QURE

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. All lines have been placed on mute to prevent any background noise. After the speaker's remarks, there will be a question-and-answer session. If you would like to ask a question during this time, simply press star followed by the number one on your telephone keypad. If you would like to withdraw your question, press star one again. Thank you. I would now like to turn the call over to Chiara Russo, Senior Director of Investor Relations. Please go ahead.

Good morning, 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 know 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, 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 acknowledged the agency's feedback and remain focused on engaging constructively to find a 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 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 U.K. 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 three-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/II-A 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 gal A 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 from AMT-260 in the second quarter, the four-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 a one-time administered therapy. Additionally, we plan to solicit feedback on our statistical analysis plan for the 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 a marketing authorization application for AMT-130 in the third quarter of this year, supported by our three-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 three-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 non-dominant and dominant hemisphere MTLE, and we plan to provide an update later in the second quarter on all six treated patients with at least six 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 8th of this year, the study cutoff date, all 11 patients across three dose cohorts demonstrated elevated alpha-galactosidase A enzyme activity that was dose-dependent and durable over the observed follow-up period, ranging from more than one year in the longest follow-up patient at the high dose to four 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 18th of this year, all 11 dosed patients have discontinued ERT. On safety, as previously reported, two 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 five 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-US 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 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 three 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 7,000-8,000 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 would not only enable access in the U.K. We believe it could also enable early access or name 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 discipline 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 anti-seizure 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 multi-system 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 for 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 three months ended March 31st, 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 three months ended March 31st, 2026, compared to $36.1 million to the same period, 2025.

The $6.9 million decrease was driven by a $2.6 million decrease in fair value of continued 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 Administrative Expenses were $20.1 million for the three months ended March 31, 2026, compared to $10.9 million during the same period, 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 record-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 projects through 2026.

We expect that cash and 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 2026, 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.

At this time, I'd like to remind everyone in order to ask a question, press star then the number one on your telephone keypad. We will pause for just a moment to compile the Q&A roster. Your first question comes from the line of Moritz Reiterer with Guggenheim Securities. Please go ahead.

Hi, this is Moritz on for David. Thanks so much for taking our question. I have two. The first one is around AMT-260.

Could you just give a little bit more sort of an overview of what the expectations are for the upcoming dataset 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. 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? Thank you.

Thank you. 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, you know, particularly seizure frequencies as measured by a diary in addition to a number of other endpoints. 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 a reduction of seizure frequency. You know, we're targeting at this stage a maybe 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. I will withhold any interpretation on these data.

Thank you.

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

Hi, this is Emily on for Paul. We wanted to ask a little bit more about the U.K. market dynamics, maybe if you could share any color. 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? Thank you.

Absolutely. Thanks, Emily, for the question. Maybe starting with the second part of the question. The vast majority of the patients that we alluded to, the 7,000-8,000, are treated at specialized centers. There is a collection of those patients that are managed by the specialized centers around the U.K., 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. That's work that has already started and is ongoing and will continue through a potential MHRA approval to bring this product to market.

Great. Thank you so much.

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

Thanks. 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?

Okay. Do you wanna start with the first one, Kylie?

Yeah, absolutely. Just talking through ability to secure reimbursement in markets outside of the U.S., Joe, 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 in parallel 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 QALY and ICER considerations. 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. That will be taking reimbursement as a primary consideration into focus.

Thanks.

This is Walid. I'll take the second question. Thanks, Joe. 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 data.

Thank you.

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

Good morning. Thanks for taking my questions. 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? Separately, just frame expectations for the four-year data in the third quarter and what sensitivity analyses these might include. Thank you.

Thanks. In terms of design elements of a new study to evaluate clinical efficacy, we can't really go into details because it depends on these 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 one-time 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. That is truly our goal in the meeting.

Regarding the analysis of the four-year data, in broad terms, they're actually going to be generally similar to the three-year analysis, with the addition, of course, of one more year of follow-up, which will bring the total number of patients at four years to 12 at the high dose and 12 at the low dose. In addition, there will be three patients at the high dose who would have completed three years, so making 15 patients who have reached the three-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 expectation 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 gonna become much more evident when compared to well-matched external controls.

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

Hi. Thanks for taking our question. This is Quan on for Yanan. Also on Huntington's disease, you mentioned that in the Type meeting you'll talk about, design of the new study and data statistical plan. Can you talk about, will you also cover the potential of an alternative regulatory path? Is there still a possibility to file without starting a new study? Thank you.

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 analysis. We do not intend to have a specific discussion about a regulatory path to filing at this point.

Got it. Thank you.

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

Hi. This is Peyton on for Joe. Thanks for taking our questions. I guess I'm 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 changed, planned changes to the surgical procedure in a potential commercial product, specifically any changes in the length of the time of the procedure? Does anything need to be done to validate or approve the cannulas that is used? Thanks.

Thanks, Peyton. 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. There are a number of centers that have already treated AMT-130 patients. This is just a small handful of the number of centers that exist in the U.K. that have neurosurgical stereotactic capabilities. 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.

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. 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.

Great. Thanks.

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

Oh, great. Thanks so much for taking my questions. maybe Matt or Walid, you know, kind of bigger picture, can you just maybe compare and contrast the Type A meeting you had in January, the FDA, versus the pre-submission meeting you had with the MHRA in the U.K.? Again, 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 data with single arm data with, like, historical control? Is that because they have a better appreciation for the unmet medical need? What's driving that dichotomy there? I think any color there much appreciated. Thanks so much.

Luca, it's obviously hard to get into the mind's eye of, you know, each of the regulatory authorities. You know, we've been saying this now for, you know, for 6+ months that we strongly believe in the strength of our data. You know, we've achieved 75% slowing of disease with high statistical significance out to three 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. There's a tremendous unmet need here where there's no disease-modifying treatments for these patients. I think, you know, based on the discussion that we had with the U.K., I think they recognized these elements. Walid, do you wanna chime in?

Yeah, I just wanna 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. 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. You know, at one point, there were more openness and flexibility with us. More recently, it's been a bit more difficult.

Again, we continue to work with the FDA, and at the end of the day, the data that we're gonna be generating will help, hopefully, to get us to where we need to go.

Got it. Thanks so much, guys.

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

Can you elaborate a bit on the range of outcomes for what we could learn from the Type B meeting? Then a second question, do you plan to request another meeting with the FDA after the data to pursue accelerated approval again based on the data? Thanks.

Yeah. I think at this juncture, just with the Type B meeting scheduled, we won't speculate on the range of meetings and on the range of outcomes. Then, you know, based on the discussion that we have, we'll ascertain whether there's 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.

Understood. Thanks.

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

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? A small one on your cash runway guidance into H2 2029. Can you remind us what parts of your business plan are or are not included in that guidance? Thank you.

This is Walid. I'll start with regulatory strategy beyond the U.K. and the U.S. 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.

Absolutely. 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. We're looking at countries that have named patient access and early access programs well-established, which there's 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 six months for a rare disease products. France also has the ATU program or the AAP program, which it has now evolved into. There's a number of other countries, Italy, for example, that has named patient and early access.

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.

Yeah. Yeah. Quickly on the runway, it's kind of the same assumption as for a couple of cues that we complete the ongoing clinical trials for TLE, HD, and Fabry. To get into the second half of 2029 does not allow us to simultaneously take forward all the candidates in kind of the most expedited manner. There will need to be prioritization decisions if we wanna maintain the runway.

All right. Your next question comes from the line of Patrick Trucchio with H.C. Wainwright. Please go ahead.

Thanks. Good morning. 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, you know, steroid prophylaxis or other follow-up criteria are necessary to move forward. 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.

Thanks, Patrick. Great questions. The per protocol, anytime we see a grade 3 increase in the or grade 3 adverse event, that could be potentially a DLT. Per protocol, we stop dosing. There's been very close collaboration with the IDMC informing the FDA. The patients are followed very closely and treated with a steroid as well as steroid sparing therapies. One patient fully recovered. The other one is really within a very close statistically recovering. I'm very pleased with the process. Once that is done, we will submit these data to the FDA for their review and discuss resuming dosing at one of these two doses.

In the meantime, the study is ongoing, we continue to dose with our low dose of 2E13, and we continue to follow the patients. At the end of the day, this is a phase I/II trial, 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 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, you know, data to suggest that there might be autoimmune in nature. We don't see that yet.

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. Based on these, we will be then making a decision about next steps with this program in the, you know, next six to 12 months.

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

Hi, good morning, everyone. Thanks for taking the questions. On AMT-130, of the 7,000-8,000 patients diagnosed today, what percent or number of them do you think would be potentially eligible for therapy at launch? Based on your timelines 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? Thank you.

Hi, Kristen. 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. I think as we sort of understand the market in more detail, we'll be able to share more specifics, more to come on that.

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. Though 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. That also will depend on how many questions, how complicated they are to get answers to. We are, you know, 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 and as I mentioned.

Your next question comes from a line of Daniil Gataulin with Chardan. Please go ahead.

Yes. Hi, good morning, guys. Thank you for taking my question. Quick one, 1:30 in the U.K., what 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 the MHRA decision for their approval, and how many patients could that potentially add?

Great. Thank you very much for the question. On the first part, which is capacity in the U.S., I think, ex-U.S., 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. 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. Obviously we would need to move through the process with NICE and ultimately NHS England to secure a formal recommendation and manage access agreement to be able to open up a larger potential pool.

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. 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's a number of countries that do that open up main 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. That's just to give you an example of some of the markets that are unlocked through a potential MHRA approval.

Thank you. Again, if you would like to ask a question, press star one on your telephone keypad. Your next question comes from the line of Rudy Li with Wolfe Research. Please go ahead.

Thanks for taking my question. I think you mentioned that you're now 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? 'Cause I'm still confused why they would require a sham control phase III instead of a single arm pivotal trial. Thanks.

Yeah. I think, you know, what we know is that we have the guidance that we got from the FDA, right, previously, which is, you know, their recommendation that we conduct another study. You know, that's why obviously we wanna go into the FDA and have a discussion around those design elements. As I say, you know, this upcoming meeting is an interaction with the review team. You know, there are tactical and technical matters that we wanna get through, you know, that include not only what I just described, but also a review of the statistical analysis plan. We're gonna continue to follow these patients.

As I said, you know, 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, you know, 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. You know, on top of that, clinical grade quality longitudinal data.

You know, to the extent that single arm studies and external control comparisons are acceptable for intractable diseases with high unmet need, we think there's a strong rationale, particularly given the slow progressing nature of HD, the one-time administrative nature of AMT-130, and the surgical delivery of the product. I think that's what we would say in that regard.

Very helpful. Thanks.

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.