Today, and welcome to the top-month report results for AMT-130 in Huntington's disease. At this time, all participants are in listen-only mode. Later, we will conduct a question-and-answer session. To ask a question at that time, please press star 11 on your touch-tone telephone. We ask that you please limit yourself to one question and reach out if you have additional questions. As a reminder, this call may be recorded. I would like to turn the call over to Chiara Russo, Senior Director of 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 UK. This three-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 opportunities. Joining us on this investor event and webcast are Matt Kapusta, our Chief Executive Officer, Dr. Walid Abi-Saab, our Chief Medical Officer, and Kylie O’Keefe, our Chief Customer and Strategy Officer. To provide a clinician's perspective on the experience of patients with Huntington's, Dr. Sarah Tabrizi, Joint Head of the Department of Neurodegenerative Disease 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 facts, are forward-looking statements. They are based on management's beliefs and assumptions and on information available to management only as of the date of this conference call. Our actual results could differ materially from those anticipated in these forward-looking statements for many reasons, including without limitation the factors described in uniQure's 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 at 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 Biologics License Application 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 Huntington gene, suppressing both the full-length mutant protein and the highly toxic exon one 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 am 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’s 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 four 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 single-digit modality test measures processing speed, attention, and concentration. Last but not least, the Stroop-Words reading test measures executive function and inhibitory control. As I will show later, high-dose AMT-130 showed evidence supporting disease slowing across all four 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 prospectively defined statistical analysis plan, or SAP, in support of a planned Biologics License Application (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 three-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. Onto 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 pre-specified primary analysis in the statistical analysis plan aligned with and submitted to the FDA. The least square means in the propensity matched external control group declined by more than 1.5 points at three years, whereas those treated with AMT-130 showed a reduction of 0.38, representing a 75% reduction in the rates of decline.
Here, looking at the time course of the observed data over three 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 matched 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 three 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 sinus 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 a 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 neurofilament light chain 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 have 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's Square Institute of Neurology. I'm the Director of the UCL Huntington’s Disease Center and joint head of the Department of Neurodegenerative Disease at University College London 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 advisor 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 Disease Rating Scale and the Total Functional Capacity, both used as outcome measures for AMT-130. The Composite UHDRS 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 Disease 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 CHDI’s 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 three 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 represent a significant step towards delivering a licensed disease-modifying therapy for Huntington's disease. 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 perspectives. 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 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. Lastly, a 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 two 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 three-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.
Thank you. As a reminder, if you'd like to ask a question, please press star 1 1. If your question has been answered and you'd like to remove yourself from the queue, please press star 1 1 again. We ask that you please limit yourself to one question and re-queue if you have additional questions. Our first question comes from Paul Matisse with Stifel. Your line is open.
Hey, great. Good morning. Congratulations on the data, and thanks for taking a couple of our questions. We appreciate it. I wanted to just drill in on this upcoming FDA meeting ahead of the planned submission, and maybe you can clarify for us what you want to learn at that meeting and what questions you're going to pose. The second question on the regulatory side is, you know, 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? 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 two of this potentially being approved, if it were, how many patients do you think could realistically get it? Thank you so much.
Thanks, Bob. Walid, I'll take the first couple of questions and then turn it over to Sarah. The pre-BLA meeting is a regularly scheduled meeting with the FDA. It's been the natural progression after we talked 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 through the regular pathway, as in full approval versus the accelerated one. I'll turn the question over to Dr. Tabrizi regarding scalability.
Thank you. Currently, the neurosurgery takes roughly about 12 hours, mentioning the ClearPoint SmartFlow delivery. This delivery system is widespread in neurosurgical centers. We at Queen's Square, which is the biggest center in Europe, have several facilities that are able to deliver MRI-guided neurosurgical gene therapy. There are other sites in the UK, several sites in Europe, and many sites in the U.S. as well. I think the plan is 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.
Thank you. Our next question comes from Joe Schwartz with Leerink Partners. Your line is open.
Great. Thanks so much, and congratulations on the amazing results. I have a question for Dr. Tabrizi and management. How has 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 three years and 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?
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 costs 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. As we hope, and I'm very invested in this, we want to be able to treat people eventually in stage zero and one, 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. That's one of my personal huge goals. What this means to patients is huge.
75% slowing of disease progression is greater than what we even anticipated and expected and hoped for. That means for one year of disease progression, it's slowed by, it will have four years longer in terms of disease-free life. The effect of 75% slowing is a huge effect size and will have massive effects for patients' lives.
Thank you. Our next question comes from Deb G. Chedepadia with Guggenheim Securities. Your line is open.
Hey, good morning, and thanks for taking the questions and 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? 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. I have run many different clinical trials. I've developed or developing drugs. When the data was so clear to me that this drug was working, the effect size was huge. 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.
Thank you. Our next question comes from Joseph Tome with TD Cowen. Your line is open.
Hi there. Good morning. Congrats on the data, and thank you for taking my question. Maybe just one. We've seen a couple of companies lately get caught up on the CMC side of things. If you could just comment a little bit on your sort of manufacturing and CMC capabilities and confidence going into the regulatory submission. Maybe one more, if I can, for the physician. I guess, what proportion of your eligible patients do you think would be interested in actually undergoing the surgery? Thank you.
OK, maybe I'll take the first question on CMC. 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. Right now, the timing is supportive of a BLA submission in the first quarter of next year. 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 two, and early stage three. 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. In terms of eligibility, that will be up for the discussion with the regulators. Myself and many colleagues from all around the world developed a Huntington's disease integrated staging system. This staging system stages Huntington's into four stages, stage zero through to stage three. This study was in late stage two, early stage three, which is symptomatic, early symptomatic. The disease process is the same across all of the stages.
Because the core problem of Huntington's is the same in everyone before and after onset of symptoms, this therapy potentially could be available for everyone from stage zero to stage three. That will be something that we will be hoping to roll out.
Thank you. Our next question comes from Oyeer with Mizuho. Your line is open.
Yeah, thanks. 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 is or sentiment with respect to how payers would look at this. Thanks.
Yeah, 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 the real work begins now. 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. Right now, there's no disease-modifying therapies available. 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. That is going to be some of the work that we have ongoing. In addition to that, showing benefit in Total Functional Capacity is incredibly important as the clear clinical endpoint, and payers appreciate that.
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.
Thank you.
Thank you. Our next question comes from Kristen Kloska with Cantor Fitzgerald. Your line is open.
Hi, good morning. Congrats on these great data. Appreciate you taking the question. 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 per 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 of noise as it relates to that, given there were so many patients in the sample? Thank you.
Thank you, Kristen. Walid, 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. 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, looked at the natural history using different types of matching, propensity score matching with different types of propensity score matching, propensity score weighting, as well as looking even at TRACK-HD and PREDICT-HD. The estimate of the decline over the three 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. That's one of the strengths of our data. 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.
Thank you. Our next question comes from Salveen Richter with Goldman Sachs. Your line is open.
Good morning. Thank you for taking my question, and congratulations on the data here. Could you just help frame the initial target patient population that you would be going into at launch? Regarding the additional cohort that's evaluating the drug in patients with lower striatal volumes, what % of this population would this cohort unlock? Thank you.
Yeah, absolutely. As we shared, there's approximately 40,000 symptomatic HD patients in the U.S. Of these 40,000, about 50% of these are currently diagnosed. 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. This is an early look, and we're continuing to evaluate the different market factors. From a cohort four perspective, I think what that size of the population represents, 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. We think this is obviously giving us an opportunity to continue to broaden the patient segments that would be eligible. More to come there.
Thank you. Our next question comes from Luca Essi with RBG. Your line is open.
Thank you so much for taking my question and congrats on the data. Just maybe a couple of questions here. On the data itself, Walid, there were obviously 17 patients at baseline at high dose versus, I think, 12 patients at 36 months. What happens to the additional five patients? Are those patients loss of follow-ups that got censored, or are those five patients that have yet to reach the 36-month mark? If it is the latter, when are you going to show us this five additional patients? Just asking simply because the N is relatively small here. Maybe a 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 timeline down to one to two months. Any call or data much appreciated.
Finally, quickly, on maybe Kylie, I appreciate still early days, but how are you thinking about pricing? Thank you so much.
Thanks, Luca. Indeed, there were 17 patients enrolled in the trial at the high dose, and we have data at 36 months for 12 of those. As we've communicated earlier, there were two patients who dropped out previously voluntarily from the trial, and there are three that are ongoing that now have passed the 24 months. You can see that in the graph that we showed. At 24 months, we have 15 patients. Those patients, we expect them that they will be able to complete their three-year time point by the middle of next year. Just to remind you, the primary analysis that we conducted, which is the MMRM, actually takes into consideration all of the data.
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 one and 15 at year two and the 12 at year three, 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. Overall, this is how the disposition of patients are and the analysis. In terms of the CNRV, we are evaluating this and evaluating actually all options. This would 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. 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. 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. 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. As we continue to evolve this, we'll share more.
Thank you. Our next question comes from Patrick Tuccio with HC Wainwright & Company. Your line is open.
Thanks. Good morning, and congrats on the data release today. Just a couple of questions from us. The first for the company. I was wondering what learnings have emerged from the cohort three immunosuppression, and what would you expect to carry forward into the commercial setting? 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. 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?
All right, Patrick. I'll take the first question on cohort three. As you know, cohort three was designed to evaluate the effects of the triple immunosuppression that was steroids, rituximab, and tacrolimus. When we analyzed those data and compared 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 two or three SAEs. Two were related to infection, related to the immunosuppression, and one was an adverse event related to steroids. Overall, we believe that a short course of steroids is probably the best way forward. That is what we're going forward with in our cohort four. We're talking about two weeks at a middle-dose level. This is something that is very commonly used by neurosurgeons, and they're very comfortable in that space.
We think that would be enough to control any potential adverse events that we might see with the therapy. With that, I'll turn it over to Sarah for the second question.
Thank you. Your question was about regulatory approval and long-term safety. The 36 months of data, so Huntington's disease is a slowly progressive disease once symptoms begin. 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. So far, as Walid mentioned in his presentation, the safety signals are excellent. With three 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. 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. The value and importance of the propensity score matched in 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.
Thank you. Our next question comes from Yan Nzing from Wells Fargo Securities. Your line is open.
Great. Congrats on the very exciting data, and thanks for taking our questions. 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. Obviously, you have more patients at today's update. I was wondering, was the larger N the main driver for the change in the TFC data point at 24 months? Secondarily, if I can quickly ask, assuming accelerated approval is the path and a confirmed trial is required, how do you think about FDA's requirement for the confirmed trial to be well underway at the time of approval? Would that be something that can be done with the current forecast? Thanks.
Thanks, Shinan. Indeed, with the TFC at two years, I think the additional three patients, you know, that's a third of that sample size. Last time we shared with you, it was nine.
Nine.
Thank you, Matt. Matt was very helpful. Actually, we have 15 patients now at two years that we're showing you. That is six patients, that's like two-thirds more than what we showed previously with nine patients. You can see that makes a bigger difference. You see the data also at 12 and 36 months is very consistent. We are very confident that TFC is starting to really come through the longer we continue to follow these patients. That really bodes very well for the efficacy of the drug and shows the robustness.
In terms of the confirmatory trial with the FDA, we've tried to have these 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 a confirmatory trial. It was very clear to us that even if they go down the path of accelerated approval, because 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 via accelerated pathway. 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. Thank you.
Thank you. Our next question comes from Ellie Murrell with UBS. Your line is open.
Hey, guys. Thanks so much for taking the question, and 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? 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 two versus the early stage three patients? Thanks.
Yeah, thanks, Ellie. I think it's obviously a little bit premature for us to have a 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 also what segments will be within the label. 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. How they confirm a diagnosis from there, I think, is something that we will need to discuss further. I don't think it'll be consistent across payers.
I think you'll see some differences. 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. I think it's going to be a two-way street, and there's more work to be done there.
On the question on stage two versus stage three, it's Walid. I'll take that. Here we're talking about very small numbers, but what we have observed at three years is that the more advanced stage three patients did not do worse than these stage two patients.
Thank you. I'm sure 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.