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 Unicure fourth quarter and year-end 2025 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 with the number one on your telephone keypad. If you would like to withdraw your question, press star 1 again. Thank you. I would now like to turn the call over to Cara Rosso, Senior Director of Investor Relations. Please go ahead.

Good morning, and thank you for joining us for Unicure's year-end 2025 earnings call. Earlier this morning, Unicure 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 Unicure.com. Our 10K was also filed with the SEC earlier this morning. Joining me on the call this morning are Matt Capista, Chief Executive Officer, Dr. Wally Abisab, Chief Medical Officer, Kylie O'Keefe, Chief Customer and Strategy Officer, and Christian Klempt, Chief Financial Officer. After our formal remarks, we'll open up the call 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 Unicure's most recent SDC 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 Capista, Unicure's CEO.

Thanks, Kiara. Good morning, everyone, and thank you for joining us on our year-end 2025 conference call. For more than 25 years, Unicure 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 two 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 three-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 EnrollHD, 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 have 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 1-2 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 30th to discuss next steps. In the meeting minutes we received on Friday, February 27th, 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 3 study designs, while preserving our commitment to advancing the program responsibly and expeditiously. In addition, we intend to update our Phase 1-2 statistical analysis plan to incorporate a four-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 Waleed to provide additional color on HD and our other clinical programs. Waleed? 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, we had a type A meeting with the FDA in late January. This meeting, we reviewed the previous FDA guidance and discussed 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 state 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, one year is generally insufficient to reliably detect a meaningful progression of their disease. In the sham control portion of our U.S. study, control patients did not show clinical worsening after one 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 datasets using statistical methodologies designed specifically for that There are multiple precedents where such approaches have supported regulatory approval. Still, during the recent meeting, the agency strongly recommended we conduct a well-designed, phase 3, randomized, double-blind, sham surgery-controlled study to demonstrate efficacy of AMT-130. We believe that a multi-year sham-controlled study could impose significant risks and burden to patients. Some might even consider this trial designed to be unethical. The HD patient community strongly agrees with this 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 one of the most comprehensive natural history databases in rare diseases. EnrollHD 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 approaches 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 1-2 study to include four-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-US regulators after our three-year data disclosure to September 2025, we have initiated regulatory discussions with several agencies. We will continue these discussions throughout the year, and will 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 manner. Meanwhile, we continue to analyze the large body of data we have accumulated with the MT-130. In February of 2026, just recently, we presented at the CHDI meeting in Palm Springs, California, a new analysis showing that propensity score methodology using clinical covariates with TRAC-HD and PREDICT-HD datasets effectively substitutes for baseline striatal volume in prediction of Huntington's disease progression. The covariates used in these analyses were the same as those used in the three-year analyses we shared in September 2025 to match AMT-133 in patients to their counterparts in the external comparator cohorts from the Rural HD study. We continue to develop a manuscript with the complete results of our three-year analysis and anticipate publication in the peer-reviewed medical journal later this year. Moving on to Febri 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 of the cutoff date of January 8, 2026, all 11 patients in three-dose cohorts exhibited elevated alpha-gal-A enzyme activity. with six 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-galae enzyme activity were observed across the three-dose level. These increases were durable for the measured period of time, ranging from more than one year, the longest follow-up patient at the high dose, to the shortest follow-up period of four months in a patient treated at the mid-dose. Stable plasma LISO-GB3 levels were maintained post-dose across all dose cohorts, regardless of ERT status through the cut-off phase. 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. Two patients at the mid-dose experienced asymptomatic grade 3 liver enzyme elevation. Per 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 our tapering of steroids with no loss of alpha-gal-A enzyme activity as of today. Turning now to AMT-260 for mesial temporal rope epilepsy, 2025 was a productive year for the program. We shared data from a case study of the first patient treated with AMT-160 with up to six 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 six months with no serious adverse events. We have since completed enrollment of five more patients in the first cohort and begun enrollment in the second cohort. We expect enrollment to be completed in the second cohort by mid-year. Additionally, we plan to provide an update in the second quarter on all six treated patients in the first cohort, including those with non-dominant and dominant hemisphere lesions with at least six months of safety, tolerability, and seizure frequency outcomes. I will now touch base on some additional pipeline updates. Phase 1-2, Episode 1 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 AMT162 in the context of a dose-limiting toxicity that was observed in one patient in the second cohort. This event of dorsal root ganglia toxicity resulted in a serious adverse event determined to be related to AMT162. 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, Willid. 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 will continue to do so. Your engagement, partnership, and determination continue to inspire us here at Unicure, 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 US, 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 XUS opportunities, evaluating priority markets based on epidemiology, regulatory pathways, pricing, and reimbursement landscape. In addition, we'll be actively pursuing named 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 anti-seizure medications and continue to face ongoing unpredictable seizures that drive injury risk, cognitive decline, psychiatric comorbidities, and reduce quality of life. Even with surgical resection or neuromodulation, many patients are not eligible or fail to achieve durable seizure reduction, underscoring the need for innovative disease-modifying approaches that can address the underlying epileptogenetic focus and provide sustained benefit from a one-time intervention. Similarly, for AMT191 in Febreed 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 infusion-related reactions and anti-drug 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. Christian?

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 filing with the SEC for additional details. Revenue for the year ended December 31st, 2025 was $16.1 million dollars compared to 27.1 million dollars in 2024. The decrease of 11 million dollars was primarily driven by 10.7 million dollar decrease in collaboration revenue and a 6.1 million dollar decrease in contract manufacturing revenues offset by a 5.8 million dollar increase in licensed revenues. Cost of contract manufacturing revenues was nil for the year ended December 31st, 2025 compared to 17.1 million dollars in 2024. Following the divestment of the Lexus facility in 2024, cost of contract manufacturing revenues are recorded net associated revenue within other expenses. Research and development expenses were 140.7 million dollars for the year ended December 41st 2025 compared to 143.8 million dollars in 2024. The decrease of 3.1 million dollars was primarily driven by 26 million dollar decrease in total other research and development expenses 25 million dollars of which related to decreases in employee contractor related and severance cost as well as facility cost resulting from the 2024 divestiture of the company's lexicon manufacturing operation and organization restructuring in the same year this was offset by 22.9 million dollar increase in total direct research and development expenses of which 19.4 million dollar related to the preparation of a potential bla substitution for amt 130. selling general and administrative expenses were 65.5 million dollars the year ended december 31st 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 MT-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 columns, and investment securities totaled $622.5 million as of December 31st, 2025, compared with $367.5 million as of December 31st, 2024. A net increase was primarily to proceed to approximately $404.2 million raised from public offerings of ordinary shares and pre-funded loans. With this strong balance sheet, we believe Unicor 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 2029. I 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 dataset, the progress in Fabry disease and MTLE, 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 at this time I would like to remind everyone in order to ask the question press start then the number one on your telephone keypad we request that you limit yourself to one question and one follow-up you are welcome to requeue with additional questions we will pause for just a moment to compile the Q&A roster. Your first question comes from the line of Paul Matais with Stiefel. Your line is open.

Hi there. This is Julian on for Paul. Thanks so much for taking our question. 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 four-year data. And then for the four-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 three-year analysis as well, or if you just plan on sharing 12 patients' data at four years? Thank you.

Okay. Yeah, I maybe will answer the first part, and then, while you can answer the second part. Yeah, I mean, the other avenues we can pursue are potentially outside the United States, quite frankly. I mean, inside the United States, you know, the avenues go through the FDA. You know, 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, you know, progress very slowly. So, you know, 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, you know, There seems to be real interest from regulatory authorities. I think that's what we're going to pursue. On the four-year data, I can hand it over to Waleed.

So on the four-year data, we informed the FDA that we will be amending the protocol, or the SAP specifically, to conduct such analysis, and we'll 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 we be evaluating? It would be essentially presenting the data of the 12 patients at four years, but also So all the patients who have by then reached, would have reached three 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.

Thanks very much.

Your next question comes from the line of Joe Schwartz with Leering Partners. Your line is open.

Hi, thank you. So in last week's CNBC interview with Dr. McCary, he seemed concerned about the morbidity associated with procedures involving burr holes, which is what you use 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. too now?

Yeah, I mean, we don't want to comment directly on what Dr. McCary 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. You know, 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 type B meeting. 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 3 trial. As I said, we believe that we are very fortunate in this space to have a very high-grade, ongoing, contemporaneous natural history. Specifically, I'm talking about Enroll HD with more than 30,000 participants. this what I call a treasure trove that is generally provided to us by CHCI and through the hard work of many, many patients and their families and the whole HD community. We think that could be leveraged 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 that's going to be the the key focus of that type B meeting thank you your next question comes from the line of Peyton Bonsek with TD Cowan your line is open hi guys this is Peyton Ancajo thanks for taking our questions real quickly when talking about the phase 3 design how quickly do you think that you would be able to enroll it would Would you be able to use an 18-month endpoint, similar to what's been seen elsewhere in the

And then, has this changed your partnering decisions, SUF? Thanks.

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 one 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 maybe 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 in September, and that has also increase through this. A lot of the great work that's been done over the past number of months for 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 in the design.

Yeah, on the partnering side, I also think it's a little too early. We need to understand what the phase three 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, you know, then we'll have to evaluate it at that time. But it's a little premature to weigh in on that right now.

Great. Thank you, guys.

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

Hi, this is Jasmine on for Ellie. Thank you for taking our question. So first, can you give some more color on the different scenarios for a potential phase three design? So what are you going to the FDA with and 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 a Huntington's Phase III program look like, and does your cash runway include this? Thanks.

Thanks, Jasmine. It's really premature to be able to get into those details. Whatever I say now would definitely be different after we talk with the FDA. 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 adequately powered, which is, again, the right thing to do, to be able to evaluate this as in 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, you know, it's very highly likely to change. So I really would not like to go down that path. And what's the other question? Oh, for Christian regarding the runway.

Yeah, so, I mean, same comment a bit as Valid with all the uncertainties around the investments into kind of the various late-stage opportunities we have kind of run scenario analysis we've 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 okay thank you your next question comes from the line of Suzanne's and worth with them with campaign your line is open hi team this is Suzanne from Kempe thanks for taking my question maybe one terrifying question on the

program about other jurisdictions what regions are you talking about and what's the status of your discussions with regulators outside of the US and then I have one for the epilepsy program did I catch correctly that the update in Q2 will be on six patients from the first dose cohort with six months follow-up or will there also be some early data from the second dose cohort and perhaps for For seizures 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? Thank you.

Absolutely. So on the first question around XUS, 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-US regions. We've obviously mentioned that we're going to be in discussions with both MHRA in the UK and IMA from a European perspective, and then we're going to be looking at what other opportunities that affords us outside of those two jurisdictions. So that's on the first question, and then handing over to Walid on the epilepsy question.

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

Your next question comes from the line of Luque Easy with RBC Capital Markets. Your line is open.

Oh, great. Thanks so much for taking my question. Maybe if you can circle back on the XUS opportunity here, Matt and Kylie. 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 Levitas XUS before the drug obviously ran into safety issues. Is that the right comp for us to think about it, or would you advise against us? Thanks so much.

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 name 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.

Got it. Thanks so much.

Your next question comes from the line of Selvyn Risher with Goldman Sachs. Your line is open.

Good morning. Thanks for taking my questions. Can you just help us understand the totality of the sticking points with the FDA here and why a sham control is required versus a prospective natural history comparator? Thank you.

Thanks, Aldine. Yeah, the FDA at the pre-BLA meeting raised the point that those studies were designed as, you know, hypothesis generating studies and and any such analyses 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 control. So as I said in my comments early, 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 one 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 one 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 one step at a time as we start getting more clarity with them.

Your next question comes from the line of Uyir Mizuhu.

Your line is open.

Hey guys, thanks for taking your question. I guess I'm just still don't quite understand why the FDA is requiring a sham study. You know, like, I understand the objection the FDA had previously, and it didn't sound that, you know, in your phase one, two study, it didn't sound like the FDA was objecting to natural history. I guess this time around, what is it about the natural, 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 involve 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? Thanks.

Yeah, I mean, Wali 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 1-2 study in comparison to an external control as the primary basis for a BLA submission. And, you know, and honestly, I'm looking at Waleed here, I don't think that they've necessarily had any criticisms of the EnrollHD 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, you know, 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 checkboxes there. And, you know, it's puzzling, you know, 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 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 these years, I've gotten to know these patients, know their families, and I understand the urgency of this unmet need, and, you know, if there is a study that we believe is feasible and ethical, we're going to do everything we can to drive Thanks.

Your next question comes from the line of Patrick Jericho with H.C. Winright. Your line is open.

Hi, everyone. This is Luis Santos in for Patrick.

I just wanted to ask if there was anything in the FDA's feedback that precluded a potential accelerated path for this supposed phase three study based on an interim analysis, say, of surrogates, including NFL?

Yeah, there was no discussion on this with the FDA, but there's no reason to think that. Actually, it was verbally communicated in a 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 three design would look like and then what potential accelerator approval or full approval pathway that would be.

Your next question comes from the line of Kristen Kloska with Cantor. Your line is open.

Hi, everyone. 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?

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 that they don't see biomarker data in that small sample size over one year. There was no specific discussion on three-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 3 and the FDA expectations after we align with them in the second.

Your next question comes from the line of Yan and Zhu with Wells Fargo. Your line is open.

Hi, thanks for taking our questions. This is Quan Aung for Yan. So in previous questions, you mentioned that you were trying to avoid Phase 3 design that would be too difficult or too challenging to the patient. 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 three-year or longer study? And I have a quick follow-up.

Yeah, 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 on the skull without like really going through the bone. All of these elements represent risk for these patients, especially if the length of the study is two or three 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 the plan type B meeting, is there any additional evidence that you plan to present to FDA or is it just a discussion on the phase three design.

So it will be only to discuss the phase three 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.

Thank you for all the comments.

Thank you.

Your next question comes from the line of Rudely with Rolf Research. Your line is open.

Thanks for taking my question. And 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 a sham control trial? Because they seem to go open to single-arm trial, like for Stokes Therapeutics and Praxis. Just wondering what are the key differences here.

There's certainly precedent for genetic diseases and one-time administered medicines, you know, 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, you know, it addresses potential bias, whether that's selection bias or motivational bias. You know, there's no disagreement that, you know, a placebo-controlled study is a higher level of robustness. But in our view, you know, it really doesn't reflect, you know, 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, you know, what, you know, based on our understanding, what we think, you know, the FDA is seeking is a, you know, 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 sham-controlled trial, we're still dedicated to move forward to a trial.

Yeah, I mean, I think, you know, 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 one-year and a much smaller study. But, you know, I think, you know, if we do our feasibility work and we think it's feasible and the patient community is supportive of it, you know, 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, you know, 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, you know, this is an endeavor that we continue to be dedicated to.

Super helpful.

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