uniQure N.V. (QURE) Earnings Call Transcript & Summary

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

Thank you. This morning, uniQure announced pivotal data on patients treated with our investigational gene therapy, AMT-130 in our ongoing Phase I/II clinical trials in Huntington's disease, taking place in the U.S., EU and the U.K. This 3-year update consists of data on clinical endpoints and exploratory biomarker and safety and tolerability as well as anticipated regulatory next steps and potential commercial opportunity. Joining us on this investor event and webcast are Matt Kapusta, our Chief Executive Officer; Dr. Walid Abi-Saab, our Chief Medical Officer; Kylie O'Keefe, our Chief Customer and Strategy Officer; and to provide a clinician's perspective on the experience of patients with Huntington's, Dr. Sarah Tabrizi, Joint Head of the Department of Neurodegenerative Diseases at University College London, Director of the UCL Huntington's Disease Center and member of the U.S. National Academy of Medicine. The slides included in this morning's webcast will be available on the Investor page of uniQure's website shortly after the conclusion of this event. Please note that we will be making forward-looking statements during this investor call. All statements other than statements of historical fact are forward-looking statements. They are based on management's beliefs and assumptions and on information available to management only as of the date of this conference call. Our actual results could differ materially from those anticipated in these forward-looking statements for many reasons, including, without limitation, the factors described in uniQure's quarterly report on Form 10-Q filed on July 29, 2025, and other securities filings. Given these risks, you should not place undue reliance on these forward-looking statements, and we assume no obligation to update these statements even if new information becomes available in the future. Now I am pleased to introduce Matt Kapusta, uniQure's CEO.

Thanks, Chiara, and good morning, everyone. Today marks a very important milestone for patients and families affected by Huntington's disease and for the uniQure team. As reported in our press release this morning, we achieved the primary endpoint of our pivotal Phase I/II study. High-dose AMT-130, our registrational dose demonstrated a statistically significant 75% slowing of disease progression as measured by the composite Unified Huntington's Disease Rating Scale of 36 months as well as positive trends across all its subdomains. Equally important, the study also demonstrated a statistically significant slowing of disease progression as measured by total functional capacity, a key measure of a patient's ability to live independently and an important endpoint for regulatory agencies in assessing efficacy. Moreover, CSF neurofilament light chain, a well-characterized and supportive biomarker measuring neurodegeneration was below baseline at 36 months, and AMT-130 continues to be generally well tolerated. Together, we believe these findings provide compelling and clinically meaningful evidence of AMT-130's disease-modifying potential, and we plan and are currently preparing to submit a BLA for AMT-130 in the first quarter of next year. Huntington's disease is one of the world's most prevalent monogenic disorders. We estimate that approximately 100,000 people in the U.S. alone carry the gene mutation that causes Huntington's. Sadly, there are no approved disease-modifying treatments with clinical failures and setbacks highlighting the urgent need within the HD community. The onset of symptoms typically between ages 30 and 50 robs people of relationships, careers, mobility and independence. Within 10 to 15 years, most patients succumb to the disease and family members live under the constant shadow of uncertainty. Over the years, we have listened to the heartbreaking stories of many individuals and families living with HD. Their courage fuels our determination to bring forward a therapy that can meaningfully alter the trajectory of this condition, provide improved quality of life and more time with loved ones. We believe AMT-130 has the potential to be the first treatment to truly modify the course of Huntington's disease with the following key attributes: First, AMT-130 is designed as a durable once-administered treatment, an especially important advantage in a slowly progressing lifelong disorder where early intervention is essential. Second, targeted administration of AMT-130 enables precision-based delivery to the brain regions affected by Huntington's disease, helping to maximize therapeutic concentrations locally, protect unaffected tissue and limit systemic exposure and related toxicity. Third, AMT-130 targets the first exon of the huntingtin gene, suppressing both the full-length mutant protein and the highly toxic exon 1 splice isoform, an advantage that most other product candidates do not offer. Finally, AMT-130 is delivered using a well-established stereotactic procedure that is well within the skill set of Board-certified neurosurgeons, supporting the potential for broad clinical adoption of AMT-130. With that, I'm pleased to turn the call over to Dr. Walid Abi-Saab, our Chief Medical Officer, who will review the updated clinical data in greater detail. Walid?

Thank you, Matt. Good morning, good afternoon, everyone. First, let me start, as always, by profoundly thanking the patients, their families and caregivers as well as the larger Huntington's disease community for their unwavering dedication to helping develop a potential disease-modifying treatment for this devastating disease. In particular, without the support of tens of thousands of patients who have volunteered over the years for observational studies such as Enroll-HD, our analysis would not have been possible. I'm thrilled to be providing you today with the exciting update on the pivotal data from our ongoing Phase I/II study of AMT-130 in Huntington's disease. Before I get into the details of the study results, let me take a moment to go over the primary clinical endpoint in this pivotal study. The composite Unified Huntington Disease Rating Scale, or cUHDRS, was designed to detect disease progression with a high degree of sensitivity. It is increasingly being used in clinical research and its ability to detect disease progression has been demonstrated in several recent clinical trials. The cUHDRS consists of 4 clinical assessments designed to test different functional capacities that are impacted by HD. Total functional capacity is a measure of the ability of patients to carry out activities of daily living, such as employment and doing their finances as well as caring for themselves. Total motor score is a measure of motor dysfunction with higher scores corresponding to worse impairment. The Symbol Digit Modalities Test measures processing speed, attention and concentration. Last but not least, the Stroop Word Reading Test measures executive function and inhibitory control. As I will show later, high-dose AMT-130 showed evidence supporting of disease slowing across all 4 of these clinical subdomains of the cUHDRS. Earlier this year, we held a Type B meeting with the FDA to discuss the proposed use of external control data and the proactively prospectively defined statistical analysis plan, or SAP, in support of a planned BLA submission for AMT-130. The FDA agreed that the cUHDRS could serve as an acceptable registrational intermediate clinical endpoint for accelerated approval. Additionally, the FDA agreed that the primary efficacy analysis for the BLA would evaluate the 3-year change in cUHDRS in the high-dose AMT-130 patients compared to a propensity score adjusted external control arm. In agreement with the FDA's recommendation, we selected propensity score matching for the primary analysis. The FDA also agreed that Enroll-HD, a large prospective longitudinal natural history study of Huntington's disease may be acceptable as the external control data set for the primary analysis with each dose matched to corresponding controls based on their baseline characteristics. As you can see on this table, the baseline demographics and key disease characteristics are overall well matched across patients treated with the high dose of AMT-130 and the propensity score matched external control group from Enroll-HD. On to the results now. In the study's primary endpoint of cUHDRS, we can see clearly that at 36 months, AMT-130 shows a statistically significant reduction in disease progression as shown on this graph. These are the results from the mixed model of repeated measures analysis or MMRM, which was the prespecified primary analysis in the statistical analysis plan aligned with and submitted to the FDA. The lead square means that the propensity matched external control group declined by more than 1.5 points at 3 years, whereas those treated with AMT-130 showed a reduction of 0.38, representing a 75% reduction in the rate of decline. Here, looking at the time course of the observed data over 3 years, compared to the propensity score matched external control, you can clearly see the slower progression of disease in those treated with AMT-130. A difference which is becoming more and more evident as time from treatment increases. Next, we look at the secondary endpoint of total functional capacity, where we again have a statistically significant difference from the match external controls with disease progression reduced by 60% at 36 months. TFC is an important clinical measure for the FDA as it assesses a patient's overall function and independence. TFC is also an integer-based scale, which, while clinically meaningful, is usually less sensitive to change than the cUHDRS. Therefore, I'm very pleased to be able to demonstrate a statistically significant difference on this key secondary endpoint, which speaks to the robustness of the effects of AMT-130. In this slide, you can see the time course for changes in TFC, which clearly shows a general level of stabilization in patients treated with AMT-130, whereas you can continue to see gradual but steady decline as one would expect in patients who are untreated. Here, we see the results of the 3 additional components of the cUHDRS, SDMT, Stroop and Total Motor Score, all of which are also supportive of disease-modifying, disease slowing in patients treated with high dose of AMT-130 with effects ranging between approximately 60% to more than 100% reduction in disease progression. These results show favorable trends in all measures used in the cUHDRS, including cognitive, motor and functional measures. On the next slide, we see the data from the low-dose group, where results were more variable. We believe that these data suggest that the low dose of AMT-130 has biological activity, but at the low end of the dose response range, supporting the notion of a dose-dependent effect when compared to the consistently positive effects seen across all these domains with the high dose. Moving on to neurofilament light chain or NfL. This is an important measure of neurodegeneration and a supportive biomarker in Huntington's disease. Several independent studies have shown a strong association between CSF NfL levels and the clinical severity of HD with expected increases of approximately 10% to 15% per year in early manifest patients. In patients treated with AMT-130, initial post-procedure increases in NfL levels were followed by a consistent decline over time, returning to and remaining below baseline after 12 to 18 months. These results suggest a slowing of neurodegeneration. Specifically, at month 36, as shown on this slide, we see approximately 5% and 8% reduction from baseline at the low and high dose, respectively. Turning to safety. AMT-130 has remained generally well tolerated with a manageable safety profile at both doses. As we have previously reported, the majority of drug-related adverse events, in particular, serious adverse events of CNS inflammation occurred within weeks post treatment and resolved with glucocorticoid medication or supportive care. I'm happy to say that there have been no new treatment-related serious adverse events observed since December of 2022. As you can see from this table, the most common adverse events tend to be related to the study procedures such as headache, procedural headache and procedural pain. Again, we have no new AMT-130-related SAEs to report. Here are the planned next steps for this program over the coming months. In the fourth quarter of this year, we look forward to holding a pre-BLA meeting with the FDA to present these updated data and to discuss the content and format of the forthcoming BLA. In the first quarter of 2026, we expect to submit a BLA for AMT-130 with a request for priority review. In summary, following the statistical analysis plan agreed upon by the FDA, at 36 months, AMT-130 met both the primary and the key secondary endpoint, demonstrating a meaningful slowing of disease progression compared to a robust external control. The data show a statistically significant 75% slowing of disease progression on the study's primary endpoint of cUHDRS with a p-value of 0.003. In the key secondary endpoint of total functional capacity, which again is important from a clinical and regulatory perspective, we have demonstrated a 60% slowing of disease progression, which was also statistically significant with a p-value of 0.033. These noteworthy and I believe, frankly, unprecedented clinical findings are supported biologically by CSF NfL levels that remain below baseline, suggesting a reduction in neurodegeneration in line with the mechanism of action of AMT-130. AMT-130 continues to be generally well tolerated with a manageable safety profile. Notably, there has been no new serious adverse events related to treatment observed since December of 2022, over 30 months ago. I will now turn the call over to Dr. Sarah Tabrizi, a leading expert in the Huntington's disease field, who will share her perspective on the data. Sarah?

Thank you. I'm a Professor of Neurology at the UCL Queen Square Institute of Neurology. I'm the Director of the UCL Huntington's Disease Center and Joint Head of the Department of Neurodegenerative Diseases at UCL in London. I'm delighted to be invited to talk about the AMT-130 results, and my comments today are based on my own experience of working in the Huntington's disease field for nearly 30 years and being a lead scientific adviser to the study. Huntington's disease is a truly devastating inherited neurodegenerative disorder. It affects people in the prime of life, often in their early 40s. It leads to a combination of progressive dementia, movement disorder and behavioral disturbances and the disease course is relentless. It results in significant disability and loss of function, which necessitates intensive multidisciplinary care over many years. The impact on patients and their families is profound as they must manage the evolving symptoms over a prolonged period. As Walid mentioned, disease progression in Huntington's disease can be objectively measured using validated tools such as the Composite Unified Huntington's Rating Scale and the total functional capacity, both used as outcome measures for AMT-130. The composite cUHDRS captures multiple key domains of the disease, including motor, cognitive and neurological functional abilities. The total functional capacity scale really assesses a patient's decline in function as the ability to work, manage their finances and perform daily self-care. As reported today in the AMT-130 pivotal study at the high dose, there was a 75% slowing of disease progression as measured by the Composite Unified Huntington's Rating scale and an impressive 60% reduction in the rate of functional decline as measured by the total functional capacity. The external comparator group were from CHDIs in Enroll-HD natural history study, which the FDA approved as a comparator arm for this gene therapy. I truly believe that these results indicate that AMT-130 could have a significant impact on slowing disease progression and offer the potential to improve and lengthen quality of life in HD patients. The study also demonstrated improved biomarkers indicative of neuronal function in the brain. CSF neurofilament levels in high-dose patients were below their original baseline level compared to what is an expected increase of 30% to 45% in the normal progression of Huntington's disease over 3 years. To me, this suggests that AMT-130's targeting of mutant Huntington and all its toxic forms is indeed preserving nerve cells and in turn, neurological function. I have over 30 years of experience in Huntington's disease research and clinical care. And I believe these data are the first to provide clear evidence of an investigational therapy inducing Huntington's disease modification. This is an immensely exciting development for the Huntington's field. To me, these game-changing data really offer a beacon of hope for patients and their families and represents a significant step towards delivering a licensed disease-modifying therapy for Huntington's disease. And I feel we, as a community must work together to help get this therapy to as many Huntington's disease patients as possible. Thank you.

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

Thanks, Matt. I will now take you through the U.S. Huntington's disease patient funnel and potential long-term growth drivers as well as the U.S. treatment centers of excellence. There are currently 200,000 Americans are at risk for Huntington's disease due to family history. Of those at risk, there will be approximately 100,000 patients who are genetically identifiable, including both presymptomatic and symptomatic HD patients. As the disease progresses, all patients eventually become symptomatic with deterioration in motor function, cognition and overall behavior. When you narrow the focus to symptomatic HD patients, there are approximately 40,000 patients in the U.S., of which about 50% of these patients are currently diagnosed, which equates to approximately 20,000 total diagnosed symptomatic HD patients in the U.S. today. If approximately 30% are considered initially treatable patients at launch, this represents a total addressable market of around 6,000 U.S. HD patients at the timing of a potential launch. This is an early estimate, taking into consideration a number of different market factors, which we will continue to evaluate in the coming months as we learn more. We will also continue to dive deeper and share additional insights into the AMT-130 opportunity and the expected ramp early next year. However, we are confident there is a large number of HD patients that could be mobilized in the early period of potential launch. Augmenting the initial addressable market, there are several potential long-term growth drivers to the patient population. Firstly, and as I mentioned earlier, patients that are progressing through the stages of their disease, transitioning from presymptomatic to symptomatic as well as new incident patients. Secondly, driving an increase in the diagnosis rate. Currently, in the HD community, there is a reluctance to do genetic testing and receive a diagnosis due to psychological, social and ethical barriers. As a disease-modifying therapy becomes available, we anticipate a shift in genetic testing behavior driven by hope rather than fear. Also, improved access to genetic testing and counseling as well as patient education could accelerate earlier identification. And lastly, our continued focus on expanding the different patient segments to broaden the patient opportunity will also be important. Moving on to the U.S. Centers of Excellence, which we see as one of our key pillars to our U.S. launch strategy. What you can see here is a heat map of the patient volume by state. The stars represent the U.S. ClearPoint capable facilities using the MRI-guided technology utilized for the treatment procedure, overlaid with the Huntington's Disease Society of America, or HDSA, certified U.S. Treatment Centers of Excellence. There are 2 key points here. The patient volume aligns nicely with the key treatment centers of excellence, and there are a substantial number of centers that we believe would have the capabilities to support the treatment of HD with AMT-130. We have ongoing efforts to profile and prioritize the key treatment centers for launch, thinking through the potential capacity needed for the first year and beyond. With that, I will hand the call back over to Matt. Matt?

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

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

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

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

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

Our next question comes from Joe Schwartz with Leerink Partners.

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

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

So as I mentioned, Huntington's disease, I think, is really one of the cruelest diseases. It's slowly progressive and inexorable with significant disability and huge health economic burden cost because it affects people when they're young and in the prime of life. The key thing that I think with a 75% slowing means that people will be able to stay and work longer. They'll be able to function longer. They'll be able to maintain their independence. And as we hope, and I'm very invested in this, we want to be able to treat people eventually in stage 0 and 1 decades before they show any signs and symptoms with such therapies, and we may be able to prevent the symptoms ever occurring, which will be the closest we can come to prevention of this disease. And that's one of our -- my personal huge goals. So what this means to patients is huge. 75% slowing of disease progression is greater than what we even anticipated and expected and hoped for. And that means for 1 year of disease progression, it slowed by -- they will have 4 years longer in terms of disease-free life. So the effect of 75% slowing is a huge effect size and will have massive effects for patients' lives.

Our next question comes from Debjit Chattopadhyay with Guggenheim Securities.

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

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

Our next question comes from Joseph Thome with TD Cowen.

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

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

Absolutely. As you know, in this study, the subjects that were studied had late Huntington's integrated staging system Stage 2 and early Stage 3. So they were early symptomatic patients, and you can see the very clear clinical benefit supported by molecular markers showing that we're helping prevent neurodegeneration because of the really impressive drop in CSF neurofilament. So in terms of eligibility, that will be up for the discussion with the regulators. But myself and colleagues at -- many colleagues from all around the world developed a Huntington's disease integrated staging system. And this staging system stages Huntington's into 4 stages, Stage 0 through to Stage 3. And this study was in late Stage 2, early Stage 3, which is symptomatic, early symptomatic. The disease process is the same across all of the stages. And because the core problem of Huntington's is the same in everyone before and after onset of symptoms, this therapy potentially should be -- could be available for everyone from stage 0 to Stage 3, and that will be something that we will be hoping to roll out.

Our next question comes from Uy Ear with Mizuho.

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

Yes. Thank you very much for the question. We have started some initial thinking around payers. As you noted, obviously, this is brand-new data. And so the real work begins now. But we've started to take a look at what the payer mix will be and how we start to think about value proposition. Huntington's disease has a huge unmet medical need. Obviously, as Sarah has talked a lot about, it has a huge impact on patients. And right now, there's no disease-modifying therapies available. And so it's about helping to educate the payers on what this value story means and what the 75% reduction in composite Unified Huntington's Disease Rating Scale means to these patients and their lives, and that's going to be some of the work that we have ongoing. In addition to that, obviously, showing benefit in TFC is incredibly important as it's a clear clinical endpoint and payers appreciate that. So more to come on the value story, but education and early payer engagement is critical to success, and that's something our access team has begun.

Our next question comes from Kristen Kluska with Cantor Fitzgerald.

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

Thank you, Kristen. It's Walid. Well, actually, one of the strengths of the Enroll-HD is it has such a large number of patients that we can really maximize the selection of which ones would be a good match. And if you look at the error bars that you see in the observed data, you can see how tight they are for the natural history. The other thing that I can say is that we -- as part of the sensitivity analysis that we conducted, we looked at the natural history using different types of matching, propensity score matching with different also types of propensity score matching, propensity score weighting as well as looking even at track and predict HD. And the estimate of the decline over the 3 years across cUHDRS and TFC were consistent across all of these. The totality of this gives us a lot of confidence in the results that we have seen that this is not an artifact of choosing Enroll-HD or choosing a specific type of analysis for Enroll-HD, and that's one of the strengths of our data. So no, I think I'm very convinced that this is really a great way to be able to compare to, and I'm confident in the results.

Our next question comes from Salveen Richter with Goldman Sachs.

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

Yes, absolutely. So as we shared, there's approximately 40,000 symptomatic HD patients in the U.S. And of these 40,000, about 50% of these are currently diagnosed. So that represents around 20,000 symptomatic diagnosed HD patients in the U.S. at present. If you take a 30% adjustment to that for looking at an initially treatable patient population at launch, that gets you to 6,000 U.S. HD patients. Now as we said, this is an early look, and we're continuing to evaluate the different market factors. From a Cohort 4 perspective, I think what that size of the population that represents, I think we're looking at that at the moment and trying to assess what opportunity this would unlock for us as we continue with obviously BLA discussions and moving forward. But we think this is obviously giving us an opportunity to continue to broaden the patient segments that would be eligible. So more to come there.

Our next question comes from Luca Issi with RBC.

Congrats on the data. Just maybe a couple of questions here. So maybe on the data itself, Walid, there were obviously 17 patients at baseline at a high dose versus, I think, 12 patients at 36 months. So what happens to the additional 5 patients? Are those patients loss of follow-ups that got censored? Or are those 5 patients that have yet to reach the 36-month mark? And if it is the latter, when are you going to show us this 5 additional patients? Just asking simply because the end is relatively small here. And then maybe on regulatory, Walid, wondering if you can comment on whether this data is potentially eligible for the commissioner's national priority review voucher that could potentially shrink the time line down to 1 to 2 months. Again, any color there, much appreciated. And then maybe finally, quickly on maybe Kylie. I appreciate it's still early days, but how are you thinking about pricing?

Thanks, Luca. So indeed, there were 17 patients enrolled in the trial at the high dose, and we have data at 36 months for 12 of those. So as we've communicated earlier, there were 2 patients who dropped out previously voluntarily from the trial. And there are 3 that are ongoing that now have passed the 24 months, and you can see that in the graph that we showed at 24 months, we have 15 patients. And those patients, we expect them that they will be able to complete their 3-year time point by the middle of next year. Now just to remind you, the primary analysis that we conducted, which is the MMRM, actually takes into consideration all of the data. So this is not just looking at the 12 at the end, but looking at the totality of the data that we have the 17 at year 1 and 15 at year 2 and the 12 at year 3, plus comparing to the natural history, which you also can see from the table that we showed that there's also some attrition over time as often is the case in trials. So overall, this is how the disposition of patients are and the analysis. In terms of the [ CNRV, ] we are evaluating this as -- and evaluating actually all options. This will be part of our thinking from a regulatory perspective and discussion with the agency, and we will communicate that to you once we have more clarity on that point. And with that, I'll turn it over for Kylie.

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

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

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

Right, Patrick, I'll take the first question on Cohort 3. As you know, Cohort 3 was designed to evaluate the effects of the triple immunosuppression of steroids, rituximab and sirolimus and when we analyzed those data and compare the various outputs in terms of immune response and the CNS edema on imaging and the clinical pictures, of course, we concluded that the risk benefit of this immunosuppression actually is not positive. We had 2 or 3 SAEs, 2 were related to infection related to the immunosuppression and one was an adverse event related to steroids. And overall, we believe that a short course of steroid is probably the best way forward. That is what we're going forward with in our Cohort 4. This -- we're talking about 2 weeks at middle dose level. This is something that is very commonly used by neurosurgeons, and they're very comfortable in that space. And we think that would be enough to control any potential adverse events that we might see with the therapy. And with that, I'll turn it over to Sarah for the second question.

Thank you. So your question was about regulatory approval and long-term safety. So the 36 months of data, so Huntington's disease is a slowly progressive disease once symptoms begin. So the 36-month data has given a long enough interval to really show progression on the composite Unified Huntington's Disease Rating Scale and total functional capacity. In addition, the 36 months of data gives us the longest-term safety data that we can. And so, so far, as Walid mentioned in his presentation, the safety signals are excellent. And so with 3 years of data, I am convinced that this drug is modifying the course of the disease. Will it get approved by the FDA in the discussions? I'm not a regulator. But I've seen many clinical trial results over my years working in Huntington's disease. And these clinical trial results are very clear cut. The numbers are small in the high dose. Of course, 12 people have reached 36 months, but that's quite typical for gene therapy trials and the value and importance of the propensity score matched Enroll-HD data, which has really been critical. I'm very optimistic that we will try and get this drug to patients and families as soon as we can.

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

Great. Congrats on the very exciting data. I wanted to dig into the TFC endpoint a little bit here. Very encouraging data today on both 36 months and 24 months. I think the 24-month data as presented previously was not as positive. So obviously, you have more patients at this -- at today's update. I was wondering was the larger end the main driver for the change in the TFC data point at 24 months? And secondarily, if I can quickly ask, assuming confirmatory trial -- assuming accelerated approval is the path and a confirmatory trial is required, how do you think about FDA's requirement for the confirmatory trial to be well underway at the time of approval? Would that be something that can be done with the current forecast?

Thanks, Yanan. So yes, indeed, at the -- with the TFC at 2 years, I think the additional 3 patients, that's 1/3 of that sample size. Last time we shared with you was 9 -- thank you, Matt. So Matt was very helpful. Actually, we have 15 patients now at 2 years that we're showing you that 6 patients, that's like 2/3 more than what we showed previously with 9 patients. And that -- you can see that makes a bigger difference. And you see the data also at 12 -- at 36 months is very consistent. So we're very confident that TFC is starting to really come through the longer we continue to follow these patients. And that's something that really bodes very well for the efficacy of the drug and show the robustness. In terms of the confirmatory trial with the FDA, we've tried to have the discussions with them a couple of times, but the agency was very clear that they would like to see data from this trial before they can decide whether they're going to take action via traditional pathway as in full approval or accelerated pathway, which will then require confirmatory trial. But it was very clear to us that even if they go down the path of accelerated approval, because it is -- we're following what they're doing, it's not going to require that we start that trial, have it 50% recruited or whatever to delay approval of the accelerated pathway. So we are looking forward to going to talk to the FDA in the fourth quarter. We will review the data with them, and that will give us a clear path as to what the next steps are.

Our next question comes from Ellie Merle with UBS.

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

Yes. Thanks, Ellie. I think it's obviously a little bit premature for us to have the clear line of sight into the label. I think the way we've tried to think about this initial estimate of patients that could be treatable at launch, we've tried to think about some of the factors that could go into it. But I think it's too premature to comment on what we think the label could look like, including both on a symptomatic level and then also what segments will be within the label. But as we learn more, we'll continue to share. From a payer perspective and how payers are expected to classify symptomatic patients, I think, obviously, a genetic confirmation will be critical. And then how they confirm a diagnosis from there, I think it's something that we will need to discuss further. I don't think it will be consistent across payers. I think you'll see some differences. And as I mentioned earlier, education and early payer engagement is going to be critical to helping us understand how they see a diagnosis and how we can help educate them on what's appropriate from a diagnostic point of view. So I think it's going to be a 2-way street, and there's more work to be done there.

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

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

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

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