uniQure N.V. Aktie

Thank you for standing by. My name is Liz, and I'll be your conference operator today. At this time, I would like to welcome everyone to the uniQure First Quarter 2026 Earnings Call.

[Operator Instructions] I would now like to turn the call over to Chiara Russo, Senior Director of Investor Relations. Please go ahead.

Good morning, and thank you for joining us for uniQure's First Quarter of 2026 Earnings Call.

Earlier this morning, uniQure released its financial results for the first quarter of 2026, 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 today.

Joining me on the call this morning are Matt Kapusta, Chief Executive Officer; Dr. Walid Abi-Saab, Chief Medical Officer; Kylie O'Keefe, Chief Customer and Strategy Officer; and Christian Klemt, Chief Financial Officer. After our formal remarks, we'll open the call up 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 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. Good morning, and thank you for joining us today.

During the first quarter of 2026, uniQure remained focused on advancing AMT-130 to patients, while continuing to execute across our broader pipeline. Following our Type A meeting with the FDA in January, we acknowledge the agency's feedback and remain focused on engaging constructively defined feasible path forward. We have since been granted a Type B meeting with the FDA later this quarter, where we plan to discuss our proposed statistical analysis plan for the 4-year data expected in the third quarter and key elements of a new clinical study.

In parallel, we are progressing toward a potential regulatory submission in the United Kingdom. Following a successful pre-submission meeting with the U.K. MHRA, we are preparing to submit a marketing authorization application in the third quarter based on the 3-year data. Taken together, these efforts reflect our commitment to advancing AMT-130 globally with urgency.

Beyond Huntington's disease, we continue to make progress across our pipeline. For AMT-260 in refractory mesial temporal lobe epilepsy, enrollment in our Phase I/IIa study is on track, and we expect to report data from the first cohort in the second quarter.

In Fabry disease, updated data from our AMT-191 program showed sustained and dose-dependent increases in alpha-GalA activity, stable lyso-Gb3 levels and the discontinuation of enzyme replacement therapy in 11 patients, supporting the potential of AMT-191 as a meaningful treatment option.

Regarding AMT-162 in SOD1-ALS, we announced our decision to discontinue development following a comprehensive review of the available data, reflecting our disciplined data-driven approach to capital allocation.

Looking ahead, key milestones include our Type B FDA meeting later in the second quarter, clinical update for AMT-260 in the second quarter, 4-year AMT-130 data analysis in the third quarter and the planned MAA submission for AMT-130 in the U.K. in the third quarter. We believe these milestones represent important opportunities to advance our programs and demonstrate the potential of our platform.

In summary, we are executing with focus, advancing our lead program through important regulatory interactions and managing our strong balance sheet to support our long-term strategy. We remain committed to delivering on the promise of gene therapy for patients and creating durable value for shareholders.

With that, I'll turn the call over to Walid to provide more information on the pipeline.

Thank you, Matt. Good morning and good afternoon, everyone.

I'll start with AMT-130 in Huntington's disease. As Matt noted, we continue to engage with the FDA and have a Type B meeting scheduled for later in the second quarter. Our goal is to work through the key design considerations for a potential new clinical study, addressing the agency's concern for an adequate and well-controlled trial while also ensuring the approach is practical, feasible and appropriate in a rare, slow progressing neurodegenerative disease. Huntington's disease is supported by one of the most robust natural history resources in rare diseases. Enroll-HD includes more than 30,000 participants and provides high-quality, longitudinal clinical data collected over many years through the extraordinary efforts of the Huntington's disease community.

We believe this body of real-world evidence can inform efficient and statistically rigorous study designs, and it should be considered as we evaluate with the agency the appropriate design of an adequate and well-controlled study for a onetime administered therapy. Additionally, we plan to solicit feedback on our statistical analysis plan for the 4-year Phase I/II study data expected in the third quarter.

Turning now to our ex-U.S. regulatory efforts, we held a successful pre-submission meeting with the U.K. MHRA earlier this quarter. Based on this interaction, we plan to submit the marketing authorization application for AMT-130 in the third quarter of this year, supported by our 3-year clinical data analysis. This is an exciting potential milestone for uniQure and the Huntington's disease community as we look to bring AMT-130 to patients around the world. We have also started engaging with regulatory authorities in Europe and are evaluating additional opportunities internationally to potentially bring AMT-130 to patients as quickly and efficiently as possible. Finally, we expect a manuscript for our complete 3-year analysis to be submitted in a peer-reviewed medical journal this year.

Moving on to the rest of our clinical stage pipeline, starting with AMT-260 for temporal lobe epilepsy. We continue to collect data on the fully enrolled first dose cohort, which included those with both nondominant and dominant hemisphere MTLE, and we plan to provide an update later in the second quarter on all 6 treated patients with at least 6 months of safety, tolerability and seizure frequency outcomes. These are expected to be presented at the Epilepsy Foundation Pipeline Conference in Leesburg, Virginia in June of this year.

Turning to AMT-191 for the treatment of Fabry disease. In February, we reported preliminary safety and exploratory efficacy data from 11 patients in the ongoing Phase I/II trial of AMT-191. As of January 8 of this year, the study cutoff date, all 11 patients across 3 dose cohorts demonstrated elevated alpha-GalA enzyme activity that was dose-dependent and durable over the observed follow-up period, ranging from more than 1 year in the longest follow-up patient at the high dose to 4 months in a patient treated at the mid-dose. Stable plasma lyso-Gb3 levels were maintained post dose across all dose cohorts regardless of enzyme replacement therapy status. As of February 18 of this year, all 11 dose patients have discontinued ERT.

On safety, as previously reported, 2 patients in the mid-dose cohort experienced asymptomatic Grade 3 liver enzyme elevations. These events met protocol-defined criteria for potential dose-limiting toxicity and were reviewed and confirmed as such by the independent data monitoring committee. Accordingly, dosing at the mid-dose and high doses were paused per protocol. To-date, no new AMT-191 -related serious adverse events have been observed. The program continues to demonstrate a manageable safety profile.

Lastly, there's AMT-162 for SOD1-ALS. As previously disclosed, the Phase I/II EPISOD1 trial of AMT-162 for SOD1-ALS has been on voluntary recruitment pause based on an independent data monitoring committee recommendation after a serious adverse event of dorsal root ganglia toxicity in one patient in the second cohort. This event was determined to be related to AMT-162.

Following review of the preliminary efficacy and safety data generated from EPISOD1, the decision was made to discontinue development of AMT-162. We will continue to collect follow-up safety from the 5 patients dosed, consistent with applicable safety and regulatory requirements.

Now I will turn the call over to Kylie, to discuss our ongoing work with the HD community and our ex-U.S. commercial efforts. Kylie?

Thank you, Walid. Before I turn to AMT-130, I want to take a moment to acknowledge the Huntington's disease community, the patients, the families and the caregivers who live with this disease every day, and the researchers, clinicians and advocates who have spent decades refusing to accept the status quo. Their resilience and their trust in us is not something we take lightly. It is what holds us accountable to the progress we are here to discuss today. We remain committed to continuing the efforts in the U.S. and globally to advance AMT-130 as responsibly and efficiently as possible.

We are encouraged by the path ahead in the U.K. following our recent engagement with the MHRA and are advancing commercial preparations across several key geographies based on this progress. Our market preparation efforts have centered on 3 near-term priorities. First, ensuring treatment center capacity and readiness and working closely with the multidisciplinary care teams at the centers of excellence that will be critical to success. Secondly, in parallel, ongoing patient engagement is critical to maintain continuity across the care journey, supporting genetic testing and referral pathways. Thirdly, market access readiness is advancing, including proactive payer engagement and development of a clear evidence-based value proposition. This is underpinned by robust health economics and outcomes research, generating data to demonstrate long-term clinical benefit and broader societal impact to support pricing, access and adoption.

We believe the U.K. unlocks a meaningful opportunity for uniQure to deliver a potentially transformational therapy to patients with HD, a community with no approved disease-modifying therapies today. There are between 7,000 to 8,000 patients living with HD in the U.K., with approximately 30,000 at risk. The U.K. has world-renowned neurosurgical capabilities and several leading HD centers of excellence, which we believe will be instrumental partners in making this potential therapy available to patients.

Importantly, an MHRA approval will not only enable access in the U.K., we believe it could also enable early access or named patient programs in other geographies, including the Gulf countries in the Middle East, Latin America, Commonwealth of Independent States and Central and Eastern Europe, enabling access to therapies ahead of formal reimbursement decisions, offering hope to patients and families, while local regulatory and broader market access processes continue. We believe this disciplined approach helps drive building a scalable global strategy to maximize the long-term value of our program for all stakeholders.

Moving to AMT-260, in mesial temporal lobe epilepsy, where many patients remain completely refractory to antiseizure medications, cycling through treatment after treatment with no meaningful seizure control. For those who do progress to surgical intervention, the options currently available are at its core, a tissue destructive procedure. We believe being able to deliver a precisely targeted gene therapy in MTLE without destroying healthy tissue may represent a new treatment paradigm.

Lastly on AMT-191. In Fabry disease patients, they face a relentless multisystem disease burden, all driven by a single genetic defect in GLA. The current standard of care, which is biweekly enzyme replacement therapy requires lifelong intravenous infusions that are logistically burdensome and has an occurrence of high rates of neutralizing antibody development, which limits efficacy over time. A single administration therapy correcting the enzymatic deficiency at the genetic level in Fabry, we believe has the potential to meet this unmet need.

Across our customer-facing functions, we're focused on delivering strong execution while being disciplined in scaling the infrastructure needed to support commercial activities with a focus on strengthening center of excellence relationships, refining the patient and provider journey and continuing to build the evidence required for access and adoption.

As we continue our efforts in the U.S., we're also energized by the potential opportunity ahead in the U.K. and other geographies, and are advancing towards an expected MAA submission and the possibility of bringing the first potential disease-modifying treatment for this devastating disease.

Now I'll turn the call over to Christian for a financial update. Christian?

Thank you, Kylie. I'll be sharing the financial highlights of the first quarter of 2026. Please refer to the earnings press release issued this morning and our quarterly filing with the SEC for additional details.

Revenue for the 3 months ended March 31, 2026, was $3.6 million compared to $1.6 million in the same period 2025. The increase of $2 million is due to an increase in license revenue.

Research and development expenses were $29.2 million for the 3 months ended March 31, 2026, compared to $36.1 million during the same period in 2025. The $6.9 million decrease was driven by a $2.6 million decrease in fair value of contingent consideration, a $1.2 million decrease in costs related to external program spend, a $1.6 million decrease in employee and contractor-related expenses, including share-based compensation, and a $1.6 million decrease in facilities and other expenses compared to the prior period.

Selling, general and administrative expenses were $20.1 million for the 3 months ended March 31, 2026, compared to $10.9 million during the same period in 2025. The $9.2 million increase was primarily related to a $5.5 million increase in employee and contractor-related expenses, including share-based compensation, mainly as a result of employees recruited in 2025 to support commercial planning for AMT-130, $1.8 million increase in professional fees, $0.6 million increase in intellectual property fees, and $1.3 million increase in information technology costs and other expenses compared to the prior period.

Cash, cash equivalents and investment securities totaled $586.6 million as of March 31, 2026, compared to $622.5 million as of December 31, 2025. We believe that uniQure continues to be well positioned to execute on its clinical and operational priorities through 2026. We expect that cash, cash equivalents and investment securities will be sufficient to fund operations into the second half of 2029.

I'll now turn the call back over to Matt.

Thank you, Christian. To summarize, our top priority remains continued engagement in the U.S. and internationally to advance a clear and viable path forward for AMT-130. In parallel, we are executing across our pipeline and maintaining a strong focus on capital allocation to support long-term value creation. With several important milestones ahead in '26, we look forward to updating you on our progress.

With that, we will open the call to take questions from our research analysts. Operator, please proceed.

[Operator Instructions] Your first question comes from the line of Moritz Reiterer with Guggenheim Securities.

This is Moritz on for Debjit. I have 2. The first one is around AMT-260. And could you just give a little bit more sort of an overview of what the expectations are for the upcoming data set in June?

I have a follow-on question about AMT-130, namely around the competitor PTC data that was published last week, we noticed that their natural history control was an order of magnitude smaller than what you used for AMT-130. So just trying to understand a little bit better what was the rationale for choosing such a large control cohort? And what are the potential upsides and downsides of that choice?

So on AMT-260, we are conducting a Phase I/II trial. As you know, the primary objective of that trial is to evaluate safety, of course, we're looking at efficacy endpoints, particularly seizure frequencies as measured by diary, in addition to a number of other endpoints. So what we're looking is to identify a dose that's safe and well tolerated based on these data. And we expect to see a signal on reduction of seizure frequency. We're targeting at this stage, perhaps a 50% reduction in seizure frequency could be a good signal for us to follow-up in subsequent well-controlled studies.

In terms of AMT-130, it's really very difficult to essentially compare or interpret results from competitors. We're not in a position to do that. We don't quite know the details of the analysis plan they've done in using Enroll-HD and why the control numbers are low. So I will withhold any interpretation on these data.

Your next question comes from the line of Paul Matteis with Stifel.

This is [ Emily ] on for Paul. We wanted to ask a little bit more about the U.K. market dynamics. And maybe if you could share any color. And another question would be like of the 7,000 to 8,000 patients in the U.K., how many of those are treated at centers of excellence currently?

So maybe starting with the second part of the question. The vast majority of the patients that we alluded to, the 7,000 to 8,000 are treated at specialized centers. There is a collection of those patients that are managed by the specialized centers around the U.K. So that is the vast majority.

Maybe just some other color from that perspective around U.K. market dynamics, I think, once we are able to secure MHRA approval, we obviously work with NICE and a number of the access bodies, including NHS England, to work through managed access agreements to be able to bring the product to market. So that's work that has already started and is ongoing and we'll continue through a potential MHRA approval to bring this product to market.

Your next question comes from the line of Joe Schwartz with Leerink Partners.

Congrats on your progress and persistence. I'd like to ask a question each about your ex-U.S. and U.S. aspirations. First, how aligned do you expect the U.K. and broader EMA review processes to be? And what is your assessment of your ability to receive adequate reimbursement in these territories outside the U.S., which may be more constructive on approval at this point?

Second, what specific feedback from the FDA are you hoping to clarify or potentially challenge in your Type B meeting? How are you preparing your briefing package to make your case?

Do you want to start with the first one, Kylie?

Yes, absolutely. So just talking through ability to secure reimbursement in markets outside of the U.S. So I think the aim is to start with named patient and early access programs that give us an ability to be able to secure patients very rapidly post approval. We will also progress with formal pricing and reimbursement negotiations.

I think one of the things that we're definitely seeing is the U.K., in particular, is a market at an inflection point. They've really tried to look at how to bring advanced therapies to market, and they've tried to shift their thinking, for example, bringing in the highly specialized technology route and other aspects of raising the QALYs and ISA considerations. And so this is really trying to ensure that they're bringing advanced therapies to patients in the U.K. and not being left behind.

Outside of the U.K., we'll be taking a very specialized approach. We'll be assessing markets on a market-by-market basis, looking at funding pathways, looking at access to therapies and ensuring we're doing this in a step-by-step approach rather than more of a simultaneous approach. And so that will be taking reimbursement as a primary consideration into focus.

Walid, I'll take the second question. Thanks, Joe. So in terms of the meeting with the FDA, we view this as a technical meeting. Our hope is to gain some clarity on key design elements of an additional new study to evaluate the efficacy of AMT-130 and also to get feedback on the statistical analysis plan for the 4-year data.

Next question comes from the line of Salveen Richter with Goldman Sachs.

Can you speak to your base case assumption for the Phase III study design of AMT-130 and whether Novartis' recent study is a precedent here? And then separately, just frame expectations for the 4-year data in the third quarter and what sensitivity analyses these might include.

So in terms of design elements of a new study to evaluate clinical efficacy, we can't really go into details because it depends on the discussions with the agency. We genuinely want to have a constructive discussion with the agency. Our position is that in this rare slowly progressing disease, where we have a onetime therapy administration and when there is a treasure trove of natural history data that we could use, we should be looking at potential flexibility in trying to utilize these resources to minimize the burden on the patient and make these studies rigorous, but still feasible. And then that is truly our goal in the meeting.

Regarding the analysis of the 4-year data, in broad terms, they're actually going to be generally similar to the 3-year analysis with the addition, of course, of 1 more year of follow-up, which will bring the total number of patients at 4 years to 12 at the high dose and 12 at the low dose. In addition, there will be 3 patients at the high dose, who would have completed 3 years, so making 15 patients who have reached a 3-year analysis at the high dose.

We are discussing with the agency whether there could be additional potential analyses that they would want to see in order to increase the level of confidence. Our expectations are that with time, treatment effects will become more and more evident and the absolute difference between those treated with AMT-130, particularly on the high dose, is going to become much more evident when compared to well-matched external controls.

Your next question comes from the line of Yanan Zhu with Wells Fargo.

This is [ Kwan ] on for Yanan. So also on Huntington's disease, you mentioned in the Type meeting, you talked about design of the new study and 4-year data statistical plan. Can you talk about, will you also cover the potential of an alternative regulatory path? And is there still a possibility to file without starting a new study?

The purpose of the meeting, as I said previously, is technical in nature to discuss elements of the design for a new additional study to evaluate the efficacy and also the 4-year analysis. We do not intend to have a specific discussion about a regulatory path to filing at this point.

Your next question comes from the line of Peyton Bohnsack with TD Cowen.

This is Peyton on for Joe. I guess kind of looking at the U.K. commercial opportunity, can you talk about the number of centers that you've identified in the U.K. that are equipped to do the MRI-guided stereotactic surgery? Are there any planned changes to the surgical procedure in a potential commercial product? Specifically, any changes in the length of the time of the procedure? And does anything need to be done to validate or approve the cannula? That'd be it.

I'll unpack. There's a few elements to answer there. Maybe just starting with the number of specialized centers in the U.K., I think, probably you do know this, but we had a number of centers that were incorporated into our European clinical trial, so there are a number of centers that have already treated AMT-130 patients. But this is just a small handful of the number of centers that exist in the U.K. that have neurosurgical stereotactic capabilities. And so we have already identified a number of those and have engaged with them to start to really plan the market in the U.K.

The second aspect of the question was related to changes in the procedure. So from that perspective, we don't anticipate any changes in the procedure transitioning from a clinical program into a commercial program. We expect it to be consistent with what was done in the clinical trials. And so from that perspective, no changes there.

The third part of the question was whether or not we see any challenges in getting the cannula into the U.K. -- and no challenges there. The cannula has been shipped to a number of different countries around the world and the U.K. is no issue there, including through clinical trials and through commercial aspects. We are not the only company that utilizes the cannula. And so there are already commercial companies that are utilizing the cannula in the U.K.

Your next question comes from the line of Luca Issi with RBC Capital Markets.

Maybe Matt or Walid, kind of bigger picture, can you just maybe compare and contrast the Type A meeting you had in January with the FDA versus the pre-submission meeting you had with the MHRA in the U.K. Again, I appreciate that these are different jurisdictions and different regulatory bodies. But why did the U.K. found your data persuasive versus the FDA did not? Is that because they're more willing to compare single-arm data with like historical control? Is that because they have better appreciation for the unmet medical need? What's driving that dichotomy there? I think any color there much appreciated.

Yes, Luca, it's obviously hard to get into the mind's eye of each of the regulatory authorities. But we've been saying this now for 6-plus months, that we strongly believe in the strength of our data. We've achieved 75% slowing of disease with high statistical significance out to 3 years on the composite UHDRS. We achieved statistical significance in a slowing of disease on total functional capacity. We see favorable trends across other clinical measures, we see neurofilament light below baseline and there's a tremendous unmet need here where there's no disease-modifying treatments for these patients. I think based on the discussion that we had with the U.K., I think they recognized these elements.

Walid, do you want to chime in?

I just want to chime in one piece. I think one of the things that also might be a bit different in the U.K. now is that focus on rare disease has been a policy for the current government. So I think this actually meets with a certain agreement within the overall policy of the government there and actually allows for more flexibility to be afforded in rare diseases like this. We hope that this could also be used in other countries as well, of course, in the U.S., and we continue to work constructively with the FDA to achieve that. At one point, there were more openness and flexibility with us. More recently, it's been a bit more difficult. But again, we continue to work with the FDA. And at the end of the day, the data that we're going to be generating will help hopefully to get us to where we need to go.

Your next question comes from the line of Ellie Merle with Barclays.

Can you elaborate a bit on the range of outcomes for what we could learn from the Part B meeting?

Then a second question. Do you plan to request another meeting with the FDA after the 4-year data to pursue accelerated approval again based on the 4-year data?

I think at this juncture, just with the Type B meeting schedule, we won't speculate on the range of meetings and the range of outcomes. And then based on the discussion that we have, we'll ascertain whether there is a need for another follow-up meeting with the FDA, and we'll certainly provide that as part of our update once we receive the minutes.

Your next question comes from the line of Suzanne van Voorthuizen with Kempen.

For the ex-U.S. strategy, can you elaborate on your current thinking on the commercial launch in Europe beyond the U.K., assuming you're also targeting a potential EU approval? For example, for the sequential rollout, which countries are most likely first to target? And what are dynamics that you see that are similar or different from the U.S., which we should consider when launching 130 for Huntington's?

Then a small one on your cash runway guidance into H2 '29. Can you remind us what parts of your business plan are or are not included in that guidance?

So this is Walid. I'll start with the regulatory strategy beyond the U.K. and U.S. So we are evaluating and we've actually started the process of engaging a number of regulatory authorities, including Europe and outside the U.S. We expect to have an update for you in the second half of the year. That's as far as regulatory.

I'll turn it over to Kylie to talk about the commercial strategy.

As mentioned, from a commercial strategy point of view, we're going to be taking each step as a sort of assessment of country by country. So we're looking at countries that have patient access and early access programs well established, which is a number of countries in Europe that would allow us to unlock treating patients early on in the process as we progress with formal pricing and reimbursement. Obviously, Germany has a well-established pathway with regards to free pricing in the first 6 months for rare disease products. France also has the ATU program or the AP program, which it has now evolved into. And there's a number of other countries, Italy, for example, that has named patient in early access.

So we would look at this on a country-by-country basis and assess the funding pathways and the ability to bring this therapy to patients ahead of formal pricing and reimbursement and take the steps from there.

Yes. Quickly on the runway, it's going to be same assumption as for a couple of Qs that we complete the ongoing clinical trials for TLE, HD and Fabry. To get into the second half of '29 does not allow us to simultaneously take forward all the candidates in kind of the most expedited manner. So there will need to be prioritization decisions if we want to maintain the runway.

Your next question comes from the line of Patrick Trucchio with H.C. Wainwright.

My questions are on AMT-191. I'm wondering what the gating criteria are to resume AMT-191 dosing or select a go-forward dose after the mid-dose DLT. Specifically, I'm wondering what IDMC regulatory steroid prophylaxis or other follow-up criteria are necessary to move forward? And separately, now that we have all 11 AMT-191 patients off ERT, I'm wondering what duration and organ level follow-up are needed to define the next development step.

Per protocol, any time we see a Grade 3 adverse event, that could be potentially a DLT. So per protocol, we stopped dosing. There has been very close collaboration with the IDMC, informing the FDA. The patients are followed very closely and treated with steroid as well as steroid sparing therapies. And one patient fully recovered. The other one is really within a very close to fully recovering. So I'm very pleased with the process. Once that is done, we will submit these data to the FDA for the review and discuss resuming dosing at 1 of these 2 doses. In the meantime, the study is ongoing, and we continue to dose with our low dose of 2x10^13, and we continue to follow the patients.

So at the end of the day, this is a Phase I/II trial. And our goal in this trial is to be able to identify a dose that's safe and well tolerated. We're going to be looking at the totality of the data. If we see these changes in LFTs as we see, as we have observed to what degree we can monitor them and manage them with steroids to what degree they're associated with any other types of data to suggest that there might be autoimmune in nature. We don't see that yet. So at the end of the day, we will pick a dose that is safe and well tolerated based on these data and that will generate a significant increase in alpha-Gal activity, especially when these patients are off steroids.

We will be engaging with the FDA in the second half of the year, I should say, to better understand any potential pathway forward, specifically essentially a pathway that would be similar to what was afforded to Sangamo. And based on these, we will be then making a decision about next steps with this program in the next 6 to 12 months.

Your next question comes from the line of Kristen Kluska with Cantor.

On AMT-130, of the 7,000 to 8,000 patients diagnosed today, what percent or number of them do you think would be potentially eligible for therapy at launch? And then based on your time lines for submission and the fact that they really seem to be pressing with this policy for rare diseases, when would you ultimately expect an approval decision?

I can take the first part of the question, and then Walid can take the second one.

From a percent eligible perspective, I think it's a little bit premature for us to put a point on a specific percentage. I think we're working through that at the moment with an understanding of what we think the label could look like because, obviously, that will have a key consideration of percent eligible. But I think as we sort of understand the market in more detail, we'll be able to share more specifics but more to come on that.

So in terms of timing, as you know, for the MHRA, the timing is not as clear as with the FDA in terms of PDUFA date. And that depends because it's variable, that depends on how many rounds of questions you have and the clock stop, which is the time that it will take us to answer those questions. So that also will depend on how many questions, how complicated there are to get answers to.

We will be working, of course, very diligently to move this as quickly as possible. But it's very difficult to give you an exact timing because it all depends on the number, how many rounds of questions as I mentioned.

Your next question comes from the line of Daniil Gataulin with Chardan.

A quick on 130 in the U.K. At launch, if it's approved, what would you expect the capacity to be with all the centers that can administer the procedure?

The second question is, are there countries that recognize MHRA decision for their approval? And how many patients would that potentially add?

So on the first part, which is capacity in the U.K., sorry -- capacity in the U.K., I think, there's a number of centers, as I mentioned earlier, that have the capabilities to be able to do this treatment procedure. So I think it depends on the process that we'll be ensuing from an access point of view. There is the Innovative Medicines Fund that allows you to secure early access and early revenue, and that would unlock some patients. And then obviously, we would need to move through the process with NICE and ultimately NHS England to secure a formal recommendation and managed access agreement to be able to open up a larger potential pool.

So in the near term, I think the capacity is very much where it needs to be. In the longer run, we'll be able to take a deeper look at what does that capacity look like. I think similarly to the U.S., the team is starting to look at the capacity and the pull-through there. And I think from where we stand today, it looks like in the near term, we're in a good position, and then we'll work through what else is needed over the longer run.

From countries outside of the U.K. that reference an MHRA approval, there is a number of countries that do that open up named patient and early access programs. A couple just to highlight from the Gulf countries in the Middle East, Saudi Arabia, UAE as an example, there's a number of countries that we're able to move forward in Latin America, in Commonwealth of Independent States and then also in non-EU, Central and Eastern Europe. So that's just to give you an example of some of the markets that are unlocked through a potential MHRA approval.

[Operator Instructions] Your next question comes from the line of Rudy Li with Wolfe Research.

I think you mentioned that you're not planning to discuss filing at the upcoming Type B meeting. Is it fair to say that the base case scenario will be running a new pivotal trial to support filing?

Secondly, what do you think is the biggest pushback from FDA regarding natural history control? Because I'm still confused why they would require a sham-controlled Phase III instead of a single-arm pivotal trial.

Yes. I think what we know is that -- we have the guidance that we got from the FDA, right, previously, which is their recommendation that we conduct another study. And that's why, obviously, we want to go into the FDA and have a discussion around those design elements.

As I say, this upcoming meeting is an interaction with the review team. And so there are tactical and technical matters that we want to get through that include not only what I just described, but also a review of the 4-year statistical analysis plan. So we're going to continue to follow these patients. And as I said, we believe strongly in the therapeutic potential of AMT-130 and the potential that the data will continue to demonstrate that. I think once we have the data, then we can engage with the FDA and discuss what is the appropriate path forward.

In terms of your question around natural history, again, that's a question for the FDA. I think what we would say is that there's probably no indication that I'm aware of in the rare disease space that has as much natural history data available to leverage. And on top of that, clinical-grade quality, longitudinal data. So to the extent that single-arm studies and external control comparisons are acceptable for intractable diseases with high unmet need, we think there is a strong rationale, particularly given the slow progressing nature of HD, the onetime administrative nature of AMT-130 and the surgical delivery of the product. So I think that's what we would say in that regard.

There are no further questions at this time. Ladies and gentlemen, that concludes today's call. Thank you all for joining. You may now disconnect.

Thank you for standing by. My name is Kate, and I will be your conference operator today. At this time, I would like to welcome everyone to the uniQure Fourth Quarter and Year-End 2025 Earnings Call. [Operator Instructions] I would now like to turn the call over to Chiara Russo, Senior Director of Investor Relations. Please go ahead.

Good morning. and thank you for joining us for uniQure's year-end 2025 earnings call. Earlier this morning, uniQure released its financial results for the fourth quarter and year-end of 2025, and our press release is available on the Investors and Media section of our website at uniqure.com. Our 10-K was also filed with the SEC earlier this morning. Joining me on the call this morning are Matt Kapusta, Chief Executive Officer; Dr. Walid Abi-Saab, Chief Medical Officer; Kylie O'Keefe, Chief Customer and Strategy Officer; and Christian Klemt, Chief Financial Officer.

After our formal remarks, we'll 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 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. Good morning, everyone, and thank you for joining us on our year-end 2025 conference call. For more than 25 years, uniQure has been driven by a singular mission to deliver transformative medicines to patients living with rare genetic and other debilitating diseases. Along that journey, we have successfully developed 2 approved gene therapies. For the past decade, we have been deeply focused on advancing AMT-130, a novel one-time administered treatment designed to address the underlying cause for Huntington's disease. In September of last year, we reported groundbreaking 3-year data from our Phase I/II study of AMT-130, which were widely embraced by the HD community.

These data demonstrated a statistically significant 75% slowing of disease progression as measured by the composite Unified Huntington's disease Rating Scale, a statistically significant 60% slowing as measured by Total Functional Capacity, a reduction in neurofilament light, a key indicator of neurodegeneration from baseline and supportive trends across other key clinically meaningful endpoints. Importantly, these outcomes were assessed against a carefully and methodically constructed patient-matched external comparator derived from Enroll HD, the largest independent Huntington's Disease natural history data set in existence encompassing longitudinal clinical grade data for more than 30,000 participants that has been rigorously and painstakingly collected over the past 14 years.

While the months since sharing our landmark data have presented certain challenges, they've only strengthened our conviction that AMT-130 has the potential to benefit patients with Huntington's disease and reinforced our unwavering commitment to the HD community. As previously disclosed, during the October 2025 pre-BLA meeting, the FDA conveyed that data submitted from the Phase I/II studies of AMT-130 were unlikely to provide the primary evidence to support a BLA submission. We subsequently held a Type A meeting with the agency on January 30 to discuss next steps. In the meeting minutes we received on Friday, February 27, the FDA explicitly affirmed their commitment to exercising appropriate regulatory flexibility to facilitate the development of safe and effective therapies for HD. Still, the FDA strongly recommended we conduct a Phase III randomized double-blind sham surgery controlled study of AMT-130.

While we respect the agency's perspective and share its commitment to rigorous science, we believe it's appropriate to fully and carefully consider how regulatory flexibility is applied in the context of a rare, monogenic, slow progressive and ultimately fatal neurodegenerative disorder, for which there are no approved disease-modifying treatments. In our view, the totality of evidence generated to date for AMT-130 warrants continued substantive dialogue regarding the most scientifically grounded and feasible regulatory pathways given the severity of the unmet need and the irreversible nature of the disease.

While this was not the feedback we were hoping for, we remain highly confident in the strength and durability of our data. Our focus now is on constructive engagement with the FDA to further define a clear and efficient regulatory path forward. We are actively evaluating the agency's recommendations, including potential Phase III study designs while preserving our commitment to advancing the program responsibly and expeditiously. In addition, we intend to update our Phase I/II statistical analysis plan to incorporate a 4-year analysis that we expect to conduct in the third quarter of 2026. We believe extended follow-up will further inform the durability and magnitude of effect observed to date.

Let me be clear, we remain unwavering in our commitment to the HD community and greatly appreciate their tireless support over the past months and years. The urgency in the community is real, and we strongly believe AMT-130 has the potential to deliver meaningful disease-modifying benefits. Our team is fully engaged in determining the clearest and most efficient regulatory pathways to bring this therapy to patients as quickly as possible around the world, and we look forward to providing further updates as these discussions progress. With that, I will turn the call over to Walid to provide additional color on HD and our other clinical programs. Walid?

Thank you, Matt. Good morning and good afternoon, everyone. I would like to start by reiterating that the recent feedback from discussions with the FDA does not change our mission. We strongly believe that AMT-130 represents the most compelling therapeutic data set generated in Huntington's disease to date and that these results provide the first clinical evidence that gene therapy can potentially alter the course of HD. As Matt noted earlier, we had a meeting where I had a Type A meeting with the FDA in late January. This meeting, we reviewed the previous FDA guidance and discuss key elements of our data package, including the statistical approach, construction of the natural history external control, biomarkers and clinical endpoints.

We also shared with the agency additional sensitivity analyses and discussed additional data generation and considerations regarding the design of a Phase III trial. The official meeting minutes received from the FDA stated they cannot agree that data from the Phase I/II studies compared to an external control are sufficient to provide the primary evidence of effectiveness to support a marketing application. The agency also highlighted the absence of treatment effects relative to sham subjects in the U.S. Phase I/II study after 12 months. We respectfully have a different interpretation of these results than the FDA.

In patients with early HD, 1 year is generally insufficient to reliably detect a meaningful progression of their disease. In the sham controlled portion of our U.S. study, control patients did not show clinical worsening after 1 year, making it virtually impossible to demonstrate any effect over that short period of time for a therapy designed to slow disease progression. To that end, evidence of disease slowing started to emerge in the second year of follow-up and has become even more pronounced in the third year. In rare diseases, where progression is slow, longer observation periods are required to demonstrate an improvement in the disease course. This is often addressed through comparison to well-characterized external controls derived from natural history data sets using statistical methodologies designed specifically for that purpose.

There are multiple precedents where such approaches have supported regulatory approvals. Still, during the recent meeting, the agency strongly recommended we conduct a well-designed Phase III randomized, double-blind sham surgery-controlled study to demonstrate efficacy of AMT-130. We believe that a multiyear sham-controlled study could impose significant risks and burden to patients. Some might even consider it this trial design to be unethical. The HD patient community strongly agree with the sentiment and has communicated directly to the FDA on multiple occasions. These considerations warrant careful evaluation, particularly in the context of a rare, progressive and ultimately fatal neurodegenerative disease.

Importantly, Huntington's disease is supported by 1 of the most comprehensive natural history databases and rare disease. Enroll HD alone includes more than 30,000 participants with high-quality longitudinal clinical data collected over many years through the extraordinary efforts of the HD community. We believe that this body of real-world evidence provides a strong foundation to inform efficient and scientifically rigorous study designs making a long-term sham-controlled study of a one-time administered therapy difficult to justify. We do hope that the FDA will be willing to work with us on ways to leverage this valuable natural history data to design an adequate and well-controlled Phase III study.

We plan to request a Type B meeting in the second quarter of 2026 to further discuss potential Phase III study design in purchase that address the agency's feedback while also considering feasibility and patient risk. Additionally, we intend to amend and submit for review an updated statistical analysis plan for the ongoing Phase I/II study to include 4-year follow-up data compared to an external control. We believe extended observation has the potential to demonstrate continued durability and increased clinical meaningfulness of AMT-130 over time.

Following unsolicited outreach by ex U.S. regulators after our 3-year data disclosure in September 2025, we have initiated regulatory discussions with several agencies. We will continue these discussions throughout the year and we'll provide an update once we have additional clarity on the regulatory pathway. We look forward to the opportunity to potentially bring forward our innovative treatment to patients outside the U.S. in an expedited matter. Meanwhile, we continue to analyze the large body of data we have accumulated with AMT-130. In February of 2026, just recently, we presented at the CHDI meeting in Folgwings, California, a new analysis showing that propensity score methodology using clinical covariants with TRACK HD and PREDICT HD data sets effectively substitutes for baseline stride volume in prediction of Huntington's disease progression.

The Coveris use in these analyses were the same as those used in the 3-year analysis we shared in September 2025 to match AMT-130 patients to their counterparts and the external competitor cohort from the Enroll HD study. We continue to develop a manuscript with the complete results of our 3-year analysis and anticipate publication in the peer-reviewed medical journal later this year. Moving on to Fabry disease. In February, we reported preliminary safety and exploratory efficacy data from 11 patients in the ongoing Phase I/II trial of AMT-191, which was presented at the World Symposium in San Diego, California. As the cutoff date -- as of the cut update on January 8, 2026, all 11 patients in free dose cohorts exhibited elevated alpha-Gal A enzyme activity with 6 patients successfully withdrawn from enzyme replacement therapy.

As of today, I'm pleased to report that all 11 patients have been withdrawn from enzyme replacement therapy. Importantly, dose-dependent elevation in alpha-Gal A enzyme activity were observed across the 3 dose levels. These increases were durable for the measured period of time, ranging from more than 1 year, the longest follow-up patient at the high dose to the shortest follow-up period of 4 months when the patients treated at the middle. Stable plasma lyso-Gb3 levels were maintained those dose across all those cohorts regardless of ART status through the cutoff date. AMT-191 continued to show a manageable safety profile. No serious adverse events related to AMT-191 have been reported in the mid- and low doses. 2 patients at the mid-dose experienced asymptomatic Grade 3 liver enzyme elevation. For protocol, any such grade 3 LFT increases are considered potential dose-limiting toxicity, which require review and confirmation by the independent data monitoring committee.

Following such a review, these events were confirmed as dose limiting toxicity. And per protocol, we have paused dosing at the mid and high doses pending further evaluation. I'm pleased to report that both patients have responded well to corticosteroid therapy and are tapering off steroids with no loss of alpha-Gal A enzyme activity as of today. Turning now to AMT-260 for metal temporal epilepsy. 2025 was a productive year for the program. We shared data from a case study of the first patient treated with MT-160 with up to 6 months of follow-up presented most recently in September 2026 at the International League against epilepsy meeting in Lisbon, Portugal.

Initial data showed a promising reduction in seizure frequency over the first 6 months with no serious adverse events. We have since completed enrollment of 5 more patients in the first cohort and begun enrollment in the second cohort. We expect enrollment to be completed in the second cohort by midyear. Additionally, we plan to provide an update in the second quarter on all 6 treated patients in the first cohort, including those with nondominant and dominant hemisphere lesions with at least 6 months of safety, tolerability and seizure frequency outcomes.

I will now touch base on some additional pipeline updates. Phase I/II episode I trial of AMT-162 for SOD1 ALS remains on voluntary enrollment and treatment hold based on the recommendations of the independent data monitoring committee following a September 2025 review of preliminary data related to the safety and efficacy of AMT-162 in the context of a dose-limiting toxicity that was observed in 1 patient in the second cohort. This event of dorsal root ganglia toxicity resulted in a serious adverse event determined to be related to AMT-162. We will continue to collect data and evaluate data from the patients as they're being accumulated. Now I will turn over the call to Kylie to discuss our ongoing work with the HD community. Kylie?

Thank you, Walid. Starting out with AMT-130 to the Huntington's disease patient community. We want to thank you for your extraordinary strength, resilience and unwavering commitment to advancing disease-modifying therapies for HD. Your courage in the face of daily challenges your willingness to participate in research and your steadfast advocacy are the driving forces behind progress in HD. Importantly, your push for regulatory flexibility for HD through petitions, congressional engagement, direct dialogue with regulators and persistent public advocacy has elevated the urgent needs of families living with HD and we'll continue to do so. .

Your engagement, partnership and determination continue to inspire us here at uniQure. And together, we will keep moving forward. We remain committed to the HD community. And as Matt noted, we remain committed to finding the most expeditious path forward for AMT-130. Over the past quarter, we have significantly expanded our engagement with neurosurgeons, neurologists and multidisciplinary care teams across the U.S. receiving overwhelmingly positive feedback on the AMT-130 data set and its potential to meaningfully impact patients. These discussions have reinforced both the clinical relevance of our data and the strong interest across the HD treatment centers of excellence in advancing this therapy. In parallel, we are actively assessing ex U.S. opportunities, evaluating priority markets based on epidemiology, regulatory pathways, pricing and reimbursement landscape.

In addition, we will be actively pursuing name patient and early access program opportunities in rare disease outside of the U.S. that help enable access to therapies ahead of formal reimbursement decisions, offering hope to patients and families while broader market access processes continue. This disciplined approach ensures we are building a scalable global strategy to maximize the long-term value of our program for all stakeholders.

Moving to AMT-260. We also see significant market opportunity for a potential gene therapy and temporal lobe epilepsy, where a substantial proportion of patients remain drug-resistant despite multiple antiseizure medications and continue to face ongoing unpredictable seizures, that drive injury risk, cognitive decline, psychiatric comorbidities and reduced quality of life. Even with surgical resection or neuromodulation, many patients are not eligible or failed to achieve durable seizure reduction, underscoring the need for innovative disease-modifying approaches that can address the underlying epileptic genetic focus and provide sustained benefit from a one-time intervention.

Similarly, for AMT-191 in Fabry disease, a one-time gene therapy has the potential to address the underlying enzyme deficiency and meaningfully reduce lifelong treatment burden, positioning it to compete in a market currently defined by chronic enzyme replacement therapies and other long-term therapies. Importantly, enzyme replacement therapies require regular lifelong infusions, may be associated with the infusion-related reactions and antidrug antibodies, and often provide incomplete tissue penetration, highlighting the potential advantage of a durable one-time genetic approach.

Overall, our customer-facing team remains intensely focused on disciplined execution today, while thoughtfully building the capabilities, partnerships and evidence base required to drive the long-term success across our full portfolio. Now I will turn the call over to Christian for a financial update.

Thank you, Kylie. I'll be sharing the financial highlights of the full year of 2025. Please refer to the earnings press release issued this morning and our quarterly filings with the SEC for additional details. Revenue for the year ended December 31, 2025, and was $16.1 million compared to $27.1 million in 2024. The decrease of $11 million was primarily driven by a $10.7 million decrease in collaboration revenue and a $6.1 million decrease in contract manufacturing revenues, offset by a $5.8 million increase in license revenues. Cost of contract manufacturing revenues was nil for the year ended December 31, 2025, compared to $17.1 million in 2024.

Following the divestment of the Lex facility in 2024, cost of contract manufacturing revenues are recorded net associated revenue within other expenses. Research and development expenses were $140.7 million for the year ended December 31, 2025, compared to $143.8 million in 2024. A decrease of $3.1 million was primarily driven by a $26 million decrease in total other research and development expenses, $25 million of which related to decreases in employee, contractor related and severance costs as well as facility costs resulting from the 2024 divestiture of the company's Lexington manufacturing operation and organizational restructuring in the same year. This was offset by $22.9 million increase in total direct research and development expenses, of which $19.4 million related to the preparation of a potential BLA submission for AMT-130.

Selling, general and administrative expenses were $65.5 million for the year ended December 31, 2025, compared to $52.7 million in 2024. The $12.8 million increase was primarily driven by a $9.4 million increase in professional fees, including $6.5 million incurred to support the preparation of the planned commercialization of AMT-130 in the United States as well as a $3.6 million increase in employee and contractor-related expenses and a $2.8 million increase in other expenses. This was offset by a $1.8 million decrease in share-based compensation expenses and a $1.2 million decrease in severance costs.

Cash, cash equivalents and investment securities totaled $622.5 million as of December 31, 2025, compared with $367.5 million as of December 31, 2024. The net increase was primarily attributable to proceeds of approximately $404.2 million raised through public offerings of ordinary shares and prefunded loans. With this strong balance sheet, we believe uniQure is well positioned to execute its clinical and operational priorities throughout the coming year. Expect cash, cash equivalents and investment securities will be sufficient to fund operations into the second half of 2026. We I'll now turn the call back over to Matt.

Thank you, Christian. As we look ahead to 2026, our priorities are clear. We are focused on constructively engaging with regulatory authorities inside and outside the United States to define the most appropriate path forward for AMT-130, advancing our pipeline programs with discipline and continuing to generate high-quality data across our portfolio. The strength and durability of our Huntington's disease data set, the progress in Fabry disease and TLE and our strong balance sheet position us well to execute on this strategy.

Most importantly, we remain committed to the patients and families we serve. The urgency in these communities is real, and we believe our gene therapy platform has the potential to meaningfully change the trajectory of devastating diseases. We look forward to updating you as we continue to advance our programs thoughtfully and responsibly. With that, we will open the call to take questions from our research analysts. Operator, please proceed.

[Operator Instructions] Your first question comes from the line of Paul Matteis with Stifel.

This is Julian on for Paul. I guess primarily are there any paths that you can potentially pursue in order to push your agenda beyond just the traditional FDA channels here I'm curious like what other levers you can pull to potentially garner support for registration based on either the existing data or the 4-year data. And then for the 4-year data, can you just confirm whether you plan on submitting that to the agency and whether we can expect the additional handful of patients in the analysis -- in the 3-year analysis as well? Or if you just plan on sharing 12 patients of data at 4 years.

Okay. Yes. I maybe will answer the first part and then Walid can answer the second part. Yes. I mean the other avenues we can pursue are potentially outside the United States, quite frankly. I mean inside the United States, the avenues go through the FDA. I think what we've seen over the last several months is a tremendous amount of advocacy on behalf of the patient community. In my view, that is a critical part of educating and informing elements outside of the FDA around the needs and the sense of urgency within the community. We've also heard from the scientific and clinical community that continue to believe that regulatory flexibility is absolutely required for genetically defined diseases like HD that are neurodegenerative and progress very slowly. .

So to me, that's going to be an essential element of this and then pursuing opportunities where we can bring AMT-130 to patients as soon as possible outside the United States, where there seems to be real interest for regulatory authorities, I think that's what we're going to pursue. On the 4-year data, I can hand it over to Walid.

So on the 4-year data, we informed the FDA that we will be amending the protocol or the SAP specifically to conduct such analysis, and will submit it to them as well. we did not specifically discuss with them what that would mean. Actually, we don't believe that there's any reason we have today to believe that this will change the FDA's position regarding the Phase I/II trials. I need to be clear on that. Having said that, what data will be evaluating it would be essentially presenting the data of the 12 patients at 4 years. but also the -- all the patients who have by then reached would have reached 3 years as well. So we'll be presenting the totality of the data.

I think those data are very important for the HD community and to be able to continue to demonstrate the durability of the effect as well as a potential even a more evident treatment effect of AMT-130.

Your next question comes from the line of Joe Schwartz with Leerink Partners.

So in last week's CNBC interview with Dr. McGarry seemed concerned about the morbidity associated with procedures and involving bur holes, which is what you used with AMT-130. So I'm just wondering, was this a major sticking point? Did it come up in the Type A meeting? Have you done everything possible to educate the FDA on that front? And what is your strategy for the Type B meeting and outside the U.S. to now?

Yes. I mean we don't want to comment directly on what Dr. McGarry said. But just in terms of the interaction with the FDA obviously, they're going to be focused on patient safety. We have, in our view, quite a strong safety profile. We have not seen disease clinical safety events associated with AMT-130 since December of 2022. We obviously saw some safety events that were associated with the procedure. It is a surgical procedure. We also know, as we've disclosed previously that there are some volumetric changes that are as to be expected, those are not associated with any clinical consequences as we've seen, and we see no increases in neurofilament light that would be associated to the extent that those volumetric changes were related to accelerating atrophy. And we've had experts in our recent meetings with the FDA, we've had experts on the call that have talked about volumetric MRI changes.

We've had clinical experts that have seen patients. So we've done everything we can to educate the FDA in this regard.

The strategy for the -- do you want to talk about that?

Sure. So for the Type B meeting, our main goal is going to be to discuss with the agency designs for the Phase III trial. As I said, we believe that we are very fortunate in the space to have a very high grade ongoing contemporaneous natural history, specifically, I'm talking about enrolled HD with more than 30,000 participants. this, what I call a treasure trove that is generally provided to us by CACI and through the hard work of many, many patients and their families and the whole HD community. We think that could deleverage to be able to help us somehow strengthen study designs for Phase III and try to avoid designs that would be difficult and challenging to the patients, so we're looking forward to be working with the FDA on that.

We hope that they will work with us and acknowledge the flexibility they often talk about that should be afforded to rare diseases. That's going to be the key focus of that type of meeting. the second quarter.

Your next question comes from the line of Peyton Bohnsack with TD Collin.

This is Peyton on for Joe. Real quickly, when talking about the Phase III design, how quickly do you think that you would be able to enroll it -- would you be able to use an 18-month endpoint similar to what's been seeing outer in the space? And then has this changed your partnering decisions at RF .

Maybe I'll take the first part and then turn it over to Matt for the partnering piece. I think it's premature for us to talk about the logistics and how easy it will be to recruit or not. Because as you heard, we haven't yet defined the design. The duration is 1 element. The duration often depends on the sample size as well, the level of control, how are we using it? Are we leveraging also external control using patient statistics or other types of techniques. So it's really premature to do that. Having said that, I think we are very comfortable with the interest of patients. We've seen that after we've published the results back at September, and that has also increased through this a lot of the great work that's been done over the past number of months, but our externally facing group in dealing with these various sites across the U.S. predominantly. And I'm not really too worried right now, but we cannot give you more details until we figure that out a bit more of the design.

Yes. On the partnering side, I also think it's a little too early. We need to understand what the Phase III study design and protocol is going to be the number of years and the investment that's required. I mean, we're obviously focused right now. We've got a strong balance sheet, and our strategy has been to take this forward and commercialize it ourselves. We really believe in this product it deserves to be taken forward. It needs to be brought to patients, and we're going to do everything we possibly can to do that. And if partnering plays a role in it, then we'll have to evaluate it at that time, but it's a little premature to weigh in on that right now.

Your next question comes from the line of Ali Merrill with Barclays.

This is Jason on for Elli. So first, can you give some more color on the different scenarios for a potential Phase III design. So what are you going to the FDA within proposing? And has the FDA so far given any guidance on the length of the study or endpoints? And then secondly, across these different scenarios, what would the cost of the Huntington Phase III program look like? And does your cash runway include this?

Thanks, Jasmine. It's really premature to be able to get into those details. I -- whatever I say now would definitely be different after we talk -- so there's been no specific discussions on the length of the trial. As we said, the FDA was very clear about their strong recommendation to do a double-blind sham-controlled trial, that is -- that is adequately powered, which is, again, the right thing to do to be able to evaluate this as the adequately powered part. Now we need to discuss with them whether there is openness to use maybe other designs or how we can leverage the external control. But honestly, whatever I say now, really is not -- it's very high likely to change. So I really would not like to go down that path. And what's the other question? For Christian, regarding the run rate.

Yes. So I mean, same comment a bit as Vale with all the uncertainties around the investments into kind of the various late-stage opportunities we have kind of run scenario analysis with built in development spend, but it's way too early to comment on specifically how much of that would relate to 130 vis-a-vis 260 or 191 .

Your next question comes from the line of Susan Zane with Kempen.

This is Suzanne from Kempen. Maybe 1 clarifying question on the indices program about other jurisdictions. What regions are you talking about? And what's the status of your discussions with regulators outside of the U.S.? And then I have 1 for the program. Did I catch correctly that the update in Q2 will be on 6 patients from the first dose cohort with 6 months follow-up? Or will there also be some early data from the second dose cohort -- and perhaps for seizure specifically, can you give a sense of what reduction in the seizure frequency we should consider as good or what level would be a great result.

Absolutely. So on the first question around ex U.S., I think we're looking at a number of different jurisdictions at the moment. We're taking into consideration a number of factors. We're looking at obviously epidemiology regulatory pathways and then also pricing and reimbursement, looking, as I mentioned, at named patient programs and early access programs that are applicable to rare diseases and really taking that into assessment as we think about the strategy moving forward for ex U.S. regions. We've obviously mentioned that we're going to be in discussions with both MHRA in the U.K. and EMA from a European perspective. And then we're going to be looking at what other opportunities that affords us outside of those 2 jurisdictions. So that's on the first question and then handing over to Walid on the epilepsy question.

Yes. So on the epilepsy, we will be presenting the data on exactly what you said, the first 6 patients, 6-month seizure frequency. Honestly, this is a Phase I study. So we have not yet set an expectation. We're trying to figure out overall safety, tolerability and evidence of pharmacodynamic effect. It's a learning process. So more to come once we share the data.

Your next question comes from the line of Luca Issi with RBC Capital Markets.

Maybe if I can circle back on the ex U.S. opportunity here Matt and Kyle. How should I think about the overall commercial opportunity here? I believe Roche was able to generate close to $100 million a quarter from selling the levies to ex U.S. before the drug obviously run into safety issues. Is that the right comp for us to think about it? Or would you advise against us? .

Absolutely. So I think it's probably a little bit premature to be talking about commercial opportunity because we're truly in the planning and strategy phase around thinking through what opportunities would we be going after. But I do think that what we're bringing into the thinking is exactly that Roche comp around how have they gone after certain regions through named patient and early access programs as well as other cell and gene therapies that have walked this path ahead of us, and we will be taking those learnings on board. So a bit premature on commercial opportunity, but I do think that we will be looking at Roche and other companies for thinking through best practices.

Your next question comes from the line of Salveen Richter with Goldman Sachs.

Can you just help us understand the totality of the sticking points with the FDA here? And why a sham controlled is required versus a prospective natural history comparator?

Thanks, Salveen. Yes, the FDA at the pre-BLA meeting raised the point that those studies were designed as hypothesis-generating studies and any such analysis after we've collected the data and we looked at them would be considered post hoc. And then recently, they reverted to start looking at the double-blind part of the U.S. study and raising questions around absence of any clinical or biomarker signal in that smaller U.S. study, which was sham-controlled. As I said in my comments earlier, we really do not have the same interpretation as the FDA in this type of rare disease where there's slow progression, and we are taking people early in their disease. It's really difficult to detect a meaningful and reliable change after 1 year in a Phase I/II study such as ours.

And as such, you need to start looking at data from a subsequent time point. And what we have seen with AMT-130 that every time we looked at the data, the signal became more and more evident and as such, we believe that this warrants an evaluation compared to an external control, which is the kind of regulatory flexibility that 1 should be affording to diseases such as Huntington, which are monogenetic, progressive and rare. And the also procedure that we do, which is one-time administered gene therapy. So these are the kind of things that we're going to be discussing with the FDA and continue that dialogue because fundamentally, the AMT-130 is doing what we have been expecting it to do, and that effect continues to be stronger and stronger.

And we're going to keep on analyzing these data and accumulating more data. And we're hopeful that we're going to be able to align with the FDA on a study design that would allow us to confirm these findings and then we will take this 1 step at a time as we start getting more clarity with them.

Your next question comes from the line of Uy Ear at Mizuho.

I guess I'm just still don't quite understand why the FDA is requiring a sham study. Like I understand the objection the FDA had previously and it didn't sound that in your Phase I/II study, it didn't sound it like the FDA was objecting to natural history. I guess this time around, what is it about the -- Is there anything about the natural history database that they objected to or the kind of data or the kind of statistical plan that we involved with using natural history that they're not comfortable with. I guess that's the first question. And the second question is, Matt, are you committed to taking this forward even with a sham study?

Yes. I mean, Walid can chime in. But I mean we disclosed that back in November of 2024, that the FDA had stated in writing that we may use the data from the Phase I/II study in comparison to an external control as the primary basis for a BLA submission. And honestly, I'm looking at Walid here, I don't think that they've necessarily had any criticisms of the Enroll HD database. I mean this is a database, again, with more than 30,000 participants. It's been collected over the last 14 years, and it's a clinical-grade natural history. I mean, this is almost -- I mean this is effectively a clinical trial. So -- and moreover, part of the comparison was actually contemporaneous with the patients that we enrolled.

So there's a lot of check boxes there. And it's puzzling to us other than the fact that a sham-controlled study is certainly gold standard science. But -- it's hard to understand why with such a plethora and treasure trove of natural history that not being able to leverage that in a way for a registrational pathway would obviously would be very disappointing.

With respect to your second question, I mean, I believe in my soul that AMT-130 can benefit patients with HD. And over the years, I've gotten to know these patients, know their families and I understand the urgency of this unmet need. And if there is a study that we believe is feasible and ethical, we're going to do everything we can to drive AMT-130 forward.

Your next question comes from the line of Patrick Trucchio with H.C. Wainwright.

This is Louis Santos and Patrick. I just wanted to ask if there was anything in the FDA's feedback that's precluded potential accelerated path with this supposed Phase III study based on an interim analysis, say, of surrogates, including NFL.

Yes, there was no discussion on this with the FDA, but there's no reason to think that. Actually, it was verbally communicated in the previous time that, that would be possible as well. So I do think that, that could be an option if we go down that path. But again, let's first discuss what that phase season would look like, and then what potential accelerated approval or full approval pathway that would be.

Your next question comes from the line of Kristen Kluska with Cantor.

Was part of your discussions with the FDA around a lack of biomarker data? And is there going to be an expectation that you'll be able to show some of this in a sham-controlled study. .

So the FDA, as I said, reverted back to looking at the 12-month data of our U.S. study because that's the only study that had the sham control in it and they raised challenges they don't see biomarker data in that small sample size over 1 year. There was no specific discussion on 3-year data or requirement for what we need to show or not at this point. So it's really premature for me to get into that. But we will provide more details on the Phase III and the FDA expectations after we align with them in the second quarter.

Your next question comes from the line of Yanan Zhu with Wells Fargo.

This is Juan on for Jan. So in previous questions, you mentioned that you were trying to avoid Phase III design that will be too difficult or too challenging to the patients. Can you elaborate on that point? Are you talking about the length of study? And what would be considered too difficult? Is it like a 3-year or longer study? And I have a quick follow-up. .

Yes. I think the concept of having a sham surgery where patients would be essentially anesthetized for an extended period of time 10 to 12 hours where you have to cut through the skin and maybe superficially drill a hole in the skull without really going through the bone. All of these elements represent risk for these patients, especially if the length of the study is 2 or 3 years, and they're going to be spending all this time not knowing that whether they get a drug or not. And then potentially at the end of this period, they might have progressed enough that they cannot benefit from the drug or they will never really get back that level of worsening. I think this is where we find it a bit difficult, particularly with the type of therapy that we provide. And so that's why we're very keen to work with the FDA.

I mean we know that ultimately, we have the same goal. We want to bring safe and effective medicine to patients. We share that. And we know that the FDA definitely cares about patients. They indicated that. We just want to work with them and appeal to their flexibility to be able to design, again, scientifically sound studies to leverage the available data that exists now so that we can minimize the burden to the patient as much as possible.

Got it. And in plan Type B meeting. Is there any additional evidence that you plan to present to FDA or is just a discussion on the Phase III design?

No, it will be only to discuss the Phase III design. We're not doing any additional analyses or anything like that until we update the SAP and the next time we share the data would be in the fourth quarter. .

Your next question comes from the line of Rod Lee with Wolfe search.

Just another quick follow-up to the trial design. So what is the biggest pushback from the FDA? Why do they feel strongly that you need to run the Sham control trial because they seem to be open to a single-arm trial like for stoke therapeutics and practices? Just wondering what are the key differences here?

Well, you're absolutely right. They're certainly precedent for genetic diseases and one-time administrative medicines to be approvable without doing a placebo-controlled study. I mean, it's a theoretical benefit, right? I mean there's a reason why sham controlled or placebo-controlled is gold standard, and that's because it addresses potential bias, whether that's a selection bias or motivational bias. There's no disagreement that a placebo-controlled study is a higher level of robustness. But in our view, it really doesn't reflect regulatory flexibility given the urgency of unmet need here nor does it necessarily take under consideration the tremendous amount of natural history data that can be leveraged in order to provide a very useful and meaningful comparator. So -- but that's what -- based on our understanding, what we think the FDA is seeking is a maximum reduction of potential bias in recommending that we do a sham-controlled study.

Right. Just to be clear, if they really want a SAM controlled trial was still dedicated to move forward to a trial.

Yes. I mean I think we're going to do some feasibility work. I mean we did do a sham controlled portion of our Phase I/II study. It was a 1-year in a much smaller study. But I think if we do our feasibility work, and we think it's feasible and the patient community is supportive of it, I think we're seriously going to consider that. I think we need to. We have to. If this is feasible and the patient community supported, we have a moral obligation given the strength of our data to continue to pursue this. I really feel that very strongly. And again, I understand these things cost money and they take time and that's something we can explore the best way to do that. But I'm here at this company because I want to bring therapies like AMT-130 to patient populations like Huntington's disease patients. .

And again, given the strength of our data, I think this is an endeavor that we continue to be dedicated to.

Ladies and gentlemen, that concludes today's call. Thank you for joining. Have a great day. You may now disconnect.

Good morning, and welcome to uniQure's Third Quarter 2025 Earnings Call. [Operator Instructions] As a reminder, this conference call is being recorded. I would now like to turn the call over to Chiara Russo, Senior Director of Investor Relations. Thank you. Please go ahead.

Good morning, and thank you for joining us for uniQure's Third Quarter of 2025 Earnings Call. Earlier this morning, uniQure released its financial results for the third 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 today. Joining me on the call this morning are Matt Kapusta, Chief Executive Officer; Dr. Walid Abi-Saab, Chief Medical Officer; Kylie O'Keefe, Chief Customer and Strategy Officer; and Christian Klemt, Chief Financial Officer. After our formal remarks, we'll open the call up 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 fact are forward-looking statements. They are based on management's beliefs and assumptions and 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 third quarter conference call. As you know, in the third quarter, we announced positive top line data from our pivotal Phase I/II study of AMT-130 in Huntington's disease, the first gene therapy to demonstrate statistically significant slowing of disease progression in Huntington's disease. These groundbreaking results represent an important milestone not only for uniQure, but also for patients and families who have long awaited a potential disease-modifying therapy.

As previously disclosed, we met with the FDA in late October to review our data and discuss the potential submission of a BLA for AMT-130. Based on discussions at the meeting, we believe the FDA currently no longer agrees that the data from the Phase I/II studies of AMT-130 in comparison to an external control may be adequate to provide primary evidence in support of a BLA submission. Consequently, the timing of a BLA submission for AMT-130 is now uncertain. This feedback represents a notable shift from prior communications with the FDA during multiple Type B meetings over the past year. We plan to urgently engage with the FDA to discuss next steps, and we expect to receive the formal meeting minutes within the next 30 days.

While the latest FDA feedback is certainly surprising and disappointing, we continue to strongly believe that AMT-130 has the potential to provide significant benefit to patients. We believe the data presented to date, widely recognized as the most compelling ever generated in Huntington's disease, provides substantial evidence of therapeutic effect. Every year, thousands of Americans die because of Huntington's disease and thousands more are newly diagnosed. We believe AMT-130 has the potential to significantly slow disease progression and exemplifies the type of transformative innovation in rare diseases the FDA has pledged to support.

We remain fully committed to our partners, investigators and most importantly, to Huntington's patients and their families and to working collaboratively with the FDA to bring this therapy to Huntington's patients in the U.S. as rapidly as possible. We will continue to act with urgency, transparency and discipline as we work to deliver on the promise of gene therapy to transform lives. I will now turn the call over to Walid.

Thank you, Matt. Good morning and good afternoon, everyone. I would like to start by reiterating that the recent feedback from discussions at our pre-BLA meeting does not change our belief in the data. We continue to believe that AMT-130 represents the most compelling therapeutic data set generated in Huntington's disease to date. The true highlight of the third quarter was the positive top line data from our pivotal Phase I/II study of AMT-130 in Huntington's disease. Before I go on, I want to thank our employees, investigators, partners and especially the patients and families who have been participating in the CHDI natural history studies and our clinical studies. It's thanks to their deep commitment and efforts that we have been able to achieve such progress.

In September, we reported top line data with the high dose of AMT-130 demonstrated a statistically significant 75% slowing of disease progression as measured by the composite Unified Huntington's Disease Rating Scale (cUHDRS) at the 3 years compared to a propensity score matched external control derived from the Enroll-HD natural data set, meeting the pivotal study prespecified primary endpoint. Equally important, patients treated with high-dose AMT-130 demonstrated a statistically significant 60% slowing of disease progression at 3 years as measured by the total functional capacity, a key secondary endpoint.

Moreover, Cerebrospinal fluid, neurofilament light chain, a well-characterized and supportive biomarker measuring neurodegeneration was below baseline at 36 months in patients treated with high-dose AMT-130. The top line data from the high dose were supported by consistent results in multiple sensitivity analyses demonstrating the robustness of these findings. We believe these results provide the first clinical evidence that gene therapy can potentially alter the course of Huntington's disease. In keeping with the spirit of full transparency for the scientific and medical communities, we are working diligently on a comprehensive publication strategy, starting with publishing our full data results in a well-respected peer-reviewed medical journal.

As Matt noted earlier, we met with the FDA for a pre-BLA meeting in October. And based on discussions of the meeting, we believe that the FDA currently no longer agrees that data from the Phase I/II studies of AMT-130 in comparison to an external control may be adequate to provide primary evidence in support of a BLA submission. This feedback was unexpected. We believe AMT-130 has the potential to significantly slow disease progression. We plan to urgently interact with the FDA and are fully committed to working with the agency to find an expeditious path forward.

Turning now to AMT-260 for mesial temporal lobe epilepsy. In May, we announced initial data from the first treated patients with 5 months of follow-up. At that time, we observed promising reduction in seizure frequency over the first 5 months of follow-up with no serious adverse events. This data generated enthusiasm among investigators and potential patients. We have now activated 17 recruiting sites in the United States and completed enrollment of the first 3 patients in the first cohort. Following a favorable review by the independent data monitoring committee, recruitment has now expanded into mesial temporal lobe epilepsy in the dominant hemisphere and the initiation of a second cohort at a higher dose for the protocol. We expect to provide updated data from the study in the first half of 2026.

Moving to Fabry disease. In September, we also reported encouraging results from the ongoing Phase I/IIa trial of AMT-191, which were presented at the International Congress of Inborn Errors of Metabolism in Kyoto. Across the 4 patients treated in the first cohort, we observed supraphysiological alpha-Gal A enzyme activity with all patients successfully withdrawn from enzyme replacement therapy while maintaining stable plasma lyso-Gb3 levels through the July 24, 2025 data cutoff date. These results, together with a manageable safety and tolerability profile, reinforce the potential of AMT-191 to be a one-time dose gene therapy for Fabry disease. Enrollment in the second lower dose cohort has been completed with a third cohort currently enrolling. We expect to share updated data in the first half of 2026.

I will now touch on some additional pipeline updates. We have voluntarily paused enrollment in the Phase I/II EPISOD1 trial of AMT-162 for SOD1 ALS based on the recommendation of the independent data monitoring committee following a September 2025 review of the preliminary data related to the safety and efficacy of AMT-162 in the context of a dose-limiting toxicity that was observed in 1 patient in the second cohort. This event resulted in a serious adverse event determined to be related to AMT-162. At this time, we will continue to collect and evaluate data from the patients treated with AMT-162. To summarize, the third quarter marked a milestone for AMT-130 with a positive top line data from our pivotal Phase I/II studies. The recent feedback from the FDA has introduced uncertainty into the path forward, but we believe in our data, and we are focused on working with the agency to define the next steps.

Now I will turn the call over to Kylie to discuss our recent patient advocacy work. Kylie?

Thank you, Walid. As both Matt and Walid have said, our commitment to the HD community remains unwavering. Following our September data announcement, we experienced a groundswell of hope and support from patients, patient advocacy groups, clinicians and scientists alike. We understand and deeply appreciate the concern and disappointment expressed by the community following our announcement last week regarding the pre-BLA meeting with the FDA. We are reminded, however, that every step of this journey, including moments like this reflect the seriousness of our mission and the importance of getting this right for HD patients.

During this period, our commercial and medical teams continue to thoughtfully plan and execute with discipline and focus. Our primary focus continues to be on stakeholder engagement and education, including treatment centers of excellence, payers and patient advocacy to best position us to be fully prepared for a strong and informed potential launch of AMT-130. Concurrently, as we have a focus on building the foundational strategy for the U.S. market for a potential launch of AMT-130, we are also looking to additional potential markets outside of the U.S., such as the EU and the U.K.

The feedback we are receiving from the physician and patient community reinforces both the high level of unmet need and the enthusiasm for the potential of AMT-130. Their support continues to motivate our team, and we remain committed to maintaining open communication and collaborating with the community as we plan next steps. We believe deeply in our science, the data we have generated to date and the impact that this therapy could have for HD patients. Now I will turn the call over to Christian for a financial update. Christian?

Thank you, Kylie. I'll now be sharing financial highlights of the third quarter of 2025. Please refer to the earnings press release issued this morning and our quarterly filing with the SEC for additional detail. Revenue for the 3 months ended September 30, 2025, was $3.7 million compared to $2.3 million in the same period in 2024. The increase of $1.4 million in revenue resulted from a $1.5 million increase in license revenues and a decrease of $0.1 million from collaboration revenues. Cost of contract manufacturing revenues were 0 for the 3 months ended September 30, 2025, compared to $0.8 million for the same period in 2024.

Following the divestment of the Lexington facility in July 2024, cost of contract manufacturing revenues are recorded net of revenue within other expenses. Research and development expenses were $34.4 million for the 3 months ended September 30, 2025, compared to $30.6 million during the same period in 2024. The $3.8 million increase was driven by an increase of $10.1 million in direct research and development expenses, of which $6.6 million related to preparation for the BLA submission of AMT-130, offset by a decrease of $3.4 million in severance costs and a $3 million decrease in costs related to disposables, facilities and other expenses.

Selling, general and administrative expenses were $19.4 million for the 3 months ended September 30, 2025, compared to $11.6 million during the same period in 2024. The $7.8 million increase was primarily related to a $2.4 million increase in employee-related expenses and a $4.9 million increase in professional fees, including $3 million incurred to support the preparation of potential commercialization of AMT-130 in the United States. Cash, cash equivalents and investment securities totaled $649.2 million (sic) [ $694.2 million ] as of September 30, 2025, compared to $376.5 million (sic) [ $367.5 million ] as of December 31, 2024. The increase is primarily related to the net proceeds of $404.2 million from our public offerings this year.

With this strong balance sheet, we believe uniQure is well positioned to execute its clinical and operational priorities. We expect cash, cash equivalents and investment securities will be sufficient to fund operations into 2029. I'll now turn the call back over to Matt.

Thank you, Christian. As you've heard today, the third quarter of 2025 was a pivotal one for uniQure, and we continue to have strong conviction in both the compelling data set and therapeutic potential for AMT-130. Our focus now is on working with the FDA to clarify next steps and determine the most expeditious path to bring AMT-130 to patients in the U.S. In parallel, we will plan to advance discussions with other regulatory agencies, including those in the European Union and the United Kingdom. As we move forward, we do so with confidence in our science, clarity in our mission and a deep determination to make a meaningful difference for patients and families affected by Huntington's disease.

Before we open up for questions, I'd like to note that because we have not yet received the final meeting minutes from our pre-BLA meeting with the FDA and out of respect for the agency and our shared goal of advancing AMT-130 for patients with Huntington's disease, we will strictly limit our responses about that meeting to the information disclosed in our November 3, 2025 press release. We appreciate your understanding and are happy to address other questions you may have. Operator, please go ahead and open the call.

[Operator Instructions] Our first question today comes from Joe Schwartz from Leerink Partners.

Great. So the treatment effect you've reported out to 3 years is quite large. So I'm wondering, to what extent have you stress tested the results in order to see what a very conservative rendition of the results would look like? For example, could you remind us how you constructed the external control arm to consider whether there were any potential sources of bias?

Thanks, Joe. Walid, do you want to answer that one?

Can you hear me?

Yes.

You can. I'm sorry, I wasn't sure if I'm muted or not.

Yes, we can.

Yes. Thank you. All right. Thanks for the question. So actually, what we have done is essentially follow a rigorous way to do the propensity score-matching with Enroll-HD. I think Enroll-HD lends itself to provide a fairly robust data because of the size of it, you get very good matches. And what we have done in discussion with the FDA prepared a series of sensitivity testing evaluating propensity score-matching using different types of matching the propensity score-weighting. We've also looked at a smaller number of variables, which was part of an SAP that we have proposed much earlier in the process during the RMAT application.

We looked at regional differences. We looked at comorbidities based on medication and so on and so forth. And last but not least, we compared to TRACK and PREDICT a sensitivity analysis, again, as part of the pre-agreed types of sensitivity analysis with the agency. And across a variety of these analyses, the results were very consistent, demonstrating the robustness of these findings. And that's why we have really strong confidence in the results that we've seen.

But regardless, if you also look at the numerical change from baseline in our patient population and compare it to a number of data that's being published by a number of studies that are run in that space in comparable patients, you see that the magnitude of the change from baseline at 3 years is very small compared to one would expect in placebo or untreated subjects.

Our next question comes from Uy Ear from Mizuho.

Maybe just help us understand a little bit about what happened in AMT-162. Could you kind of remind us what -- whether this -- what the vector was and whether it was similar to the other pipeline studies? And along with that, what was the dose difference between the first cohort and the second cohort?

Yes. Thanks for the question. We haven't quite disclosed all of the data about the dose so far. But with this product, we have seen previously in a compassionate use that was the case of dorsal root ganglion toxicity. It's a known adverse event, particularly for this route of administration. And we knew and we were monitoring very carefully with this. Unfortunately, we've seen that at the middle dose, which I can tell you is about threefold higher than the low dose. And as a result, we backed down. But now we're monitoring the data to see over time how this will evolve, and we will have a discussion with the experts and the IDMC to determine the next steps for this program. We should be able to come back in the first half of next year with some answers on this.

And just to be clear, Uy Ear, this is a totally different capsid than what we use in our other programs and a different mode of administration.

Our next question comes from Salveen Richter from Goldman Sachs.

This is Lydia on for Salveen. Could you just talk to what details you hope to learn from the final meeting minutes here in the next 30 days?

Yes. I think what I would say is we don't want to speculate on what will be in the minutes. We assume that they'll reflect mostly the conversation that we had in Washington, D.C. But most importantly, we hope it will give a sense of the concerns that the FDA has and give us an outline for how to address those concerns in a subsequent meeting with the FDA.

Our next question comes from Joseph Thome from TD Cowen.

I guess, are you able to kind of confirm that prior meeting minute documents did confirm the ability to file for accelerated approval based on the cUHDRS, maybe like the meeting minutes from the RMAT meeting at the end of 2024. Was that officially documented in what they sent to you? And maybe how much detail do they go into in these meeting minute documents around the definition of the statistical analysis plan and the external comparator?

Yes. Joe, I can confirm that in our November 2024 multidisciplinary meeting with the FDA and the written comments that we received, the FDA stated that the data from the Phase I/II study in comparison to an external control may serve as the primary basis of a BLA submission. They also confirmed that the composite UHDRS would be considered an acceptable intermediate clinical endpoint to support accelerated approval. In that particular meeting, they didn't get into specifics on the statistical analysis plan, but had recommended that we prespecified stats plan, and that was discussed in detail as well as the natural history protocol in our April 2025 meeting with the FDA.

Our next question comes from Luca Issi from RBC Capital Markets.

Maybe, Matt, again, I appreciate the situation is still fluid here, but can you just talk about what needs to happen from here over the next few weeks in order for you to continue to invest capital in Huntington? I guess what I'm trying to ask here is, where do you draw the line between continuing to fight this versus just give up? Like any color there much appreciated.

Yes, I wouldn't characterize this as a fight. I think that we are 100% committed to continuing to collaborate and partner with the FDA to determine an expedited path to submit a BLA. I think we strongly believe that AMT-130 can meaningfully benefit patients. I think we feel that we have what is considered to be the most compelling data set in the field of Huntington's with 3 years of clinical outcomes data showing a meaningful slowing of disease progression. And we think that if there are concerns or issues that they ought to be addressed in a proper review.

And so we will continue to work with the FDA to address any concerns they have with the hope of having an expeditious submission of a BLA in the near future. That is the pathway that we're going to be focused on. And we are committed -- we believe we have a drug that works. We have a patient group that is -- that has an urgent need, and we're committed to doing everything we can to bring this to them as quickly as possible.

Our next question comes from Yanan Zhu from Wells Fargo.

Just first, a quick clarification for the ALS program, is it intrathecal delivery? And if so, is the AE, the dorsal root ganglion AE previously known to this route? Then maybe just on the Huntington's program, just wondering, can you characterize how motivated or mobilized the patient and doctor community is on this issue and how that could help move the issue around?

Okay. Walid, do you want to answer the first one, and then I'll kick it to Kylie to do the second.

Thanks, Matt. Yes. On the first question, the answer is yes to both. So intrathecal delivery, and it's dorsal root ganglion toxicity, which, again, as I said, unfortunately, is associated with this mode of administration, and we knew this was a risk. So yes. Over to you, Kylie.

Thanks, Walid. Yes, as I just said, the patient and physician community are very motivated. They have a huge unmet medical need and are collaboratively working together to look at how to move this forward. I think one of the things that's important is we received a big expression of hope and excitement coming out of the data and then to have this disappointment a few weeks later is a bit of an emotional roller coaster for the community. But I think they're working together to look forward and say, "How do we bring this therapy to patients."

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

This is [ Erabella ] on for Patrick. I was just wondering if you could clarify if you've received any EMA or MHRA preliminary feedback on accepting the same data set and external control for AMT-130 as primary evidence? And could you see ex U.S. submissions proceeding ahead of FDA approval?

Walid, do you want to answer that?

Sure. So we have not yet engaged in the U.K. or EMA -- MHRA or EMA. That is the plan to go next. We're prioritizing the FDA. But I will say that we are committed to work with the FDA also to continue to find a path forward and also with other regulatory agencies. And we will advance as quickly as possible on all these fronts to bring this therapy to patients as quickly as possible.

[Operator Instructions] Our next question comes from Paul Matteis from Stifel.

As it relates to the meeting, again, answer whatever you're comfortable with. But given that your dialogue here, I guess, as I understand it, has been with a relatively similar group of people across the spring meeting and then last -- November last year, when they came out and told you that they didn't think this path was no longer supportive of a BLA, did you ask them why and what exactly had changed? And then just separately, can you clarify for us what specific data have you shared with the FDA at this point? And have they seen more data from this 3-year analysis than we have?

Yes, Paul, unfortunately, we're not going to be able to comment on the details of the specific meeting. But we do hope for clarity once we do receive minutes. And to the extent that there are material updates, we will endeavor to update investors and analysts. So I think that's the answer to your first question. And then the second question. Okay. Yes. On the data -- no, the data that was submitted to the FDA was consistent with the data that we've shared publicly a number of weeks ago. Obviously, there's some additional data like sensitivity analyses that haven't been presented, but there was no new follow-up or additional data that was provided to the agency.

We have no further questions. This will conclude today's question-and-answer session and today's call. You may now disconnect.

Good day, and welcome to the top line results for AMT-130 in Huntington's disease. [Operator Instructions] As a reminder, this call may be recorded. I would now like to turn the call over to Chiara Russo, Senior Director, Investor Relations.

Please go ahead.

Thank you.

This morning, uniQure announced pivotal data on patients treated with our investigational gene therapy, AMT-130 in our ongoing Phase I/II clinical trials in Huntington's disease, taking place in the U.S., EU and the U.K. This 3-year update consists of data on clinical endpoints and exploratory biomarker and safety and tolerability as well as anticipated regulatory next steps and potential commercial opportunity.

Joining us on this investor event and webcast are Matt Kapusta, our Chief Executive Officer; Dr. Walid Abi-Saab, our Chief Medical Officer; Kylie O'Keefe, our Chief Customer and Strategy Officer; and to provide a clinician's perspective on the experience of patients with Huntington's, Dr. Sarah Tabrizi, Joint Head of the Department of Neurodegenerative Diseases at University College London, Director of the UCL Huntington's Disease Center and member of the U.S. National Academy of Medicine.

The slides included in this morning's webcast will be available on the Investor page of uniQure's website shortly after the conclusion of this event. Please note that we will 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 quarterly report on Form 10-Q filed on July 29, 2025, and other securities 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 I am pleased to introduce Matt Kapusta, uniQure's CEO.

Thanks, Chiara, and good morning, everyone.

Today marks a very important milestone for patients and families affected by Huntington's disease and for the uniQure team. As reported in our press release this morning, we achieved the primary endpoint of our pivotal Phase I/II study. High-dose AMT-130, our registrational dose demonstrated a statistically significant 75% slowing of disease progression as measured by the composite Unified Huntington's Disease Rating Scale of 36 months as well as positive trends across all its subdomains. Equally important, the study also demonstrated a statistically significant slowing of disease progression as measured by total functional capacity, a key measure of a patient's ability to live independently and an important endpoint for regulatory agencies in assessing efficacy.

Moreover, CSF neurofilament light chain, a well-characterized and supportive biomarker measuring neurodegeneration was below baseline at 36 months, and AMT-130 continues to be generally well tolerated. Together, we believe these findings provide compelling and clinically meaningful evidence of AMT-130's disease-modifying potential, and we plan and are currently preparing to submit a BLA for AMT-130 in the first quarter of next year. Huntington's disease is one of the world's most prevalent monogenic disorders. We estimate that approximately 100,000 people in the U.S. alone carry the gene mutation that causes Huntington's.

Sadly, there are no approved disease-modifying treatments with clinical failures and setbacks highlighting the urgent need within the HD community. The onset of symptoms typically between ages 30 and 50 robs people of relationships, careers, mobility and independence. Within 10 to 15 years, most patients succumb to the disease and family members live under the constant shadow of uncertainty. Over the years, we have listened to the heartbreaking stories of many individuals and families living with HD. Their courage fuels our determination to bring forward a therapy that can meaningfully alter the trajectory of this condition, provide improved quality of life and more time with loved ones.

We believe AMT-130 has the potential to be the first treatment to truly modify the course of Huntington's disease with the following key attributes: First, AMT-130 is designed as a durable once-administered treatment, an especially important advantage in a slowly progressing lifelong disorder where early intervention is essential. Second, targeted administration of AMT-130 enables precision-based delivery to the brain regions affected by Huntington's disease, helping to maximize therapeutic concentrations locally, protect unaffected tissue and limit systemic exposure and related toxicity. Third, AMT-130 targets the first exon of the huntingtin gene, suppressing both the full-length mutant protein and the highly toxic exon 1 splice isoform, an advantage that most other product candidates do not offer.

Finally, AMT-130 is delivered using a well-established stereotactic procedure that is well within the skill set of Board-certified neurosurgeons, supporting the potential for broad clinical adoption of AMT-130. With that, I'm pleased to turn the call over to Dr. Walid Abi-Saab, our Chief Medical Officer, who will review the updated clinical data in greater detail.

Walid?

Thank you, Matt.

Good morning, good afternoon, everyone. First, let me start, as always, by profoundly thanking the patients, their families and caregivers as well as the larger Huntington's disease community for their unwavering dedication to helping develop a potential disease-modifying treatment for this devastating disease. In particular, without the support of tens of thousands of patients who have volunteered over the years for observational studies such as Enroll-HD, our analysis would not have been possible. I'm thrilled to be providing you today with the exciting update on the pivotal data from our ongoing Phase I/II study of AMT-130 in Huntington's disease.

Before I get into the details of the study results, let me take a moment to go over the primary clinical endpoint in this pivotal study. The composite Unified Huntington Disease Rating Scale, or cUHDRS, was designed to detect disease progression with a high degree of sensitivity. It is increasingly being used in clinical research and its ability to detect disease progression has been demonstrated in several recent clinical trials. The cUHDRS consists of 4 clinical assessments designed to test different functional capacities that are impacted by HD. Total functional capacity is a measure of the ability of patients to carry out activities of daily living, such as employment and doing their finances as well as caring for themselves.

Total motor score is a measure of motor dysfunction with higher scores corresponding to worse impairment. The Symbol Digit Modalities Test measures processing speed, attention and concentration. Last but not least, the Stroop Word Reading Test measures executive function and inhibitory control. As I will show later, high-dose AMT-130 showed evidence supporting of disease slowing across all 4 of these clinical subdomains of the cUHDRS. Earlier this year, we held a Type B meeting with the FDA to discuss the proposed use of external control data and the proactively prospectively defined statistical analysis plan, or SAP, in support of a planned BLA submission for AMT-130.

The FDA agreed that the cUHDRS could serve as an acceptable registrational intermediate clinical endpoint for accelerated approval. Additionally, the FDA agreed that the primary efficacy analysis for the BLA would evaluate the 3-year change in cUHDRS in the high-dose AMT-130 patients compared to a propensity score adjusted external control arm. In agreement with the FDA's recommendation, we selected propensity score matching for the primary analysis.

The FDA also agreed that Enroll-HD, a large prospective longitudinal natural history study of Huntington's disease may be acceptable as the external control data set for the primary analysis with each dose matched to corresponding controls based on their baseline characteristics. As you can see on this table, the baseline demographics and key disease characteristics are overall well matched across patients treated with the high dose of AMT-130 and the propensity score matched external control group from Enroll-HD.

On to the results now. In the study's primary endpoint of cUHDRS, we can see clearly that at 36 months, AMT-130 shows a statistically significant reduction in disease progression as shown on this graph. These are the results from the mixed model of repeated measures analysis or MMRM, which was the prespecified primary analysis in the statistical analysis plan aligned with and submitted to the FDA. The lead square means that the propensity matched external control group declined by more than 1.5 points at 3 years, whereas those treated with AMT-130 showed a reduction of 0.38, representing a 75% reduction in the rate of decline.

Here, looking at the time course of the observed data over 3 years, compared to the propensity score matched external control, you can clearly see the slower progression of disease in those treated with AMT-130. A difference which is becoming more and more evident as time from treatment increases. Next, we look at the secondary endpoint of total functional capacity, where we again have a statistically significant difference from the match external controls with disease progression reduced by 60% at 36 months. TFC is an important clinical measure for the FDA as it assesses a patient's overall function and independence. TFC is also an integer-based scale, which, while clinically meaningful, is usually less sensitive to change than the cUHDRS.

Therefore, I'm very pleased to be able to demonstrate a statistically significant difference on this key secondary endpoint, which speaks to the robustness of the effects of AMT-130. In this slide, you can see the time course for changes in TFC, which clearly shows a general level of stabilization in patients treated with AMT-130, whereas you can continue to see gradual but steady decline as one would expect in patients who are untreated. Here, we see the results of the 3 additional components of the cUHDRS, SDMT, Stroop and Total Motor Score, all of which are also supportive of disease-modifying, disease slowing in patients treated with high dose of AMT-130 with effects ranging between approximately 60% to more than 100% reduction in disease progression.

These results show favorable trends in all measures used in the cUHDRS, including cognitive, motor and functional measures. On the next slide, we see the data from the low-dose group, where results were more variable. We believe that these data suggest that the low dose of AMT-130 has biological activity, but at the low end of the dose response range, supporting the notion of a dose-dependent effect when compared to the consistently positive effects seen across all these domains with the high dose. Moving on to neurofilament light chain or NfL. This is an important measure of neurodegeneration and a supportive biomarker in Huntington's disease.

Several independent studies have shown a strong association between CSF NfL levels and the clinical severity of HD with expected increases of approximately 10% to 15% per year in early manifest patients. In patients treated with AMT-130, initial post-procedure increases in NfL levels were followed by a consistent decline over time, returning to and remaining below baseline after 12 to 18 months. These results suggest a slowing of neurodegeneration. Specifically, at month 36, as shown on this slide, we see approximately 5% and 8% reduction from baseline at the low and high dose, respectively. Turning to safety. AMT-130 has remained generally well tolerated with a manageable safety profile at both doses.

As we have previously reported, the majority of drug-related adverse events, in particular, serious adverse events of CNS inflammation occurred within weeks post treatment and resolved with glucocorticoid medication or supportive care. I'm happy to say that there have been no new treatment-related serious adverse events observed since December of 2022. As you can see from this table, the most common adverse events tend to be related to the study procedures such as headache, procedural headache and procedural pain. Again, we have no new AMT-130-related SAEs to report. Here are the planned next steps for this program over the coming months. In the fourth quarter of this year, we look forward to holding a pre-BLA meeting with the FDA to present these updated data and to discuss the content and format of the forthcoming BLA. In the first quarter of 2026, we expect to submit a BLA for AMT-130 with a request for priority review.

In summary, following the statistical analysis plan agreed upon by the FDA, at 36 months, AMT-130 met both the primary and the key secondary endpoint, demonstrating a meaningful slowing of disease progression compared to a robust external control. The data show a statistically significant 75% slowing of disease progression on the study's primary endpoint of cUHDRS with a p-value of 0.003. In the key secondary endpoint of total functional capacity, which again is important from a clinical and regulatory perspective, we have demonstrated a 60% slowing of disease progression, which was also statistically significant with a p-value of 0.033. These noteworthy and I believe, frankly, unprecedented clinical findings are supported biologically by CSF NfL levels that remain below baseline, suggesting a reduction in neurodegeneration in line with the mechanism of action of AMT-130. AMT-130 continues to be generally well tolerated with a manageable safety profile. Notably, there has been no new serious adverse events related to treatment observed since December of 2022, over 30 months ago.

I will now turn the call over to Dr. Sarah Tabrizi, a leading expert in the Huntington's disease field, who will share her perspective on the data.

Sarah?

Thank you.

I'm a Professor of Neurology at the UCL Queen Square Institute of Neurology. I'm the Director of the UCL Huntington's Disease Center and Joint Head of the Department of Neurodegenerative Diseases at UCL in London. I'm delighted to be invited to talk about the AMT-130 results, and my comments today are based on my own experience of working in the Huntington's disease field for nearly 30 years and being a lead scientific adviser to the study.

Huntington's disease is a truly devastating inherited neurodegenerative disorder. It affects people in the prime of life, often in their early 40s. It leads to a combination of progressive dementia, movement disorder and behavioral disturbances and the disease course is relentless. It results in significant disability and loss of function, which necessitates intensive multidisciplinary care over many years. The impact on patients and their families is profound as they must manage the evolving symptoms over a prolonged period.

As Walid mentioned, disease progression in Huntington's disease can be objectively measured using validated tools such as the Composite Unified Huntington's Rating Scale and the total functional capacity, both used as outcome measures for AMT-130. The composite cUHDRS captures multiple key domains of the disease, including motor, cognitive and neurological functional abilities. The total functional capacity scale really assesses a patient's decline in function as the ability to work, manage their finances and perform daily self-care. As reported today in the AMT-130 pivotal study at the high dose, there was a 75% slowing of disease progression as measured by the Composite Unified Huntington's Rating scale and an impressive 60% reduction in the rate of functional decline as measured by the total functional capacity.

The external comparator group were from CHDIs in Enroll-HD natural history study, which the FDA approved as a comparator arm for this gene therapy. I truly believe that these results indicate that AMT-130 could have a significant impact on slowing disease progression and offer the potential to improve and lengthen quality of life in HD patients. The study also demonstrated improved biomarkers indicative of neuronal function in the brain. CSF neurofilament levels in high-dose patients were below their original baseline level compared to what is an expected increase of 30% to 45% in the normal progression of Huntington's disease over 3 years.

To me, this suggests that AMT-130's targeting of mutant Huntington and all its toxic forms is indeed preserving nerve cells and in turn, neurological function. I have over 30 years of experience in Huntington's disease research and clinical care. And I believe these data are the first to provide clear evidence of an investigational therapy inducing Huntington's disease modification. This is an immensely exciting development for the Huntington's field. To me, these game-changing data really offer a beacon of hope for patients and their families and represents a significant step towards delivering a licensed disease-modifying therapy for Huntington's disease. And I feel we, as a community must work together to help get this therapy to as many Huntington's disease patients as possible.

Thank you.

Thanks, Sarah, for your very meaningful perspective. I will now turn the call over to Kylie O'Keefe, uniQure's Chief Customer and Strategy Officer, who will frame the commercial opportunity.

Kylie?

Thanks, Matt. I will now take you through the U.S. Huntington's disease patient funnel and potential long-term growth drivers as well as the U.S. treatment centers of excellence. There are currently 200,000 Americans are at risk for Huntington's disease due to family history. Of those at risk, there will be approximately 100,000 patients who are genetically identifiable, including both presymptomatic and symptomatic HD patients.

As the disease progresses, all patients eventually become symptomatic with deterioration in motor function, cognition and overall behavior. When you narrow the focus to symptomatic HD patients, there are approximately 40,000 patients in the U.S., of which about 50% of these patients are currently diagnosed, which equates to approximately 20,000 total diagnosed symptomatic HD patients in the U.S. today. If approximately 30% are considered initially treatable patients at launch, this represents a total addressable market of around 6,000 U.S. HD patients at the timing of a potential launch. This is an early estimate, taking into consideration a number of different market factors, which we will continue to evaluate in the coming months as we learn more.

We will also continue to dive deeper and share additional insights into the AMT-130 opportunity and the expected ramp early next year. However, we are confident there is a large number of HD patients that could be mobilized in the early period of potential launch. Augmenting the initial addressable market, there are several potential long-term growth drivers to the patient population. Firstly, and as I mentioned earlier, patients that are progressing through the stages of their disease, transitioning from presymptomatic to symptomatic as well as new incident patients. Secondly, driving an increase in the diagnosis rate. Currently, in the HD community, there is a reluctance to do genetic testing and receive a diagnosis due to psychological, social and ethical barriers.

As a disease-modifying therapy becomes available, we anticipate a shift in genetic testing behavior driven by hope rather than fear. Also, improved access to genetic testing and counseling as well as patient education could accelerate earlier identification. And lastly, our continued focus on expanding the different patient segments to broaden the patient opportunity will also be important. Moving on to the U.S. Centers of Excellence, which we see as one of our key pillars to our U.S. launch strategy. What you can see here is a heat map of the patient volume by state. The stars represent the U.S. ClearPoint capable facilities using the MRI-guided technology utilized for the treatment procedure, overlaid with the Huntington's Disease Society of America, or HDSA, certified U.S. Treatment Centers of Excellence. There are 2 key points here.

The patient volume aligns nicely with the key treatment centers of excellence, and there are a substantial number of centers that we believe would have the capabilities to support the treatment of HD with AMT-130. We have ongoing efforts to profile and prioritize the key treatment centers for launch, thinking through the potential capacity needed for the first year and beyond. With that, I will hand the call back over to Matt.

Matt?

Thanks, Kylie. In summary, we are extremely excited by the 3-year data shared today. These results underscore our belief that AMT-130 has the potential to become the first therapy to slow the progression of Huntington's disease, offering real hope to patients and families who have waited far too long for an effective treatment. As we move closer to a planned BLA submission, our focus remains clear: to advance AMT-130 with urgency, maintain the highest scientific and ethical standards and be fully prepared for a potential launch. We want to once again express gratitude to the patients, caregivers, investigators and advocacy groups who have made this milestone possible as well as to the entire uniQure team for their unwavering dedication.

With that, operator, please open the line for questions.

[Operator Instructions] Our first question comes from Paul Matteis with Stifel.

Congratulations on the data. We appreciate it. I wanted to just drill in on this upcoming FDA meeting ahead of the planned submission. And just maybe you can clarify for us what you want to learn at that meeting and what questions you're going to pose. Second question on the regulatory side is the TFC data here are super encouraging. And do you feel like that changes the conversation now on potential full approval and whether there could be a faster path to full approval? And then for Dr. Tabrizi, it would be great to hear from you on how you think about the scalability of this at your center, at other centers that look like yours, realistically in the first year or 2 of this potentially being approved, if it were, how many patients do you think could realistically get it?

Thanks, Paul. This is Walid. I'll take the first couple of questions and then turn it over to Sarah.

So the pre-BLA meeting is a regularly scheduled meeting with the FDA. It's been the natural progression after we talk with them. We will be sharing with them the data that we presented today so that they will get to review and then go over all of the material that will need to be included in the BLA so that we maximize the chances of the BLA being accepted. Regarding TFC and full approval, I think this was a question that we asked the FDA at the time. They said this would be a review issue. But I do not think that before having reviewed these data with them, that would be appropriate for us to comment any more on the likelihood of any action to the regular pathway and full approval versus the accelerated one.

And then I'll turn the question over to Sarah regarding scalability or Dr. Tabrizi?

Thank you. Currently, the neurosurgery takes about -- roughly about 12 hours, mentioning the ClearPoint SmartFlow delivery. This delivery system is widespread in neurosurgical centers. We, at Queen Square, which is the biggest center in Europe, we have several facilities that's able to deliver MRI-guided neurosurgical gene therapy. There are other sites in the U.K., several sites in Europe and many sites in the U.S. as well. I think the plan that the surgical procedure will be streamlined. It will be smoothed and made as rapid as possible. And I'm not concerned about getting the drug to patients. I think we have the neurosurgical capability and expertise, and it will be for the sponsor to make sure that's rolled out seamlessly.

Our next question comes from Joe Schwartz with Leerink Partners.

Congratulations on the amazing results. I have a question for Dr. Tabrizi and management. How is the value of AMT-130 grown over time with each successive year of benefit? What does it mean to patients in the health care system to flatten the disease progression curve by so much for 3 years in counting in such a challenging disease. With the absolute delta in cUHDRS seeming to widen and now a TFC benefit, can you put that value into perspective for us from the standpoint of patients as well as the health care system pharmacoeconomically?

Sarah, why don't you go and answer that?

So as I mentioned, Huntington's disease, I think, is really one of the cruelest diseases. It's slowly progressive and inexorable with significant disability and huge health economic burden cost because it affects people when they're young and in the prime of life. The key thing that I think with a 75% slowing means that people will be able to stay and work longer. They'll be able to function longer. They'll be able to maintain their independence.

And as we hope, and I'm very invested in this, we want to be able to treat people eventually in stage 0 and 1 decades before they show any signs and symptoms with such therapies, and we may be able to prevent the symptoms ever occurring, which will be the closest we can come to prevention of this disease. And that's one of our -- my personal huge goals. So what this means to patients is huge. 75% slowing of disease progression is greater than what we even anticipated and expected and hoped for. And that means for 1 year of disease progression, it slowed by -- they will have 4 years longer in terms of disease-free life. So the effect of 75% slowing is a huge effect size and will have massive effects for patients' lives.

Our next question comes from Debjit Chattopadhyay with Guggenheim Securities.

Congrats on the data. One question for Dr. Tabrizi. Dr. Tabrizi, are there any shortcomings to these data, the low dose versus high dose, et cetera, that would give you a pause? And I have a follow-up for Matt.

Thank you for that. No, I don't think there's any shortcomings. I am here because I think the data are really very exciting, a 75% slowing in the composite Unified Huntington's Disease Rating Scale, which captures all aspects of function, motor score, cognition and a 60% slowing in total functional capacity. We really just haven't had anything like that. And I have run many different clinical trials. I've developing drugs. But when the data was so clear to me that this drug was working, the effect size was huge. So in all honesty, I don't see shortcomings. I am just truly excited having worked in this field for a long time that we now have a drug targeting all the toxic forms of mutant Huntington that will slow this dreadful disease.

Our next question comes from Joseph Thome with TD Cowen.

Congrats on the data. Maybe just one. We've seen a couple of companies lately get caught up on the CMC side of things. So if you could just comment a little bit on your sort of manufacturing and CMC capabilities and confidence going into the regulatory submission. And then maybe one more, if I can, for the physician. I guess, what proportion of your eligible patients do you think will be interested in actually undergoing the surgery?

Okay. Maybe I'll take the first question on CMC. So Joe, as you know, uniQure being founded more than 25 years ago, CMC has always been a strength of the company. We have a facility that is a licensed facility that is producing a commercially available gene therapy that is supporting AMT-130. As we mentioned in August, we started our performance process qualification campaign. That campaign is going well. And it's -- right now, the timing is supportive of a BLA submission in the first quarter of next year. So we're feeling really good about where we are and looking forward to moving that work forward.

Sarah, do you want to answer the second question about eligibility?

Absolutely. As you know, in this study, the subjects that were studied had late Huntington's integrated staging system Stage 2 and early Stage 3. So they were early symptomatic patients, and you can see the very clear clinical benefit supported by molecular markers showing that we're helping prevent neurodegeneration because of the really impressive drop in CSF neurofilament.

So in terms of eligibility, that will be up for the discussion with the regulators. But myself and colleagues at -- many colleagues from all around the world developed a Huntington's disease integrated staging system. And this staging system stages Huntington's into 4 stages, Stage 0 through to Stage 3. And this study was in late Stage 2, early Stage 3, which is symptomatic, early symptomatic. The disease process is the same across all of the stages. And because the core problem of Huntington's is the same in everyone before and after onset of symptoms, this therapy potentially should be -- could be available for everyone from stage 0 to Stage 3, and that will be something that we will be hoping to roll out.

Our next question comes from Uy Ear with Mizuho.

Congrats on the great data. Just wondering have you done any sort of reimbursement work? I know that you just got the data, but just wanted to see what your feeling or sentiment with respect to how payers would look at this?

Yes. Thank you very much for the question. We have started some initial thinking around payers. As you noted, obviously, this is brand-new data. And so the real work begins now. But we've started to take a look at what the payer mix will be and how we start to think about value proposition.

Huntington's disease has a huge unmet medical need. Obviously, as Sarah has talked a lot about, it has a huge impact on patients. And right now, there's no disease-modifying therapies available. And so it's about helping to educate the payers on what this value story means and what the 75% reduction in composite Unified Huntington's Disease Rating Scale means to these patients and their lives, and that's going to be some of the work that we have ongoing.

In addition to that, obviously, showing benefit in TFC is incredibly important as it's a clear clinical endpoint and payers appreciate that. So more to come on the value story, but education and early payer engagement is critical to success, and that's something our access team has begun.

Our next question comes from Kristen Kluska with Cantor Fitzgerald.

Congrats on these great data. So I wanted to ask about the natural history data that you compared this to. I know it was a very large data set. But generally speaking, as there were several patients that were matched for each one with the uniQure data set, would you say that the natural history really does tell a very clear story about the progression of this disease? Or was there a bit noise as it relates to that given there were so many patients in the sample?

Thank you, Kristen. It's Walid. Well, actually, one of the strengths of the Enroll-HD is it has such a large number of patients that we can really maximize the selection of which ones would be a good match. And if you look at the error bars that you see in the observed data, you can see how tight they are for the natural history.

The other thing that I can say is that we -- as part of the sensitivity analysis that we conducted, we looked at the natural history using different types of matching, propensity score matching with different also types of propensity score matching, propensity score weighting as well as looking even at track and predict HD. And the estimate of the decline over the 3 years across cUHDRS and TFC were consistent across all of these. The totality of this gives us a lot of confidence in the results that we have seen that this is not an artifact of choosing Enroll-HD or choosing a specific type of analysis for Enroll-HD, and that's one of the strengths of our data. So no, I think I'm very convinced that this is really a great way to be able to compare to, and I'm confident in the results.

Our next question comes from Salveen Richter with Goldman Sachs.

Congratulations on the data here. Could you just help frame the initial target patient population that you would be going into at launch? And regarding the additional cohort that's evaluating the drug in patients with lower striatal volumes, what percentage of this population would this cohort unlock?

Yes, absolutely. So as we shared, there's approximately 40,000 symptomatic HD patients in the U.S. And of these 40,000, about 50% of these are currently diagnosed. So that represents around 20,000 symptomatic diagnosed HD patients in the U.S. at present. If you take a 30% adjustment to that for looking at an initially treatable patient population at launch, that gets you to 6,000 U.S. HD patients.

Now as we said, this is an early look, and we're continuing to evaluate the different market factors. From a Cohort 4 perspective, I think what that size of the population that represents, I think we're looking at that at the moment and trying to assess what opportunity this would unlock for us as we continue with obviously BLA discussions and moving forward. But we think this is obviously giving us an opportunity to continue to broaden the patient segments that would be eligible. So more to come there.

Our next question comes from Luca Issi with RBC.

Congrats on the data. Just maybe a couple of questions here. So maybe on the data itself, Walid, there were obviously 17 patients at baseline at a high dose versus, I think, 12 patients at 36 months. So what happens to the additional 5 patients? Are those patients loss of follow-ups that got censored? Or are those 5 patients that have yet to reach the 36-month mark? And if it is the latter, when are you going to show us this 5 additional patients? Just asking simply because the end is relatively small here.

And then maybe on regulatory, Walid, wondering if you can comment on whether this data is potentially eligible for the commissioner's national priority review voucher that could potentially shrink the time line down to 1 to 2 months. Again, any color there, much appreciated. And then maybe finally, quickly on maybe Kylie. I appreciate it's still early days, but how are you thinking about pricing?

Thanks, Luca. So indeed, there were 17 patients enrolled in the trial at the high dose, and we have data at 36 months for 12 of those. So as we've communicated earlier, there were 2 patients who dropped out previously voluntarily from the trial. And there are 3 that are ongoing that now have passed the 24 months, and you can see that in the graph that we showed at 24 months, we have 15 patients. And those patients, we expect them that they will be able to complete their 3-year time point by the middle of next year. Now just to remind you, the primary analysis that we conducted, which is the MMRM, actually takes into consideration all of the data.

So this is not just looking at the 12 at the end, but looking at the totality of the data that we have the 17 at year 1 and 15 at year 2 and the 12 at year 3, plus comparing to the natural history, which you also can see from the table that we showed that there's also some attrition over time as often is the case in trials. So overall, this is how the disposition of patients are and the analysis. In terms of the [ CNRV, ] we are evaluating this as -- and evaluating actually all options. This will be part of our thinking from a regulatory perspective and discussion with the agency, and we will communicate that to you once we have more clarity on that point. And with that, I'll turn it over for Kylie.

Wonderful. Thank you. As you said, Luca, it's obviously a bit premature to comment too much on pricing. But what I will say is, as we've talked about, there's a large number of patients that are ready to be mobilized. And we have a high focus on the value proposition of what AMT-130 brings to the Huntington's disease patients. And then what I would also go on to say is that for now, the guidance we can give is that we're looking at pricing AMT-130 in line with other gene therapies. And as we continue to evolve this, we'll share more.

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

On the data release today. Just a couple of questions from us. Just the first for the company. I was wondering what learnings have emerged from the Cohort 3 immunosuppression? And what would you expect to carry forward into the commercial setting? And for Dr. Tabrizi, I was wondering if you could further characterize for us what your view is of the long-term safety profile, how this looks across both high and low-dose cohorts? And just based on that, we've met the primary and secondary endpoints here, how confident are you these data will be sufficient for an accelerated approval?

Right, Patrick, I'll take the first question on Cohort 3. As you know, Cohort 3 was designed to evaluate the effects of the triple immunosuppression of steroids, rituximab and sirolimus and when we analyzed those data and compare the various outputs in terms of immune response and the CNS edema on imaging and the clinical pictures, of course, we concluded that the risk benefit of this immunosuppression actually is not positive. We had 2 or 3 SAEs, 2 were related to infection related to the immunosuppression and one was an adverse event related to steroids.

And overall, we believe that a short course of steroid is probably the best way forward. That is what we're going forward with in our Cohort 4. This -- we're talking about 2 weeks at middle dose level. This is something that is very commonly used by neurosurgeons, and they're very comfortable in that space. And we think that would be enough to control any potential adverse events that we might see with the therapy. And with that, I'll turn it over to Sarah for the second question.

Thank you. So your question was about regulatory approval and long-term safety. So the 36 months of data, so Huntington's disease is a slowly progressive disease once symptoms begin. So the 36-month data has given a long enough interval to really show progression on the composite Unified Huntington's Disease Rating Scale and total functional capacity. In addition, the 36 months of data gives us the longest-term safety data that we can. And so, so far, as Walid mentioned in his presentation, the safety signals are excellent.

And so with 3 years of data, I am convinced that this drug is modifying the course of the disease. Will it get approved by the FDA in the discussions? I'm not a regulator. But I've seen many clinical trial results over my years working in Huntington's disease. And these clinical trial results are very clear cut. The numbers are small in the high dose. Of course, 12 people have reached 36 months, but that's quite typical for gene therapy trials and the value and importance of the propensity score matched Enroll-HD data, which has really been critical. I'm very optimistic that we will try and get this drug to patients and families as soon as we can.

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

Great. Congrats on the very exciting data. I wanted to dig into the TFC endpoint a little bit here. Very encouraging data today on both 36 months and 24 months. I think the 24-month data as presented previously was not as positive. So obviously, you have more patients at this -- at today's update.

I was wondering was the larger end the main driver for the change in the TFC data point at 24 months? And secondarily, if I can quickly ask, assuming confirmatory trial -- assuming accelerated approval is the path and a confirmatory trial is required, how do you think about FDA's requirement for the confirmatory trial to be well underway at the time of approval? Would that be something that can be done with the current forecast?

Thanks, Yanan.

So yes, indeed, at the -- with the TFC at 2 years, I think the additional 3 patients, that's 1/3 of that sample size. Last time we shared with you was 9 -- thank you, Matt. So Matt was very helpful. Actually, we have 15 patients now at 2 years that we're showing you that 6 patients, that's like 2/3 more than what we showed previously with 9 patients. And that -- you can see that makes a bigger difference. And you see the data also at 12 -- at 36 months is very consistent. So we're very confident that TFC is starting to really come through the longer we continue to follow these patients. And that's something that really bodes very well for the efficacy of the drug and show the robustness.

In terms of the confirmatory trial with the FDA, we've tried to have the discussions with them a couple of times, but the agency was very clear that they would like to see data from this trial before they can decide whether they're going to take action via traditional pathway as in full approval or accelerated pathway, which will then require confirmatory trial. But it was very clear to us that even if they go down the path of accelerated approval, because it is -- we're following what they're doing, it's not going to require that we start that trial, have it 50% recruited or whatever to delay approval of the accelerated pathway. So we are looking forward to going to talk to the FDA in the fourth quarter. We will review the data with them, and that will give us a clear path as to what the next steps are.

Our next question comes from Ellie Merle with UBS.

Congratulations on the data. Just to follow up on the number of initially eligible patients, specifically as you think about the potential label, how should we think about how broad or narrow the label might be in terms of the eligible patients? Specifically, would you expect the label to be restricted to symptomatic patients? And then just from a commercial perspective, how do you expect payers to define symptomatic patients? Lastly, just a question in terms of the data. Did you see any different effects in the late Stage 2 versus the early Stage 3 patients?

Yes. Thanks, Ellie.

I think it's obviously a little bit premature for us to have the clear line of sight into the label. I think the way we've tried to think about this initial estimate of patients that could be treatable at launch, we've tried to think about some of the factors that could go into it. But I think it's too premature to comment on what we think the label could look like, including both on a symptomatic level and then also what segments will be within the label. But as we learn more, we'll continue to share.

From a payer perspective and how payers are expected to classify symptomatic patients, I think, obviously, a genetic confirmation will be critical. And then how they confirm a diagnosis from there, I think it's something that we will need to discuss further. I don't think it will be consistent across payers. I think you'll see some differences. And as I mentioned earlier, education and early payer engagement is going to be critical to helping us understand how they see a diagnosis and how we can help educate them on what's appropriate from a diagnostic point of view. So I think it's going to be a 2-way street, and there's more work to be done there.

So on the question on Stage 2 versus Stage 3, it's Walid. I'll take that. So here, we're talking about very small numbers. But what we have observed as 3 years is that the more advanced Stage 3 patients did not do worse than the Stage 2 patients.

I'm showing no further questions at this time. I'd like to turn the call back over to Matt Kapusta for any closing remarks.

Okay. Thank you, everyone, for joining us today and for your thoughtful questions. A real special thanks to Dr. Tabrizi for her time and participation on today's call. We are all enormously excited about these pivotal results and look forward to keeping you informed as we move closer to our planned BLA submission.

Have a great day.

Thank you for your participation. This does conclude the program. You may now disconnect. Everyone, have a great day.

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 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. 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.

Good day, and thank you for standing by. Welcome to the regulatory update on AMT-130 for Huntington's disease. [Operator Instructions] Please be advised that today's conference is being recorded.

I would now like to hand the conference over to Chiara Russo, Senior Director of Investor Relations. Please go ahead.

Good morning, and thank you for joining us. This morning, uniQure announced alignment with and further productive guidance from the Food and Drug Administration on key components of the primary statistical analysis plan and CMC requirements in support of the accelerated approval pathway for our investigational gene therapy, AMT-130 for the treatment of Huntington's disease.

On this call, we will walk through the key components we have reached alignment on and guidance from the agency as well as our anticipated next steps. Joining me on this webcast are Matt Kapusta, our Chief Executive Officer; and Dr. Walid Abi-Saab, our Chief Medical Officer.

Please note that we will be making forward-looking statements during this conference 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. These statements are subject to various risks and 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.

Thank you, Chiara, and good morning, everyone. We are very pleased to share an important regulatory milestone for AMT-130, our wholly owned investigational therapy for the treatment of Huntington's disease. Following 2 Type B meetings with the FDA, we've now aligned with the agency on key components of the primary statistical analysis plan and CMC requirements to support a BLA submission planned for the first quarter of 2026.

This alignment represents a critical step forward in the development of AMT-130 and adds to the growing momentum behind the program. It further strengthens our confidence in the accelerated regulatory path ahead and in our ability to bring this potentially transformative therapy to patients. Let me briefly walk through the highlights from our recent FDA interactions, and then I'll turn it over to Walid to provide additional details.

Starting with CMC, following our Type B meeting in March, the FDA agreed that validation of the AMT-130 manufacturing process should be possible using our experience and prior knowledge from HEMGENIX. This will be complemented by additional full-scale AMT-130 GMP batches and a single Process Performance Qualification or PPQ batch. We view this outcome as a strong endorsement of both the quality of our manufacturing platform and the productivity of our interactions with the FDA thus far. This alignment streamlines our path forward and enables us to move forward more efficiently towards a BLA submission.

In our second Type B meeting focused on the proposed statistical analysis plan, the FDA also agreed that the primary efficacy analysis will be based on the 3-year change in cUHDRS in high-dose AMT-130 patients compared to a propensity score adjusted external control group derived from the ENROLL-HD natural history database. We believe this approach to accelerated approval based on multiple years of clinical outcomes data represents a differentiated and robust strategy that positions AMT-130 for success. We are grateful for the FDA's continued recognition of the critical unmet need in Huntington's and for their constructive engagement as we work to advance AMT-130 and prepare for a BLA submission.

As a reminder, Huntington's disease is a rare, inherited neurodegenerative condition that affects tens of thousands of people in the U.S. and Europe with hundreds of thousands more at risk. It remains one of the largest genetically defined areas of unmet medical need and AMT-130 is uniquely positioned as a potential onetime treatment targeting the root cause of the disease. Interest in AMT-130 continues to grow across all stakeholders, including patients, clinicians, investors and strategic parties. At the same time, we are advancing our commercial readiness in a phased manner to support a planned launch of AMT-130 in 2026.

With that, I'd like to turn the call over to Dr. Walid Abi-Saab, our Chief Medical Officer, to provide more detail on the regulatory path ahead and next steps for the program. Walid?

Well, thank you, Matt. Good morning and good afternoon, everyone. I'm generally excited that we've continued to receive clear and constructive guidance from the FDA on both our CMC strategy and statistical analysis plan for AMT-130. This guidance provides important clarity for our development path and allows for continued hope for the Huntington's disease community whose resilience and support remain instrumental to advancing AMT-130.

Now I'd like to walk you through the outcomes of our recent Type B meetings with the FDA. Following the successful initial RMAT multidisciplinary meeting in November of last year, the FDA agreed that data from our ongoing Phase I/II studies when compared to a natural history of external control may serve as the primary basis for the BLA submission under the accelerated approval pathway. The agency also confirmed that the composite Unified Huntington's Disease Rating Scale or cUHDRS may be used as an intermediate clinical endpoint and reductions in CSF NfL levels may be considered supported evidence of therapeutic benefit.

Building on this positive momentum, the uniQure team prepared briefing books for 2 Type B meetings a CMC meeting, which was held in the first quarter of this year and a statistical analysis plan meeting, which took place earlier this quarter. I will cover the outcome of the CMC meeting first.

During this meeting, the FDA provided us with guidance that supports our plan to submit a BLA for AMT-130 in the first quarter of 2026. First, the FDA agreed that it should be possible for uniQure to demonstrate validation of the AMT-130 manufacturing process using experience and prior knowledge from the HEMGENIX process, complemented with additional full-scale AMT-130 GMP batches and a single PPQ run. Additionally, the FDA agreed with our proposed drug product release testing plan, including our proposed potency assay, pending completion of qualification and specification setting. We view this as a very positive outcome and are pleased that we will be able to fully leverage our previous experiences to achieve a daily ambition early next year.

Turning to the recent statistical analysis plan meeting. The FDA continued to support its prior agreement that cUHDRS may serve as an acceptable registrational intermediate clinical endpoint for accelerated approval. The FDA agreed that the primary efficacy analysis will evaluate the 3-year change in cUHDRS in the high-dose AMT-130 patients compared to a propensity score adjusted external control. Consistent with our July 2024 data analysis, we will be using a propensity score weighted methodology for the primary analysis. Based on feedback from the agency, we will also be using additional sensitivity analysis using a propensity score matching methodology and supplemental analyses to further assess the robustness of the conclusions.

Lastly and most importantly, the FDA agreed that ENROLL-HD a large prospective longitudinal natural history study may serve as an acceptable external control data set for the primary analysis of the trial data along with additional sensitivity analyses using TRACK-HD and PREDICT-HD data sets. This is significant as we believe the ENROLL-HD database is a better fit for purpose comparator than data sets such as TRACK-HD and PREDICT-HD.

With more than 33,000 patients enrolled and approximately 37,000 patients meeting the eligibility criteria for the AMT-130 Phase I/II studies, we believe ENROLL offers a more comprehensive contemporaneous data set, lower attrition rates and a significantly larger pool of patients who meet our eligibility criteria. These attributes allow us to better adjust for compounding variables and enhance the robustness of our propensity score model.

Recall that earlier this year, a competitor who used a similar propensity score adjusted methodology with the ENROLL-HD database observed a 2-year decline in cUHDRS that was consistent with the earlier analysis presented by uniQure using the TRACK-HD and PREDICT-HD databases. We view this as further support of the suitability for ENROLL-HD as an external control. Overall, and again, we are very pleased with the guidance provided by the FDA and are grateful for the agency's continued productive engagement.

In terms of next steps, we plan to submit an updated statistical analysis plan later this quarter. We will present top line Phase I/II data in accordance with that plan in the third quarter. We expect to hold a pre-BLA meeting with the FDA in the fourth quarter, and finally, in the first quarter, we expect to submit a BLA for AMT-130 with a request for priority review.

And with that, I'll turn the call back over to Matt.

Thank you, Walid. As you've heard, our recent interactions with the FDA marked continued execution and meaningful progress in our journey to bring AMT-130 to patients with Huntington's disease. We now have a clear regulatory path that is reinforced by our ability to leverage our proven manufacturing platform and a robust natural history data set. With this momentum, we are moving forward with confidence fully focused on presenting 3-year data in the third quarter of 2025 and submitting our BLA in the first quarter of 2026. .

I want to take a moment to sincerely thank the uniQure team for their hard work, dedication and professionalism. Your commitment and collaboration have been instrumental in reaching this milestone. I also want to thank the Huntington's disease community for their continued support and partnership. Their strength, commitment and trust have been essential to our progress with AMT-130.

We will now open the call for questions. Operator, please proceed.

[Operator Instructions] Our first question comes from Paul Matteis with Stifel.

It sounds good that ENROLL-HD in terms of the natural history progression is consistent with what you've used previously. But can you just talk about if you did the 2-year analysis with ENROLL-HD, what percent disease slowing at the high dose are you seeing at 2 years? And then as it relates to the 3-year data, is this the right way to ask the question? What are you powered for? Do you need a p-value? Is there a specific effect size hurdle? Any way that you can kind of help set up success relative to what you've seen so far in efficacy would be super helpful.

I will take this question. So in terms of ENROLL, we have looked at these data and as you saw with data from our competitor, we expect that the rate of decline in this early-stage disease like the patients who are enrolled in our trial to be about 0.5 points in cUHDRS and that's what they found, that's what we found when we look at natural history TRACK and PREDICT as well. So it tends to be fairly robust.

The last time we shared data was based on the March 2024 cutoff of the data, which we shared with you last July. And there, we saw at the high dose of 80% reduction compared to cUHDRS in that data set. We do expect that the reduction or slower decline will continue past year 2 and into year 3 and more. We don't expect this to change at all.

In terms of magnitude of effect and p-values, those were not specifically discussed or request by the agency. But if you recall, even with that smaller data set at that time, we had only 9 out of the 12 subjects who had data at 2 years, we've had a statistically significant p-values when we compare to external control.

So overall, I feel very confident with our mechanism of action with data progression overall. And with the robustness of the plan that we have. And I expect that the 3 years, this will continue to remain steady and actually become even more salient when we compare to natural history.

So if I could just ask a follow-up. I guess, there isn't a specific hurdle for success at 3 years. The hope is that the data is consistent and ultimately, the assessment of the 3-year data is going to ultimately come down to just being a review issue. Is that the right way to think about it?

Yes, that's correct. The right way to sort of think about it. There's no particular level of cleaning meaningfulness that we proposed in our SAP nor it was raised by the agency. My personal interpretation is that the magnitude of effect that they have seen and the consistency of the data that they've seen so far lends itself to a level of comfort if those are maintained into 3 years. And then that is why I believe this was not specifically requested.

Okay. And again, not p-value driven. Is that right?

That is correct.

Our next question comes from Ry Forseth with Guggenheim.

This is Ry from Debjit's team. Could you elaborate on the sensitivity analyses using TRACK-HD, TRACK-ON and PREDICT-HD? How do outcomes from these analyses influenced the probability of accelerated approval? And what would be the potential drug label implications for this analysis?

So in general, we believe that the propensity score methodology is robust enough that -- to some degree, it's agnostic as to external database to compare to. Of course, ENROLL with its much larger sample size would lend itself to more robustness when you're comparing to -- when you're trying to deal with potential confounding bias. The agency very clearly looks at consistency of the results across various analyses and across various data sets.

So that's why it is important to do these sensitivity analyses because if you just happened to pick the 1 that is "the winner" and the others are not consistent, that doesn't mean that you're going to be getting approval. The data has to show consistency across those. And -- when you look at all of what we have seen so far with the natural history, I'm very confident that the data are going to look fairly similar, whether we use TRACK-HD or a ENROLL-HD in terms of the effect.

Our next question comes from Joseph Schwartz with Leerink Partners.

This is Jenny on for Joe. Congrats on all the progress. I was just wondering, in the PR you -- and on the call, you've mentioned that ENROLL-HD has a larger number of patients. Are there any other differences in these data sets versus TRACK and PREDICT that are important we should be aware of? And did the FDA give you any specific reasons that they prefer this study versus the other 2?

Well, first, let me start that we were the one actually who proposed ENROLL-HD. The -- as part of our due diligence, when we compare what natural history we need to compare to that are set of assessments that we do in terms of better fit for purpose. There are many reasons why ENROLL-HD would be the data -- the better fit-for-purpose database. They have more than 33,000 patients enrolled. It's contemporaneous has a lower attrition rate. It has higher follow-up, longer follow-up when you match to our patient population. So clearly, for us, it was the most appropriate database to use. We proposed it and the FDA agreed with our proposal.

The key difference between TRACK, PREDICT and ENROLL is that TRACK and PREDICT include the striatal volume calculation, which was an inclusion in our trial. And that's one of the reasons why we will include that in the sensitivity analysis because it would be very, very informative.

Interestingly, for us, when we try to evaluate the effect of the striatal volume, we tested it in the TRACK and PREDICT, and essentially, whether you include the striatal volume after you include the other prognostic factors that we use to generate our propensity score, it turns out that there's no difference anymore between patients where we had striatal volume included or not. And what that tells me is that the prognostic factors that we are using are highly correlated with the striatal volume. So to a great extent, they take that factor into consideration, and makes such that if we use ENROLL, we're not losing out on this piece.

So the bottom line ENROLL is the more robust. We think that the prognostic factors that we use will update the need to add striatal volume. Nonetheless, we will be using the sensitivity analysis with TRACK and PREDICT, which I expect to have very similar results to what we saw in -- what we will see with ENROLL in terms of the reduction in cUHDRS after 3 years.

And if I can just ask one more follow-up. Can you give us any details about attendance in the 2 Type B meetings? Were there any significant changes from previous meetings or any new additions?

We -- Matt, do you want me to take this? Or do you want to take it?

Yes. I mean no, the answer is both meetings were very well attended, senior officials from CBER in the Office of Therapeutic Products and no material changes to the participation from meeting to meeting to meeting.

Our next question comes from Joseph Thome with TD Cowen.

This is Peyton on for Joe. I guess can you talk a little more about the manufacturing process about how long it would take? Any differences between the HEMGENIX and the AMT-130 process? And do you still anticipate needing a site inspection?

Yes, I didn't get -- what was the last part? Do we still anticipate what?

Needing a manufacturing site inspection, sorry.

Okay. Yes. So the reality is the AMT-130 manufacturing process is highly homologous with what is done now for HEMGENIX. Obviously, the biggest difference is that it's a different transgene, but the manufacturing would take place at the same license facility. It would take place at the same train with the same personnel, leveraging the same quality management systems. Of course, you know that both use the same AAV5 vector. So things like testing for impurities, right, or testing for viral clearance, right? Those methods are identical, right? There's really no changes, and those are things that we can leverage.

We would expect to initiate process performance qualification in the third quarter as we guided. And we would expect that, that would take approximately 4 to 5 months to complete. This is there -- it's a meaningful amount of work. I wouldn't call it high risk work, but just in terms of the extended characterization and all the testing that has to be done, that's how we would expect it to be. I will tell you that in doing, we were deeply involved in doing the HEMGENIX PPQ and that took well over a year to complete. So an estimate of it being 4 to 5 months, we think it's a huge win to be able to leverage that experience from HEMGENIX and move forward in a streamlined manner.

Yes, in terms of the site inspection, the -- we -- I think we would assume that the site is inspected. It has to do routine inspections. So we're not necessarily sure that this would trigger its own inspection, but there may be routine inspections that need to occur as the FDA typically wants to do those inspections every couple of years, and that will depend on their availability of personnel and where this sits on their inspection priorities.

Actually, if I can ask a quick follow-up. When was the last time the site had an inspection?

We said that the site has had an inspection as part of the oral for HEMGENIX. It's been inspected by EMA more recently, but has not been inspected by the FDA since the approval of HEMGENIX back in 2022.

Our next question comes from Luca Issi with RBC Capital Markets.

Congrats on the conversation with the FDA. And maybe I want to circle back the prior question, you captured correctly, it sounds there's no specific p-values threshold that is required. Why is that correct? And if so, does it mean that there's no formal statistical analysis that needs to be done on the primary endpoint? This is all based on kind of the totality of the evidence, but I think any additional color would be much appreciated. .

Yes. You were breaking up a little bit, but I think I got the gist of what you were saying. I don't mean to imply that there will not be any formal statistical analysis. We will be doing a formal statistical analysis with the primary end point. And we will also be generating sensitivity analysis, looking at also p-values and all of this.

What I meant to say is that there was no predefined degree of clinical meaningfulness that we were requested to meet or any discussion on that topic that were raised by the FDA. Beyond that, I think we will be sharing the data, in my opinion, based on our understanding of the space, rare disease, advanced therapies that the -- it matters a lot, consistency of the results and depending on the -- based on the statistical analysis and the various sensitivity analysis, the results have to be consistent enough.

I don't know to what degree a specific p-value needs to be met, whether you are close to it or not. Those were not things that were discussed specifically and would be a matter for review in my opinion. But definitely, we will be doing formal testing, and we'll be generating p-values, and those will be submitted as part of the documents.

Got it. Super. If I can just follow up. If you are doing a statistical analysis, formal statistical analysis on the primary end point -- do you have a sense what the minimum delta and cUHDRS did you need to show in order to actually hit the stats? And if so, what are the delta will be viewed as clinically meaningful to the physician community, especially in the context of this therapy requiring an intracranial injection. Again, any color there, much appreciated.

Yes. Thanks. That's very helpful. We have not conducted formal power analysis to evaluate what would be the minimum difference that we would need to see compared to an external control. To a large extent, that also depends on the size of your external control. So those analyses have not been conducted. So it's really difficult to speak about power. All I can say is with a smaller external data set with like TRACK and PREDICT that we essentially presented last July and only with 9 patients we saw a very low p-value, very highly significant when we compare to the external control with a large magnitude of slowing of disease progression when measured with cUHDRS after 2 years.

In terms of what constitutes a clinically meaningful difference for patients for this therapy, honestly, when we talk to our KOLs, they will tell us and then the patients as well that we discussed with patient organizations, they say any slowing of the disease matters a lot because that could translate into years of improved quality of life on the back end. But I don't think there has been a consensus or published figure that would indicate what would be minimal clinically meaningful difference. When we talk to our KOLs, I mentioned anything north of 30% would be meaningful. But again, this has not been confirmed or agreed to in the field in general.

Our next question comes from Suzanne van Voorthuizen with VLK.

This is Suzanne from Kempen. Congrats on this alignment. Maybe one on the difference between the propensity score weighted approach for the primary analysis and then the matched approach as a supplementary analysis. Given these are pointed out so specifically, can you remind us what the exact difference is and how these 2 approaches may influence the comparison? And secondly, can you elaborate a bit on what type of pre-commercial preparations you'll be undertaking in the time frame between now and a potential approval in the second half next year?

All right. I'll take the first question and turn it over to Matt for the second question. So propensity core methodology, both matching and waiting are approved, well-established methodologies that leverage real-world data to support regulatory decisions. The FDA recognizes multiple models exist and multiple methodologies, and they often look at the consistency of the results using different methodologies to evaluate the robustness of the conclusion.

So what is the difference between the 2? Essentially, you generate capacity score based on a series of attributes that you have, and that would be the same for matching and waiting. With matching, then you will select the matches from the natural history that closely resemble your subjects, and you end up with 1 to 10, 1 to 20 matches between the natural history and your subjects and you compare them then using regular statistics. Propensity score weighting takes that a little bit further and essentially utilizes the total sample to generate what you call a synthetic control group that will have different ways in those external control depending on how well they resemble your subjects.

And as such, it leverages the larger sample and you don't lose information from the natural history, you utilize the totality of that information. These methods are fairly robust. And actually, we expect that these 2 methods should yield fairly comparable results. And that's why it's important to conduct both analysis and be able to present them to the agency, which is what our plan is.

Matt?

Sure. Yes. Suzanne, yes, so just in terms of commercial preparation, as I mentioned, we're going to be doing this in a phase appropriate manner. But initially, we're going to be focused on medical education and market access reimbursement. Those areas, we think, are going to be essential for commercial success in ramping, and in addition to that, we'll be looking at onboarding and identification of treatment centers as well as patient mapping. So those are kind of the broad work streams, and we'll be bringing on some key personnel and talent to help advance those initiatives.

Our next question comes from Kristen Kluska with Cantor Fitzgerald.

Congratulations on this alignment. Did you speak with the agency in regards to any other endpoints more as supportive pieces of evidence in addition to the cUHDRS? And then were there any talks about the post-marketing studies and plans to launch such a study ahead of filing?

Thank you, Kristen. We have previously discussed with the FDA, the fact that changes from baseline in CSF NfL levels may be supportive of evidence of therapeutic benefit. In this statistical analysis plan, there was no additional discussions on this. So in our opinion, whatever was agreed with the FDA still holds, that would be of the same opinion. There's been no other discussion on any other endpoints, no requested by the FDA to evaluate those to support our submission.

In terms of post-marketing or confirmatory trials, the FDA said they would be open to evaluating the data from this current study, whether based on the cutoff that we will be submitting of June 30 or after longer periods of observation to evaluate whether this could serve the basis for potential full approval as such, any discussions for what it would take to have a full approval and what evidence will be needed to be generated will take place only after they have a chance to review those data because if they are sufficient, then there will be no need to do another study. And that will greatly inform what the next steps are.

So our anticipation is that, that discussion will happen at the pre-BLA meeting. We don't expect that to be slowing us getting approval, because the agency would be much more open to have those customers at that time and be informed with the data from our 3-year cutoff.

Our next question comes from Ellie Merle with UBS.

I think earlier in the call, you said you expect a rate of decline of 0.5 a year with ENROLL-HD. Just to clarify, is that what you've already seen from the propensity score matched external control from that data set or just what you would expect. And just further to that, I guess, have you done this analysis yet looking at the ENROLL-HD external control using the propensity score matched analysis yet? And also have you, I guess, done this analysis, compared to your data with the 30-month follow-up yet?

Thank you, Ellie. We have not conducted any formal analysis comparing our efficacy to the natural history since we last did that and communicated to the FDA as part of the November 2024 meeting, and that data set included June 30 cutoff where we have 12 patients on the high dose and 12 patients on the low dose that had 24 months of data. Having said that, the rate of decline that was observed recently by a competitor using ENROLL-HD, they was fairly similar at 2 years to the rate of decline that we've seen at 2 years when we use TRACK and PREDICT with propensity score rating as well.

In our evaluating of the fit for purpose for the natural history for ENROLL-HD, Track-HD, PREDICT-HD, we conduct propensity score weighted and propensity score matched analysis based on the baseline characteristics. And just to be very clear, we're not comparing how our patients are compared to this, we just look what would be the rate of decline of a matched sample of ENROLL-HD with -- based on the baseline characteristics of our patients. And in general, you get that same rate of decline of about 0.5 per year, whether you use propensity score matching or waiting with ENROLL-HD or for that matter, TRACK and PREDICT. And that's why we believe that the propensity score methodology especially with our competitors showing same data set with generally similar patient population is a very robust method, and we expect the data to be very consistent across the board.

Understood. And just a quick follow-up. I know not a formal analysis yet, but have you looked at the 30-month data internally yet?

No. This is -- look, this is an open-label study ongoing. We do look at the data to be able to manage safety. There are a small number of people who have access to these data for that purpose. We have not conducted a statistical analysis on this. We're just managing the study. We did not look at the 30-month data.

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

Congrats on the update. I have a question about the sample size in the external control arm. Obviously, the larger the sample size, the smaller the error bar and the better the p-value when compared with the treatment arm. So I think I heard you mention for the matching roughly 1 to 10, 1 to 20, is that a rough kind of boundary for the end? Or do you have flexibility in -- including even greater number of matched patients given that ENROLL-HD is a very large study, I'm sure you have no problem, including more patients.

Thanks, very astute question. There are no black and white way of doing this. The best guidance that we could get is that you should try to match the highest end to make sure that the quality of the match remains good enough. And the way to do this is you calculate something called standardized mean differences and there are criteria that you need to stay within those -- within a range to make sure that you have a good comparison. Because otherwise, if you loosen this, then you might have a higher number. You can have a precise estimate, but you have a precise estimate on a not well-matched group and that's not really what you're looking for.

So without doing the analysis, I cannot give the exact number, but I would imagine with a database as big as ENROLL, we would be getting somewhere in the 10 to 30 range because you need to limit again that -- those standardized mean differences to be close enough. But I cannot give you the exact number.

Got it. Super helpful. And maybe if I can follow up with a question about the pre-BLA meeting. I think you mentioned at least 1 component or agenda for the meeting that is for the confirmatory trial requirement. Is there anything else regarding to this filing itself that remains to be discussed at that meeting? If you can help us understand the need for that meeting, that would be super helpful.

Yes, sure. I mean private meetings are usually very helpful for us to align with the agency about what we propose to submit. Is this what they want? Do they think that we need more data like this or like that or we need to address a particular question. I think since we have an RMAT designation, I think this is the purpose is to stay in closer contact with the FDA. And so far, they've been extremely helpful. I cannot tell you how pleased we are with our interactions with them repeatedly now. And I expect that the pre-BLA is exactly has that purpose in mind, which is to look at the data that we have, we're going to be submitting and then align with them as to whether this would be, I guess, meeting their requirements so that they can accept the BLA submission. And I view that as very positive and collaborative as it has happened so far.

Our next question comes from Lydia Erdman with Goldman Sachs.

This is actually Lydia on for Salveen Richter. Congrats on update. Can you just remind us whether the third Q update -- the third quarter update will include both high and low dose patients given your filing on only high-dose patients? And then separately, could you just speak to the potential ex U.S. strategy?

Yes. So our plan on for the third Q is to present the top line data based on the updated SAP that we would have filed with the FDA. And with regard to the ex U.S., we are engaging with the EMA with discussions as to what the next steps would be like. I have to admit that we prioritize the FDA at this point because things move forward with faster pace with RMAT. And we're putting our resources there, but we continue to work with the EMA as well to try and figure out the way forward. I don't have more color to give you at this stage, but perhaps later, we can provide some more information.

Our next question comes from Uy Ear with Mizuho.

This is Charles on for Uy. So in the upcoming update, can you guys confirm how many high-dose patients will be included? And also if you guys will be including the low-dose patients in that update? And then also on the natural history cohort, what key changes have you guys made to the criteria for the matching? Are there any other besides the volumetric measurements?

Thanks, Charles. So the cutoff will be the June 30 of this year. At that point, there will be 12 people on the high dose who would have completed 3 years and 12 people on the low dose would have completed 3 years. In addition, all patients in the trial would have completed their 2 years. So that will be the data set that we will be analyzing data on.

In terms of the top line results, I believe we will be -- yes, it's difficult for me to say because we have not fully aligned yet internally on this. We have to be cognizant of the fact that we need to follow what the SAP says. And -- but we will be providing top line results, which I believe will include both the high dose and the low dose, but I'm not -- we haven't yet fully aligned on this until after we submit the SAP and have a discussion internally on that.

In terms of the natural history criteria and what has changed, actually, it's very similar to what we have done before with the exception of, as you said, the striatal volume. And as I said, when we did the analysis with the only database where you can do that analysis, which is the one TRACK and PREDICT where you have a portion of the subjects who striatal volume meet our criteria versus those who don't. When we use the propensity score variables, prognostic variables that we include in this and do those without including striatal volume or do those while adding striatal volume, the difference is essentially the change of in cUHDRS after 2 years and 3 years are virtually identical.

And this tells us that the model is actually very robust and the prognostic factors that we use are obviating the need to have that striatal volume. And that's why I think that the result of the ENROLL-HD look very similar to TRACK-HD and PREDICT-HD. And I'm really very confident -- I mean throughout this exercise, if I may give you some color personally, I felt very of comfortable with how the propensity model operate because they're fairly robust and they show very similar results if you apply them correctly and you match your sample patients to these, and you end up with very similar results, which gives us very good confidence that we're actually comparing apples-to-apples in this case.

I'm showing no further questions in queue at this time. I'd like to turn it back to Matt Kapusta for closing remarks.

Thank you very much, operator, and everybody, for attending the call. We're really excited about our path forward for accelerated approval, and we very much look forward to providing you additional updates in the near term. Thanks so much.

This concludes today's conference call. Thank you for participating. You may now disconnect.