I think we are hot. All right, thank you. Good afternoon. Thank you for joining us at Guggenheim's inaugural Healthcare Innovation Conference. I am Debjit, and joining us today from uniQure is CEO Matt Kapusta. Thank you so much, Matt. Let's get straight to it. There's a meeting calendared with the FDA in the fourth quarter. I believe this will be your first meeting since the RMAT ? How are you setting expectations on the outcome?
Yeah, I think we're trying to be very clear that we view the process of aligning with the FDA as just that, a process. We've had a lot of interactions with companies that have gone through the RMAT process, and in particular, having conversations with the FDA about the potential for expedited development or accelerated approval. So we have a very good understanding of what to expect. The meeting that we have on the calendar is scheduled for late November. This is a meeting that the FDA requested that we schedule once we were granted RMAT designation. And the meeting is going to be a type B multidisciplinary meeting. So this is really meant to kick off the set of interactions. There'll be representatives from all the different subdisciplines, like CMC, clinical stats, non-clinical, safety, tox.
Remember that we really haven't had in-person interactions with the FDA really since our IND process, which was about five years ago. We obviously submitted a substantial amount of information to them as part of the RMAT designation application. There's going to need to be a foundational education about the program. We've submitted a briefing package that is very comprehensive, covers all those topics, including CMC. Obviously, one of the things that we want to lay out for them is our thoughts around clinical development, and in particular, how we feel we can demonstrate therapeutic benefit for the purposes of submitting a BLA. That's going to be a core focus of what we want to lay out. I think really what we want to gather from this meeting is an understanding of the feedback from the FDA.
Do they have any sensitivities? Do they have any concerns? Where might they be? Because what we expect from this meeting is to align with the FDA on what's called a communication plan, where we will lay out for them what we would propose as specific interactions with these specialized divisions of the FDA and the proposed rough agendas of those meetings. And so getting the feedback from the FDA in this Type B meeting will enable us to prepare for those interactions, which we would expect to happen in the first half next year.
How are you planning to communicate with the street? Do you wait for the minutes 30 days later and then put out a PR, or there's going to be no formal communication?
Yeah, so we've tried to be very clear at this stage before we initiate our interactions what our disclosure is going to be. We will disclose where we are with the FDA once we have confidently aligned with them on the path forward. We do not, as a base case, assume that will happen in one meeting. What we will do is we will, in our ongoing interactions, confirm that we've had the meeting, and after we get minutes to the meeting, we will discuss what we anticipate as our next steps, which will likely be approximately a JP Morgan, but we don't expect necessarily to issue an intervening press release, and we won't expect to provide ongoing commentary on those interactions until we achieve that alignment.
Is there a plan to provide a formal communication for 2025 outlook around the time of JP Morgan, where you can plug in the next anticipated meeting with the FDA?
I don't, to me, it doesn't. I mean, we haven't decided on exactly, you know, if you're referring to like a press release. I think we will plan for sure around JP Morgan to provide commentary. Like, we don't. I don't view confirming the meeting and discussing next steps as necessarily requiring a press release, but that's something that we would expect to be able to provide some insight on by the time around JP Morgan.
Got it. And in your dealings with subject matter experts, Huntington's disease experts, do you think there is a buy-in on the quality of the data that has been generated from the 29 patients, especially on the biomarker side, and then correlation on the functional side?
So there has been a tremendous amount of excitement generated from our data thus far. And I believe that excitement is truly sincere. I think what we hear from KOLs is, for sure, we hear from many KOLs that they don't believe necessarily that a placebo-controlled, randomized, blinded study would be required in HD. I think what concerns them and what concerns patients is that, you know, the likelihood is it would require a very significant amount of patients and a considerable amount of follow-up that make the conducting of those studies impractical. So I think that what they, I think there's really two things that we hear from them. One is the statistical significance around a functional composite endpoint that encompasses psychiatric, cognitive, motor, and behavioral elements of it. I think is very convincing for them, understanding that this was not a pre-specified analysis.
The second part of that is that it's being compared to a propensity-weighted natural history, which is robustly collected in a clinically compliant manner, and trying to neutralize some of the biases that come around when you have imbalances in your comparator arm. So I think those couple of things are really important. And then I think the last point is that on the neurofilament light data, we've heard from a number of key opinion leaders that that was particularly striking, that they've just never seen evidence of long-term suppression or lowering of neurofilament light in Huntington's patients out to 2+ years , and that they view that as evidence that we're actually quote unquote saving neurons. So it doesn't mean that there's not questions. I mean, we appreciate there's questions, but I think there's been a lot of excitement generated from the data we have thus far.
Got it. T here seems to be this, at least on the street, trying to compare the NfL reductions with Huntington's versus ALS. How flawed do you think that comparison is? Because you're at about 10%, whereas in ALS, it's a very different disease, much faster progressing.
Yeah, I completely agree. I think part of the issue with the biomarkers is that there's just not substantial validation of the correlation of those biomarkers with progression of disease, particularly over discrete shorter-term periods of time. I do think that you have to keep in mind the natural history data that we do have comes from a seminal study that was done by Dr. Ed Wild that actually shows that patients with early manifest Huntington's typically would see somewhere around a 10%-15% increase per year. But the real exciting part of this is that over a two-year period, they saw about a 25% increase, and that, so when you compare a 10% decline to a 25% increase, that's quite meaningful. You're completely right that the kinetics or the PKPD associated with neurofilament light in Huntington's is very, very different than in ALS.
In ALS patients that were in the Biogen study, Tofersen typically had gross amounts or nominal amounts of NfL that were 3x to 4x as high as patients presenting in the Huntington's study, so they come in with higher levels of neurodegeneration, and of course, that disease is accelerating at a much more rapid pace, so I do think 10% is a meaningful reduction, particularly in light of the increases that we see in Huntington's patients.
Got it. So one of the reasons why it's taken this long to resolve is you ended up enrolling very healthy patients based on the initial FDA feedback. So as you think forward to your next study, whatever form that is, what's the ideal patient population?
Yeah, I mean, the hope would be that we can generate sufficient data, long-term outcomes data that can support registration. But I do think that when we look at the life cycle management of the disease, there's no doubt that the prevailing view is that the earlier that you can treat patients, the better. I think for any neurodegenerative disorder, you know, if you medically intervene too late, the likelihood that you can alter the course of the disease is going to be very difficult. We also know that even patients that are pre-symptomatic, right, they still have Huntington's disease.
If you look at images of their brain, they have atrophy in their brain. So there's no doubt that being able to administer AMT-130 to patients as early as possible, I think would be preferable. The other thing that we're exploring is that we had a prerequisite in our phase 1/2 study that patients have a minimal striatal volume. And we've talked in the past about why we did that, but we don't necessarily think that that's a prerequisite to have therapeutic benefit. And so those are things that we can continue to explore.
Then the last thing would be just simply making the procedure more efficient, shorter in duration, less anesthesia. And there are some things that we can look at that go as simple as just automating the setting up and the taking down of the frame to potentially different trajectories that we can go in for the catheter infusions. But the bottom line is we don't think that these are things that we necessarily have to do for registration. But as we think about life cycle management, these are things we want to keep in mind.
I believe one of your competitors has sort of proposed, or in their recent R&D day, caudate volume preservation was an acceptable endpoint, at least according to the KOLs. Is that something that you could go after, or what's been the experience with?
Yeah, I think that the, so there's an interesting thing about caudate volume. There's no doubt that a lot has been scientifically evaluated and clinically evaluated about volumetric MRI. We know that a hallmark of Huntington's disease is striatal and cortical atrophy. So there's no doubt about that. I think the issue, there's a few issues with this. One is that because we're going in directly and intraparenchymally, we are inserting catheters into the brain. The brain changes morphologically. And the algorithms around brain volumes become confusing to really understand the changes in brain volume after you introduce catheters into the brain. So the positive is we know under real-time MRI, contrast-enhanced, that we're filling the structure, right? So we know we're getting it to the place. The alternative is that it makes interpretation of volumetric MRI more challenging for us, okay?
The second thing that I would mention is we know from other neurodegenerative studies, in particular Alzheimer's, that there's a weird correlation between volumetric MRI. It turns out in a number of Alzheimer's studies, the patients that actually demonstrated therapeutic benefit actually showed increasing atrophy or reduction in brain volume, and it's not exactly understood biologically what's happening, but some of it could be that you are reducing inflammation of the brain, which also can be detected as a reduction of volume.
The last thing I would say is that from a regulatory point of view, the question is how much follow-up do you need and how do you power a study? It's not a very rapid biomarker, right, caudate volume. So how much follow-up do you need? Do you need 12 months, 18 months, two years? At some point, you get to enough follow-up where the clinical outcomes become meaningful. So it's importance in accelerated development, you know, I think are things that have to be discussed. But it's definitely a factor that I think is interesting to key opinion leaders for sure.
So talking about inflammation, you have the third cohort where you're giving prophylactic immunosuppression. How do you expect that to play out both in the initial NfL spike that you saw in the low and high dose cohorts? Do you think that could be sort of addressed and then you get a faster resolution of the actual NfL changes?
Yeah, we've never, even when we initiated this study, this was not about the spike in NfL. I want to be very clear. That perioperative spike in NfL happens very, very quickly. We also saw a very similar spike in NfL, even in animals that received saline, right? And the conclusion or high degree of confidence is that the actual intraparenchymal nature of introducing catheters into the brain causes some level of mechanical damage and scarring. That's just natural. And we've seen increases in NfL even with the administration of deep brain stimulation. So that we believe is mechanical. The peak in the spike of NfL is not dose-dependent. So this is not about addressing the initial spike in NfL. This is about the fact that at the higher dose, in particular, we do see in some patients some idiosyncratic edema and inflammation.
And we think that can be optimized and addressed potentially by tweaking the immunosuppression regimen. And so that's really what we're exploring. And we'll be looking at the evidence of adverse events, looking at MRIs. And then also maybe more precisely is looking at the pace at which NfL returns to baseline. That may be more relevant than the actual initial spikes themselves.
That’s what I was sort of alluding to, right? You get the spike, but with immunosuppression, do you get that to move down faster?
Yeah, I mean, that's something possible. I mean, part of that is going to be just the resolution of the actual procedure itself. But there's no doubt we did see a longer timeframe to return to baseline in the higher dose. And it's possible that that could be impacted by immunosuppression.
Got it. So 2025 mid-year will be the next update. And the reason you chose a three-year update is only because natural history doesn't have a three-year matching control. And that keeps your propensity match scoring alive.
Yeah, I mean, yeah, so I mean, we've provided four different updates generally almost every six months. We think that the two-year update was very meaningful. We know that the comparisons against this propensity-weighted natural history are going to be important, that the availability of that data is on an annual basis. So for us, we're really focused now on really preparing and putting our best foot forward into these regulatory discussions. We will be providing some additional data of longer follow-up that we receive from patients at the two-year mark to the FDA as part of these discussions. But in our view, I mean, you get to a point when you're out 2+ years where the visits are almost semi-annually. So really, the most you can probably do is on a six-month basis.
And because of the availability of natural history data, there's a limited benefit to it. So that was really the rationale in trying to focus on the regulatory process and providing the next update in the middle of the year. We do plan on having some commentary in the first half of next year on that third dose cohort to talk and characterize and qualify some of what we're seeing on perioperative safety in those patients.
Got it. Let's switch gears and move to the Fabry program. When you were designing this program, did you anticipate Sangamo or any other company to get an accelerated approval pathway based on GFR? And since that, have you sort of reconsidered, retooled how quickly this program should move forward?
Yeah, I mean, I think we thought it was a possibility. I think Sangamo had made comments. I mean, you may know better or remember better, maybe up to like 18 months ago on some of the earlier interactions they've had where they talked about potential FDA openness to it. But clearly, you know, their recent announcement in our view seemed to reflect a much more meaningful and formal alignment on that pathway. I think it's great because, you know, I think that the biomarkers like eGFR are fairly well characterized. And I think that when you start to think about outcomes associated with Fabry, which is a relatively slow progressing disease, so if you're looking at cardiac outcomes, you know, you put those studies almost in a situation where it becomes very difficult to demonstrate impact on those kinds of long-term outcomes prior to registration.
I don't know much about how they're going to confirm that, but I would imagine that that's going to be of interest to the FDA. It's not terribly surprising, but I think it's fantastic news. I think there's read-through to our HD program. I think this is just another further demonstration of rational flexibility that CBER is demonstrating and looking at totality of data and being practical and collaborating with sponsors about how to get transformative therapies to patients. So I do think it certainly changes our view on what's possible for Fabry disease. And, you know, just to be clear, I mean, you know, we're obviously, you know, still going after what we hope would be a superior gene therapy, even if, you know, we're to market later. But I think the fact that it's an accelerated pathway only benefits the risk-benefit and the cost associated with development.
So you brought up CBER. We've seen a lot of flexibility from CBER in a range of different rare diseases, but somehow it's not rubbing into the CNS side of things, right? We haven't really seen significant movement on part of the FDA trying to expedite CNS diseases. So I don't know if there is something fundamental going on there or that's still out of Peter Marks' control.
Yeah, I don't think so. I don't see what a rational delineation would be with CNS disorders compared to other, you know, neuromuscular disorders. I don't see a rational delineation for that. I mean, we do know this is publicly available information that Biohaven, you know, and I believe this might be the other side of the FDA with CDER, this is spinocerebellar ataxia, another neurodegenerative disorder that is also slow progressing where they're potentially pursuing and have alignment with the FDA on a full approval associated with a single-arm study and looking at a comparison to an external control with a functional endpoint. So it's an interesting analog.
So I don't know if it's just the opportunities that have been brought forth to CBER, but I just don't see a natural delineation in CNS disorders, particularly ones that are very slow progressing, because I think the feasibility of running blinded, randomized, controlled studies becomes, you know, very, very challenging in those kinds of disorders.
If the FDA were to be flexible and sort of agree to some sort of an accelerated approval pathway based on the three-year data based on the current data set, what would be a rational registration or confirmatory study on the other side?
I mean, I think we would likely propose a single-arm study. I mean, it's, you know, I think it's possible that the, you know, the FDA, you know, may want to look at different kinds of functional primary endpoints. I think we believe that a Composite Unified Huntington's Disease Rating Scale endpoint is compelling. We believe it has a, it's been validated in independent studies to have a strong signal-to-noise ratio and is particularly suitable for smaller patient populations. You know, the FDA may be interested in total functional capacity. That can always be a primary endpoint that can be further justified in a single-arm study to the extent that the FDA views that as a key measure that they want confirmatory evidence on. But I think obviously doing, it's difficult to do randomized controlled studies after, you know, there's a therapy that is commercially available.
We don't necessarily think that that should be needed given the substantial amount of real-world data that has been collected through registries and natural history.
So in the last minute, let's talk about the TLE program. What's taken so long and are you there at the cusp to get your first patient in?
Yeah, so we announced last week that we have the first patient enrolled in what is a protocolized observation period. So I think, you know, I think we're happy with that progress. Really, the issue has been that in our discussions with the FDA as part of the IND, they had asked us to consider the first three patients as quote-unquote "sentinel patients." And they had asked that these patients have, you know, MRI positive hippocampal lesions that are confirmed in the non-dominant lobe. And the issue is that those are precisely the patients that are the best candidates for resection surgery.
So it's not only a smaller, more narrow inclusion criteria, but we're also up against resection surgery on those first three patients. So, you know, we're doing a lot of work, activating a lot of sites. We have 10 sites that are activated. I think we're making good progress, and I think if we can get the first patient treated and demonstrate safety there, that also opens up an avenue to have a dialogue with the FDA about possibly relaxing that inclusion criteria as well.
Well, awesome. Unfortunately, we are out of time. I'm looking forward to a really productive 2025.
Yeah, same. We are as well. We're really encouraged.
Good luck. Thank you so much, Matt.
Thanks, Debjit.