both anyway.

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. I mean I think we're asked that question a lot. It's an important question. Honestly, as you said, there's nothing for these patients. Matt mentioned that before. When we talk to a number of KOLs, what they tell us is, look, anything that is -- that would reduce the disease progression by 25% to 30% would be great. It would add potentially many years of quality of life to these patients who have nothing. But from our perspective, just like you said, we would like our data to continue to show any meaningful slowing of disease progression that will be something that the agency will consider appropriate for approval, but also the patients will find clinically meaningful. That is -- we believe in our mechanism of action. We saw the data at 2 years. We feel optimistic that the 3-year data will continue to show a meaningful improvement that will both satisfy the patients, but also the FDA.

Our next question comes fromJoseph 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. Walid, maybe I'll take the first one, you take the second one. So yes, I mean, honestly, we've always operated in a way where patient safety is our utmost priority. So it's not like anything going on in the sector is going to change that view. I think we've always thought that for AMT-130 that there are going to be at the time of launch, centers of excellence that have experience with the surgical procedure that are conducting these procedures. And we're going to be -- something that we're going to be continually monitoring as we launch the product. But at the same time, we treated 45 patients. I think we really believe that AMT-130 is generally safe and well tolerated. I'll also mention that our administration of AMT-130 is a local administration. So the systemic exposure that occurs when we administer AMT-130 is meaningfully less than a gene therapy that is systemically administered. And we have just simply not seen any liver toxicity associated with AMT-130. We're also utilizing an AAV5 vector that has been studied with systemic administration vis-a-vis HEMGENIX. And we've also not seen any significant adverse events associated with HEMGENIX or AAV5 in that context as well, even with systemic administration. So it's very important to understand these technical differences, differences with administration, but nothing is going to change our view that patient safety is always going to be at the top of our priorities.

Okay. So on the striatal volume, just maybe taking a step back, the way this came to be was as the study was initially designed some six years ago or so, out of the abundance of caution, we wanted to make sure that we have a striatal volume that would be large enough so we can safely administer the product to these patients. But over the years, and as we've accumulated a lot of experience with more than -- a total of 45 intraparenchymal administrations to date, the experience that we accumulated with our neurosurgeons and in discussions with them, we are -- we've decided that we should be relaxing these criteria and now evaluating an approach where we will use the neurosurgeons clinical judgment, whether they can reach the targeted structure safely without fixing a specific minimum volume. And in order for us to study that, we needed to include patients who have otherwise would have been excluded from our trial, those with lower striatal volume to start generating safety data with this. Now whether this will be in the label or not, those discussions have not taken place with the FDA. That would be something that would have to occur later in the review process. Of course, generating these data and depending on the outcome of the safety profile of this, those will be included in the safety update and will be part of our discussions with the agency, but it's premature right now to be able to speculate or give guidance as to what we think the label would look like.

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?

Madam, I suppose I'll take both, right? Yes -- so with the fourth cohort, the expectations in the short term is to document the safety of the procedure that we can administer this safely that the neurosurgeons that we have and the system that we have in place to be able to evaluate whether we can safely administer AMT-130 for those who would have otherwise been excluded from our trial because they would have lower striatal volume. The system is in place. It operates well and we can [indiscernible] it. And then, of course, we will be monitoring them for efficacy and so on and so forth. But I personally do not foresee where there would be any difference once we establish that the AMT-130 is actually effective in slowing disease progression. There's no reason for this to be different based on an arbitrary cutoff of striatal volume. In terms of AMT-260, yes, indeed, as Matt said, we have increased the number of sites. We now have 14 active. There's a lot of activity since we've disclosed the data on that first patient with the very positive results. It have been received very positively. We've seen a very significant uptick in screening activities, and we really do feel quite confident that we will be getting a number of 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, just thinking ahead of on any -- are there any differences? Do you expect any differences from regulatory path to approval in Europe versus the U.S. And then on the 130. And then on 160, how should we think about the planned Phase II portion look like in terms of patients? Will we plan to enroll the same disease stage patients with -- or also include [indiscernible] patients as well?

Yes. Just -- I'll maybe take the first one, Walid, maybe you can address the second one. So we have not yet met with EMA to solicit scientific advice with respect to the registrational path forward. Our focus right now is on the U.S. And of course, we'll expect to have the 3-year data presented, which we think could be also important information to furnish EMA when we have those scientific advice discussions. So we'll look to have them in the near term. And once we do, we'll make sure we provide an update to the market.

Regarding AMT-260, in terms of design of the Phase II study, it's premature to discuss that. The reality is that we do Phase I to learn from it. So that will also dictate the design of the subsequent trial. But in terms of the patient population, we start with those on the nondominant because that way you establish the risk-benefit profile and then you start branching out to those with dominant disease. I think the next natural step will be also to look at bilateral. The reality is that it's those with dominant and bilateral is where the high unmet need is because those would be unlikely to benefit from invasive therapy like ablation -- laser ablation or resection surgery. But that's kind of the thinking that we have around expansion as we advance in the program.

Our next question comes from Eliana Merle with UBS.

This is [ Jasmine ] on for Ellie. So first, can you give any color on what you plan to talk about and learn from the pre-BLA meeting with the FDA in 4Q? And will we get an update after this meeting? And then secondly, on the Huntington's commercial opportunity, how many sites in the U.S. are capable of doing the administration procedure? And based on the study enrollment criteria, can you give an estimate of the prevalence of patients that would be eligible in the U.S.?

Yes. So I'll answer the last question first, Walid, and then you can answer the first question, if that's okay. So yes, I mean, in terms of the commercial potential, there's 35,000 patients that are currently diagnosed with Huntington's disease. And then there's probably 3x as many people that have Huntington's disease, but have not been genetically confirmed because there's obviously nothing for those patients. Our view is that there's going to be -- we'll provide obviously more detail on this, but the overwhelming majority of the patients that are diagnosed have Stage II and Stage III because typically, the diagnosis of Huntington's disease happens once their symptom onset. So there's going to be many thousands of patients that, in our view, are going to be eligible for the procedure. Now the last part of this was the number of sites that are capable of doing the procedure. Just to be very clear, this is not a novel procedure. This is a very standard procedure for a neurosurgeon. There's probably somewhere between 50 and 55 sites that have the neurosurgical expertise and the imaging equipment to be able to do this procedure. We don't even think we need to be in every one of those centers to address the market. And certainly, at launch, there's going to be a center of excellence strategy. And then I'll hand it over to Walid to answer 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?

Yes. So our last interaction with the FDA occurred in late April. Vinay was appointed. He didn't attend our meeting, but he was in charge at that point in time. I have been -- I was fortunate enough to attend the CEO listening tour with Dr. Makaryi and Dr. Prasad in Boston. So I had a chance to meet with him and to understand his perspectives and approaches. What he made very clear is that he is very interested in willing to evaluate additional data sets other than randomized controlled studies. Dr. Prasad is an epidemiologist by training, and he deeply understands the use of external controls and synthetic cohorts in order to evaluate therapeutic benefit. So I'm confident that given the statements that Dr. Prasad has made, that he's open and supportive of faster accelerated pathways for cell and gene therapies that are addressing severe unmet needs like Huntington's disease. Just in terms of the full approval, accelerated approval, our base case, of course, and what we're going to be seeking is accelerated approval. Having said that, the FDA did make it very clear to us that the Phase I/II study results can be used and leveraged to support full approval. So to the extent that additional evidence is going to be required for confirmation associated with full approval, and that data can be incremental to what we already have established and generated from the Phase I/II study thus far.

Our next question comes from Salveen Richter with Goldman Sachs.

This is [ Althea ] on for Salveen. Just another on AMT-130 ahead of the September update. Could you just speak to how consistent the 2.5-year data has been versus the 2-year data we saw 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.

[Operator Instructions] Our next question comes from Yanan Zhu with Wells Fargo Securities.

On the topic of propensity matched versus propensity score weighted analysis methodologies. I was wondering in the data you have submitted to FDA for your SAP proposal, could you comment on whether those two methodologies, the data look similar with each other? And I also -- I'm wondering whether the approach of which one to use affects the sample size that you can use for the external control arm.

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

Thanks, Matt. Yes, very good question. So to be clear, the SAP that we submitted to the agency does not include the results, right? It includes the methodologies. What I was trying to describe earlier is in our -- as we are evaluating the natural history protocol to evaluate which natural history database, ENROLL, TRACK, HD, PREDICT-HD would be most appropriate to be compared to, we've employed various propensity score methodologies to essentially select the patients that meet the baseline criteria for our subjects in our trial and observe what is the decline after three years using these various methodologies. And what we -- what gives us a lot of confidence both in the methodology itself, the propensity score methodology is the fact that whether we use propensity score weighting or matching. And by the way, there are multiple ways to match. You can have optimal matching, you can have greedy matching, full matching. I can go on and on, and we can go into a lot of details maybe offline if you want to. Those will generate various different levels of size of control. But at the end, the estimate around the score in cUHDRS or in TFC that the decline after three years tend to be generally very similar and not materially different. And that's what gives us confidence that these methodologies will yield similar results once you compare our data and subtract the 3-year change in our data from the change in the natural history control. But that analysis comparing our 3-year data to [Technical Difficulty] has not been done yet. So I need to be very clear on that. In terms of the size of the external control, yes, of course. The propensity score weighting is the one that utilizes essentially all of the controls that you have available that meet the criteria for your trial. In the case of ENROLL-HD, it's somewhere around 3,000. That's a propensity score weighting and it uses a variety of methodology to be able to allow to include everybody, which contributes to a varying degree based on how closely they resemble your sample. Matching uses a proportion of those patients. And again, there are different types of matching. You can have a very simple matching 1:1. You have matching one of your patients to maybe 20, 30 of the control depending on how large the control group is. And there are many ways that you can tailor this optimal matching or full matching and so on and so forth. And those could lead somewhere around maybe 200, 300 if you want to do 20 or 30 full, your patients in your trial to 600 if you want to do full matching and those are the types of different types of methodologies. I apologize, I might have gone a bit too much in the details, but I like that topic so much that I can speak on it for a long time. But you should rest assured that the estimate of change after three years tend to be fairly similar regardless of the method you use, and that gives us very good confidence that the results will not be materially different when we compare them to the change in our patients.

Our next question comes from Sami Corwin with William Blair.

I guess I was curious if 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. Yes. So to be clear, the NfL topic has not been a topic of discussion with the agency. We were the one who brought it up back in November of last year when we asked the question actually whether NfL data could be supportive. And the FDA said, yes, the NfL data could be supportive. But there's been no discussion at all about whether there should be any correlation with the cUHDRS or what change should be from baseline or anything. The difficulty with this is that -- and I think it's a relevant question as well, relevant to the update that we're going to have at three years that when we presented data to you last time, we used 2-year data because there are data available from an external study looking at longitudinal 2-year change from baseline in CSF NfL levels. Unfortunately, we don't know such data exists for the 3 years time point, which will limit interpretation of our upcoming data. So it becomes a little bit difficult to figure out, okay, so what does good look like? We know what bad looks like in NfL when you have increases and so on and so forth. We know that patients usually go up by about 15% a year. And clearly, our data at two years show that we -- both doses were below baseline. So we were looking forward to see what our 3-year data would look like, but it would be a bit difficult because we don't have an external comparator. But going back to your original question, there has been no specific discussions with the FDA about what the NfL data should look like. But we were, I guess, our expectations are, and we're confident in our data that the NfL data 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, [ immune-ablated ], 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 on for Kristen. Just one from us. Can you kind of walk us through the natural history comparators that could sort of inform the external comparator that we could see in the September update? And how should -- and should we be expecting to see ENROLL-HD comparators at that time or any other analyses?

Walid?

Thank you. Yes. So as part of our meeting with the FDA back in November, we were -- we discussed with the FDA how to proceed to evaluate the various natural history databases that we could use, and we asked whether we should include ENROLL-HD because it's -- has a very large database. And the FDA encouraged us to do so, which we did. And the follow-up meeting that we had with them back in April, we walked them through all of our assessments comparing the natural history for a variety of reasons, which I could perhaps take offline and walk you through this. The ENROLL-HD was deemed the one that's the best fit for us to compare to. We made that proposal and the FDA agreed with us that ENROLL-HD will be the comparison. So the data that you will see in September will be a comparison of our data to the ENROLL-HD 3-year data using propensity score matching as a primary endpoint. As again, as I said before, we will be including a number of other sensitivity analyses, including propensity score weighting as well and submit to the FDA.

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