uniQure N.V. (QURE) Q4 2025 Earnings Report, Transcript and Summary

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.