Well, good morning, and thank you for joining Guggenheim's 3rd Annual Healthcare Innovation Conference. I am Debjit, one of the therapeutic analysts, and my privilege to welcome Matt Kapusta, the CEO of uniQure. Thank you so much for joining us and making time for us.
Thanks for having us.
Well, obviously, you've had an interesting series of one and a half years, almost close to a decision point at this point. What is the market missing from the story, and what's the disconnect from your perspective?
Yeah. I think that the market right now is pretty locked in on regulatory risk. Honestly, I think that's understandable given the last 18 months that we've had, and given some of the changes that have occurred within the regulatory environment. I think that the market right now is not fully appreciating the significance of the critical unmet need here and the opportunity. I mean, we see this as one of the largest unmet needs within the genetically defined rare disease space. Huntington's is a ferociously devastating disease, and I think that I don't know how much the market understands or appreciates how the HD community sees the risk-benefit. These patients understand the risks associated with transformational medicines, and they really want to be able to make decisions, treatment decisions with their clinicians.
We think as we move on through the end of this year and early next year, we're going to talk more about how we see that commercial opportunity and how we think we can be successful, not only in the launch of the product, but long term as well.
The question that we have been getting since the September data update was switching to the Enroll-HD B cohort, and obviously, that was sort of pre-specified on your part. That produced a non-significant cUHDRS outcome and sort of caused confusion with what is the FDA going to actually look at, right? On hindsight, was that the right call, or should we just have stuck to the original cohort?
Yeah. No, it was absolutely the right call scientifically, and let me go through this and explain it. Before I do, let me just say that we know what the FDA is going to look at. The FDA is going to look at the data that is in our BLA submission. That data was based on the Enroll-HD, what we're calling Enroll-HD A cut, which was the original cut that we presented in September 2025. The crux of the situation is, Enroll-HD is an ongoing natural history. This natural history is still recruiting and following up patients. The analysis that we presented in September of 2025 was based on the latest data cut that CHDI, the sponsor of that natural history study, had available. That data cut was as of January 2023, and it included about 19,000 HD participants.
CHDI does not update this database on a monthly basis, even on an annual basis. In fact, the next update that they did was two and a half years later. That update was done in September of 2025, and that update included an additional two and a half years of follow-up data on the existing patients, plus 6,000 new patients that were recruited in that two-and-a-half-year period. That database not only represented the largest set of data, it was the most recent set of data, and it was the most contemporaneous set of data with the patients in our study. Scientifically, it made sense to use the latest dataset. Now, the second piece of this is that, again, if you remember where we were in the beginning of this year, the FDA had strongly recommended that we do a sham-controlled double-blinded study.
We were the ones that proposed doing the four-year analysis, and one of the concerns that they had was around the lack of pre-specification. To make the analysis as clean as possible, we pre-specified the most recent Enroll-HD data cut, and we had no access to the data. That's the reason we did it. Scientifically, it's sound. I will just say that we provided all the context associated with the amount of missing data, and we believe that those are important contexts and considerations that have to be evaluated when interpreting that data. I know we'll probably get into that in a little bit more detail, but that's the background of utilizing the more recent Enroll-HD.
Got it. When you look at that cUHDRS data, it dropped about 0.52 points from year three to year four. TFC remained rock solid, right? How do we get around that discrepancy? Given the focus is going to be on TFC for the primary endpoint for the future in a confirmatory study, where do you think the FDA is going to line up on the overall dataset?
Yeah. Let's go through that. The question is, why do we believe there's a durable, robust clinical effect out to 48 months? There's a couple of reasons, and then we can get into the impact potentially of the comparator. Firstly, as you point out, Total Functional Capacity, which is the most important clinical outcome measure for patients, clinicians, and regulatory authorities. It's the primary endpoint of our confirmatory study. That has been rock solid between years three and four. Actually, if you look at the 48-month trends, the patients treated with high-dose AMT-130 haven't even lost, on average, 0.1 points per year. Not even a tenth of a point on average per year have these patients lost. Remember, patients that are diagnosed with Huntington's, I mean, they live 10 - 15 years, right?
This is a four-year period, a significant period of time, and they haven't even lost a tenth of a point on average per year, when the patients that are untreated, right, have lost more than a point of Total Functional Capacity. That's very significant. Total Functional Capacity is important because it is not a performance-based test, right? This is a test of how the disease manifests in Huntington's disease patients' lives. This measures, can you hold a job? Can you perform chores in your daily life? Can you balance your checkbook? These are things that are not necessarily impacted on a given day, right? So it tends to be less variable. For the other measures in cUHDRS, they are performance-based tests.
You will come in on a given day, you will do finger tapping, you will sit behind a computer, you will do various tasks, and at this point, we are doing them once a year. There is going to tend to be a little bit more variability associated with that. Number one, TFC, which is the most important thing, is rock solid. Number two, through 48 months, we continue to see clear dose-dependent effect. If you look at the high dose compared to the low dose, and you can almost consider the low dose as almost like a quasi-placebo, even though we believe there is minimal clinical effect there, the high dose on the composite UHDRS was more than a point favorable at 48 months compared to the low dose, right? That I think is important.
On the cUHDRS, I think that one of the things that you mentioned was the decline between years three and four. The one thing I will say is, it is difficult, it is easy, I should say, to potentially over-interpret one measure in one given year. On cUHDRS, we saw at year one, it had a favorable movement at year one, and year two was unfavorable, year three it was favorable, year four it was unfavorable. We do not interpret this as variations in treatment effect. I mean, the drug working one year, not working another year. If you actually look at the first two-year period, cUHDRS change compared to the second two-year period, it is nearly identical. I think you have to look at it over perhaps longer periods of time.
Got it. Let me just jump the gun here a little bit and talk about the FDA disclosures about a potential AdCom, which is totally logical for the first gene therapy to be approved in Huntington's disease. Historically, we have seen physicians and patients talk about the benefits and risks of the drug. Do you expect a substantial number of your patients who have been treated with the high dose be present and talk about their experience?
We are not going to comment on who will be attending the AdCom and whether or not that will include patients from the study. What we do expect, if there is an AdCom, which obviously is in the FDA's discretion, that the patient voice will be represented in one way, shape, or form at that AdCom. I think that is one of the benefits of an advisory committee, and I think this is one of the reasons why the FDA does it, is to get various stakeholder views and to have them evaluated by independent panel members. The FDA has prioritized and has made numerous public comments about the importance of the patient voice.
The Huntington's disease community has been very active and very vocal, and we think that it would be appropriate that their voice is represented in one way, shape, or form to the extent that an advisory committee occurs.
Got it. Going back to the 200-patient study that should be underway shortly. Could you talk to the powering of the TFC, given that you're going to be a 36-month endpoint? Is that powering consistent with what we have seen in the data so far, or are you taking a more conservative approach?
Yeah. We have not disclosed the powering assumptions, and the statistical analysis plan is still being finalized. That's separate from the operations. The study is advancing very well. What I will tell you is this, we have put a lot of thought into the design of the study, a lot of thought in terms of the assumptions, and we have not simply just taken the experience from the phase I/II study, which was obviously a smaller number of patients compared to an external comparator. We have not just taken those assumptions and applied them to the confirmatory study. We've thought through this and built in the appropriate margins to ensure that we can get an answer that is interpretable.
Got it. The enrollment, would that be very similar from a baseline perspective? Would it be very similar from the repeat length and caudate and putamen volumes that we have seen in the phase I/II study?
Yes. The inclusion criteria, the types of patients that we will enroll in that study will be nearly identical, if not identical, to what the patient characteristics were in the phase I/II.
How difficult do you think it will be to find these patients, given you need to do some sort of an imaging to figure out what that caudate and putamen volumes are, especially if you have to do it ex-U.S.?
Yeah, I don't think it'll be, I don't believe it'll be difficult because we've already enrolled 51 patients thus far in the phase I/II program. In our last cohort four, we were able to enroll that very quickly. There is a screening procedure. There is an MRI required, but it's not something that we haven't done in the United States and outside the United States. So I believe that there will be demand for the study and that we are fully committed to it and can enroll it in an expeditious manner.
If everything goes according to plan, is there a minimum number of patients you want to enroll in the U.S. between now and the May 1st PDUFA?
I don't think we necessarily have a specific number. We weren't given a specific number. What is most important, what I've told my team is, this is the number one clinical priority. We recognize that it's considered a confirmatory study, but we are 100% committed to doing it expeditiously and to being able to demonstrate to the FDA that we're serious about it and that we have the study well underway. Well underway is going to mean that we're going to have a plethora of sites open, we're going to have a plethora of patients in screening, we're going to have patients enrolled in the study, and be able to walk the FDA through why we're confident that post-approval, that we can complete this study in a timely manner.
You sort of talked about the 50+ patients who have already been treated across the two dose cohorts. What's been the typical screen failure rate? I'm just trying to figure out, if you have a bunch of patients screening, how many would actually be on therapy by, let's call it, the PDUFA date?
Yeah, I think we've disclosed that the screening failure rate can be 50%-60%. That's something that we've seen in the phase I/II study. Having said that, many of these sites have hundreds of patients that are available, and being able to do MRIs and get their volumetric data is not difficult to do and shouldn't take a lot of time.
What's the team hearing from the field and the patients and the families in terms of enthusiasm to enroll in the study, given, again, the lack of options here?
It's a high degree of enthusiasm, is what we're hearing. I don't want to necessarily repeat the anecdotes. When we presented the data back in September of 2025, the stories that we were hearing about the interest in a treatment option were quite extraordinary. The reality is there are no treatment options, so we expect patients to have demand here in the U.S. Even if a patient is randomized to an open -label or to standard of care, they're guaranteed to get treatment as long as a clinician says it's safe to do so. Of course, outside the U.S., there's nothing commercially available and expected anytime soon.
Let's assume AMT-130 is available, call it middle of the year. How do you handicap dropouts, especially in the U.S., from the patients who get randomized to standard of care?
Yeah, I think the truth of the matter is, these patients are going to be in a clinical trial under the care of an investigator, and they're going to be guaranteed to get treatment after that period of time. It is not necessarily a given that everybody that demands the product is going to be able to get treatment immediately upon launch. Obviously, we're going to do everything we can to make sure that we have treatment centers up and running. But the demand is going to be quite high, and it's going to take some time for us to be able to work through those treatments. It's likely that the patients that are already under care at HD treatment centers are going to be prioritized. They're going to have to be. There may be patients that are newly diagnosed.
The bottom line is that the confirmatory study is one way that they can potentially get treatment straight away. Once we get the product approved, we are going to wind up really having an emphasis on outside the U.S. enrollment. That is common for confirmatory studies. There's no differences in standards of care. So from a data perspective, we don't believe the agency is going to have any issue with enrolling patients. Of course, as I said before, the product won't be commercially available there.
I know you don't necessarily want to comment on the ongoing regulatory process, but is the MHRA process any different than what the FDA may or may not ask?
Yeah, it's tough for us to comment on what, are there differences between agencies about what they may or may not ask. The process is different though, for sure. There is no PDUFA date in the U.K., so there's no specific date where they really have to target making a decision. There are specific clock stops where they will provide you a list of aggregated questions, and the review clock will stop while the sponsor is preparing answers, and that could happen one, two, three times during the course of the review. We would expect that the MHRA process will probably take three-plus months more than the FDA process.
When we talked to one of your lead investigators, he was basically suggesting almost 30% of the patients under his care might be eligible. If the label reflects striatal volume, they may not be able to stick to it simply because you don't do volumetric assessments in every patient. What's the realistic launch curve? From the number of centers, for example, when ELEVIDYS launched, it was mostly one patient per month per site. Is that something what you're thinking about?
Yeah, I think there's going to be different dynamics at different treatment centers. I mean, we've been out meeting 40, 50 different hemophilia centers of excellence, and what I can tell you is we hear different things. There are different things that impact potential efficiency at each site. You can have a site that potentially is highly motivated to do one procedure a week. You can have another site that may be focused on doing one procedure a month. There are going to be different dynamics associated with this. Then, of course, these dynamics are going to be changing. I think sites' efficiency and throughput will be increasing over time. I do not think that a volumetric MRI requirement is going to be a hurdle. I mean, today, volumetric MRI is achievable. It is commercially available.
It is not necessarily a standard of care in HD patients, but there's no I will tell you that if this is a requirement in our label, we're going to be doing everything we can to work with the treatment centers to make sure that it's available for patients and it does not create an impediment.
Given that the procedure's involved and you still need the ClearPoint, if I may call it an apparatus, not many centers are still equipped to it. For example, again, your UAB investigator was basically saying, "Vanderbilt, which has got more patients, they don't have it." Those patients will roll over to his site. How are you thinking about broadly making it available for all the sites with lots of patients?
Yeah, I mean, ClearPoint is available fairly broadly. In fact, we've identified around 60 Huntington's disease centers of excellence that have ClearPoint available. There are plenty of sites that have ClearPoint, and we're going to be focused on the sites that we believe have the highest ability to do volume in year one. There are probably, I don't know, I'm looking at Kylie here, but 100? Yeah, 100 sites that have ClearPoint across the U.S. Not all of them are Huntington's disease centers of excellence, but they have the ability and are equipped to do procedures as we expand our treatment center network.
Unfortunately, Matt, we have run the clock down. We can go on, but-
Yeah
appreciate the time and really wishing you all the best and hope for-
It's always great to see you, Debjit. Appreciate the great questions.