Okay, welcome everyone, to this Fireside Chat with uniQure. My pleasure to host Matt Kapusta, CEO, for an update today. Thanks for joining us.
Thanks for having us. Really appreciate it.
So, great. The uniQure story has evolved considerably over the last year. So maybe we can have you start us off with a quick overview of, you know, your key programs and technology and visions for developing it.
Yeah, I mean, our mission at uniQure is to really develop and bring transformative medicines to patients with severe needs. And, you know, we're one of the few companies in the cell and gene therapy space that have been able to demonstrate that twice over our history, over the last quarter of a century. So of course we did that with Glybera, and then more recently did that with HEMGENIX, and we're very proud of that. I think that validates our capabilities, our people, our technology, and, you know, just our ability to get our arms around very complex clinical studies and to really get the most out of them.
So, you know, we have been over the last several years really focused on trying to advance a number of programs into the clinic and become a multi-asset clinical stage story. And we were really excited last year to get 2 INDs cleared, and now have 4 clinical stage programs that are in various different stages. So our lead program is in Huntington's disease. You know, we're now at a critical juncture for the program. I'm sure we'll talk more about that a little bit later on in the chat. But we're in the process of preparing for a mid-year update that will include data now with up to 3 years of follow-up, right? So you're starting to get, you know, really significant understanding of the potential therapeutic profile for the product.
And then we have three other clinical stage programs that are all in the initial startup phases, where we expect to initiate enrollment in the first half of this year, one in epilepsy, the other one in ALS, and then the third one in Fabry disease. And then, we have a, I think, a more narrowly focused effort in research, after our October restructuring last year, where we have a few projects that we're working on that we're excited about, one in Alzheimer's, the other one, another familial ALS, and then a third undisclosed project.
Okay, great. So let's start with Huntington's, and can you summarize for us the clinical data that you've generated so far, to this point, and tell us what you see there?
Yeah. So, you know, one of the goals of this study, which is... We're really the first one-time administered gene therapy in the clinic and have been now for the last 5 years. So one of the goals of the study was to really collect as much information as we possibly could generate from the study. So all sorts of safety data that we collected in the study, biomarker data, imaging data, and then clinical outcomes data. And we've presented them at a number of different times over the course of the last 1.5 years since we've unblinded the US clinical study. So in total, we have treated 33 patients. In December of last year, we presented data on 29 of those 33 with up to 2.5 years of follow-up data.
I think that, there's really two stories with Huntington's. One is the biomarker story, which is a complicated one. I think it's complicated because, for Huntington's, there's really not a significant number of biomarkers that have been validated to correlate with progression of disease. And then there's a functional story, which is, of course, what clinicians and patients care about. The problem is that the disease progresses very slowly in nature, so to really capture meaningful functional data requires a meaningful amount of follow-up. So what I think encouraged us the most about our Huntington's data is that we are beginning to see, what appears to be signals of a dose-dependent effect on a number of the different parameters on the clinical outcomes. And we're looking at things like motor function, behavioral function, psychiatric function, cognitive function.
What we're seeing is that, generally speaking, there's preservation of a patient's function now out to about 2.5 years, and we're beginning to see a dose-dependent relationship with the higher dose having greater impact on cognitive functions, which are really required to get cortical penetration, which we actually saw in our animal studies, had greater biodistribution at the higher dose. So obviously, the data is in the process of maturing. In this mid-year update, we're going to have at least 2 years of follow-up data on 25 of the 33 patients that we treated. So you're really getting to the meat of the follow-up, where you really would expect to see patients lose function.
And so if we continue to see generally preserved function with a stable neurodegenerative profile as measured by NfL, I think that will be, continue to be encouraging for us.
Okay. What comparisons are you referring to when you talk about your... I know obviously, you, you talked about the dose-dependent effect. You also have some sham injections and a natural history comparator. So can you talk about the different levels of comparisons that you've made?
Yeah, so there are three different comparisons. One, of course, is a patient's own follow-up to their baseline, so that's how we would interpret or measure preservation of function. So they come into the study with a certain level of function that has been tested prior to treatment, and then we follow them and continue to test their function throughout the course of the trial. So that's one. The second one is the treated patients versus a blinded, sham-controlled or imitation surgical procedure, and we did that in our U.S. study for one year. So we had a blinded period of one year, at which point we unblinded the study, and then patients that were eligible for treatment were to cross over, and patients that were not eligible dropped from the study.
Unfortunately, the control length is only 1 year, and because of the relatively slow, progressing nature of the disease, it's very difficult to see much in that comparison. The third one is to natural history, and I think one of the benefits that Huntington's has is that it has an abundance of natural history data collected in numerous registries and thousands of patients. What we did was we put together a preliminary natural history of 31 patients that generally matched the inclusion criteria of our study. We've been able to get multiple follow-up of those untreated natural history inclusion criteria matched patients and compare those to patients that were treated.
What we do see is, you know, meaning not only generally preserved function compared to a patient's own baseline, but we see meaningful improvement of functional parameters compared to that natural history cohort or synthetic cohort.
Mm-hmm. Okay, and so what do you do with this data now? That's a loaded question because I know you're planning to talk to regulators and so when does that happen?
Yep.
And how do those discussions progress?
So that's the key thing. This IND was cleared at the end of 2018. So we've been at this phase I/II study, or studies in the U.S. and Europe. We've completed enrollment of the first couple of cohorts. We're now enrolling a modest-sized third cohort to get a better understanding of immunosuppression, but that's going to be relatively short-term follow-up. The key thing right now is for us to understand how the regulatory agencies view late-stage clinical development for Huntington's. So, we plan to initiate interactions with the FDA in the second quarter. That will be likely a number of interactions that we'll have, and we have guided that we will provide an update from our learnings with the discussions from the FDA before the end of this year. We're really focused on learning three key things.
One is we want to share the data, which we have not yet done with the FDA, our interpretation of the data, and get their feedback on the data. The second thing is we want to get an understanding of how the FDA views the usage of a natural history comparator arm, as opposed to having to run a placebo-controlled, large, long-term study, like we did in the first year of the U.S. study. Then the third is to understand, and this is an important one, how we might be able to leverage some of the long-term clinical outcomes data that is generated from our phase I/II study in demonstrating efficacy for registration purposes. So we won't likely be covering all those topics in one meeting.
We're not gonna give necessarily play-by-play updates, but we do commit to providing an update before the end of this year about what the regulators are considering.
Okay. Helpful. So yesterday, we heard from Peter Marks at the conference, who was talking about how he's motivated to lean into gene therapy and support sponsors who are addressing grave diseases. And Huntington's is, you know... I'm wondering, where does Huntington's fit into that rubric in your mind? And I'm asking because at the same time, I heard you say that it's relatively slowly progressing, and we know that the or we think we know that the treatment community has been burned a couple times in the recent past with other things that looked like they were very promising and then had, you know, safety problems in the face of limited efficacy.
So, all that being said, you know, how do you think that AMT-130 could fit into this rubric that Peter Marks and the CBER division seem to be outlining for other sponsors, like in neuromuscular disease and in DMD, for example? How optimistic are you that that there's a regulatory path that is straightforward?
Yeah. Well, so let me talk about a couple of aspects of this. One is, after spending the time that I've spent with the Huntington's community, I don't think that anybody who understands the disease will debate that this is an extraordinarily high unmet need that has no disease-modifying treatments that are available for it. So I do think that in terms of assessing the risk-benefit equation, which is really what the FDA is always trying to balance, you know, the severity of the unmet need is a critical aspect, and I do think Huntington's will check that box.
It is a slow progressing disease, but it is a death sentence nevertheless, and it is one that impacts adults in the prime time of their lives when they're building careers, when they have young or teenage kids, so it is devastation. So I don't think that will be an issue. I do think the other aspect, as I mentioned just a few minutes ago, was there is an abundance of natural history data. So, much of this data has been collected in a compliant, clinical-oriented manner. So I don't think. I do think that there's a lot of opportunity to create really robust synthetic comparators that I think are, you know, very reasonable comparators for determining efficacy.
I do, you know, there is a difference, you know, in some respects, where, you know, this is not an ultra-orphan disease where it's nearly impossible to run a placebo-controlled study. We know that from tominersen and Roche. I mean, they were able to obviously do a rather large study. It's also not a pediatric disease, right? Where you have, you know, mothers and fathers, you know, that are, you know, storming the, you know, the front halls of the FDA. But nevertheless, it is a devastating disease. I think there's a lot of rationale to support trying to facilitate getting these potential therapeutics to the market faster.
The one other thing I will mention is that, you know, the gene therapy, and I do believe Peter and the FDA understand this. Gene therapy affords this really unusual, almost unprecedented opportunity, where you can collect long-term clinical outcomes data from very early clinical studies. Because it is a one-time administered therapy where patients are theoretically on drug for life. And so I do think that Peter and the FDA understand this uniqueness of gene therapy, the rarity of these diseases, the fact that they're monogenic in nature, and the likelihood that they can work. And so this potential for us to generate long-term follow-up data from our phase I/II study, that is not necessarily based on biomarkers, but based on actual clinical outcomes, is, I think, a unique one.
I do think my hope is that will resonate with the FDA, but of course, we'll see.
Yeah. Yeah. Good luck.
Thanks.
So, recently, you said that the company will need regulatory clarity with a clear and timely approval pathway that is financially feasible, including a partnership before you pursue phase III for AMT-130. So could we take those piecemeal and have you tell us what is your view of regulatory clarity with a clear and timely approval pathway?
Yeah, I mean, we wanna know how the FDA is thinking about registration. Is the FDA going to require a placebo control? Are they gonna require a phase III? Do they look with interest on long-term clinical outcomes of a phase I/II? So I think all those questions are going to be really important. I mean, if the FDA basically says, you know, "Look, you know, we can't make heads or tails of your data because we don't look at natural history comparators," you know, that will mean one thing, right?
Yeah.
It will mean one thing not only for uniQure, but really for the entire therapeutic field in Huntington's disease. So I think we wanna understand what the pathway is, what would the, the timeframe be potentially to, getting registration, and then what is the cost going to be, right? Those are gonna be important questions, not only for uniQure, but even for potential partners. Secondly, we wanna have, access to the additional data, which we, which we plan to have in the middle of the year. And as I mentioned, again, this will be up to 3 years, with between 2-3 years of follow-up on 25 patients.
So it's getting to a point where, you know, if we continue to see the trends that we've seen over the last couple of data readouts, that the likelihood that this is some random noise, right, is simply just lower and lower. But having said that, I think what we wanted to be clear about in the press release was, you know, we are... We are very dilution sensitive. We are pragmatic. We understand how the market is viewing this opportunity today. We understand where we're valued, and, you know, we are not going to initiate a multi-year, long-term, expensive phase III study without a partner. I mean, and that's, I think, you know, rational behavior. We wanted to make that very clear for shareholders.
Perfect. That addressed both parts. Thank you. So I wanna ask another question on AMT-130 before we touch on the rest of your pipeline. So I'm intrigued by the third cohort of patients who are being treated with perioperative immunosuppression, based on some things that we've, you know, been talking about with our KOLs, about how that might help both safety and efficacy. So can you talk about your goals there, and when we might see that data?
Yeah, so we initiated. We're gonna likely do up to 10-12 additional patients in Cohort III. We started already enrolling that study at the end of last year, and what we've guided is that we expect to complete enrollment this year. I do not expect that we'll provide an update on that cohort in the middle of the year, but I do want to make the point that, while there's obviously the potential that it can enhance efficacy, I mean, and we'll follow these patients, right, of course, for the duration of five years.
What we're really focused on to inform how we think about, you know, late-stage development is on the safety side, to look at perioperative follow-up, probably in the approximately three months of follow-up, to understand, you know, the adverse event profile, what's happening on imaging data, what's happening on NfL. We really want to understand that, you know, the potential to show immune-mediated responses that we saw in a few patients at the higher dose, in particular, where we saw some level of CNS inflammation and edema. We want to understand the impact of immunosuppression on that. And of course, we already know that even the folks that had adverse events, responded very well to corticosteroids.
But we also want to look at other potential immunosuppression regimens that, you know, have been utilized in other studies to make sure that we're doing this in an optimized way.
Mm. Yeah. So you've already had some patients treated with corticosteroids, but was this just not a essentially managed or systematized approach and-
Yeah, kind of. That's right. I mean, there was-
An idea now of what you want to test now.
Yeah, that's, that's exactly right. I think we have... You know, we've had many, many conversations with experts, immunologists, virologists, the neurosurgical and neurological community, our DSMB, our steering committee, to talk about the pros and cons of immunosuppression with Huntington's patients, to review some of the data that we've collected over the years, and to also talk about, you know, what's been done in other CNS-oriented clinical studies. You know, we have used immunosuppression in even the first couple of cohorts, but generally speaking, it was not systematized, as you mentioned, and the amount of steroid usage after the procedure was very, very limited.
Mm.
That's particularly what we want to look at is potentially extending that immunosuppression window and then looking at other agents beyond corticosteroids.
Okay, very helpful. And as a segue to the rest of the pipeline, you know, you must have learned a ton from undertaking this, these efforts that you can apply to the next agents in development. So maybe you can talk a little bit about those learnings and, you know, will this help speed development of your TLE, Fabry, and ALS programs at all?
Yeah. In fact, every single one of the programs we're doing has leveraged prior programs that we've used, and we can cover that a little bit. So let's take. We just talked about actually one of them, right? We just talked about immunosuppression-
Yep.
for Huntington's, and, of course, those are learnings that we're now applying to our temporal lobe epilepsy program. The other one is on direct intraparenchymal administration of gene therapies into deep areas of the brain. So we've... You know, I don't know if there's anybody else that's done as much work on animals and non-human primates and transgenic pigs around the best way to administer the right trajectories. Where do you get biodistribution if you do go the thalamus only or the caudate and putamen plus the thalamus, right? So we have a really good understanding of these things. What's great about the temporal lobe epilepsy program is that, you know, the Huntington's procedure is somewhat lengthy because there's three infusions per hemisphere.
For temporal lobe epilepsy, there's only really one infusion directly into the heart of the hippocampal lesion. And so I think, you know, I would suspect that commercially this would be an outpatient procedure, despite the fact that it's infusing a catheter into the brain. And then the last part of it is, you know, on how to actually design these microRNA constructs. You would think that when you impregnate, you know, an AAV with some cargo, that it's just really easy. You just kind of put it in there, right? But actually, the way that you design these constructs, the scaffolds that you use, the level of expression, you know, we have one that, you know, does not have a hairpin on it, right? So that reduces off-target effects.
We also have one that preferentially sorts for exosomes, so you get cross-correction of neighboring cells. It doesn't overwhelm the RNA machinery, which can create tox. So we've learned a lot about that, and we've applied that to both the SOD1 ALS program that utilizes RNAs as well as temporal lobe epilepsy.
Talk about a bit about the target in TLE and what you've seen in animals and how you're hoping it might translate into these patients.
Yeah, so kainate. So our target is a kainate receptor, and it's a, it is called a GluK2 subunit, of which GRIK2 is a particular enzyme or protein that we are targeting, and we're targeting this with two microRNAs. So really, what you're trying to do here is you've got these kainate receptors that you're trying to suppress. The kainate receptor is well-characterized and implicated in the neuronal excitatory pathway. So in fact, there are animal models that are done to induce seizures, right? That excite the kainate receptor pathway. We are trying to bind to and degrade this GRIK2 to suppress this receptor and reduce the seizure activity. So it's fairly well-characterized and understood, the pathophysiology of GRIK2, and we've done a number of animal models.
One is a pilocarpine mouse model, which is a seizure or diseased mouse model, where we've shown very significant reduction of seizure frequency. And then we've also tested this in hippocampal slices from actual epilepsy patients and confirmed that it substantially reduces the neuronal firing activity. So I think that gives us a high degree of confidence in the pathway. And what we love about it is it's obviously a significant opportunity, and one, at least in terms of the timeframe to generate a clinical proof of concept, can be done with relative efficiency, given that you're really looking at seizure frequency, which can be collected rather quickly.
Yeah, sure. And will you be measuring some objective data as well, in order to illustrate what could be happening?
Yeah. I mean, we'll be looking at. You can do a lot of EEG measurements, which can give you a readout, an objective readout on the stability or lack of stability in the neuronal activity of the brain. So that's certainly one, and there's some, you know, reasonable biomarkers there. But quite frankly, they all get you know, dwarfed or trumped by the fact that you're going to be generating actual clinical outcomes data quickly. So you could have beautiful EEG suppression, but if you're not seeing lowering of seizures, that's critical, as well as vice versa. So you know, that's gonna be the key thing is really the clinical outcomes from this phase I/II study.
Okay. And how, what progress are you making in the clinic in terms of, like, site activation and enrollment for that, as well as the other two programs?
So on the three programs that are all starting, we've guided that we're working hard and expect to initiate enrollment in the first half of this year. So you can assume, you know, we are well underway and working with sites, going through IRBs and really establishing SOPs for those procedures, thinking about patient identification. So there's a lot of activity that's underway right now, and we're really looking forward to being in a position where we're treating patients across these three studies and generating data, you know, with relative speed. Yep.
Okay, great. And lastly, how is the company capitalized, and what's the cash runway in order to undertake all of this?
So we've guided. So we ended the year with about $620 million. We've guided that that's sufficient runway to get us into the second quarter of 2027. What I will say is this is outside of, you know, Huntington's regulatory clarity and the initiation of these clinical studies. The management of our cash burn, the conservation of our capital, is top priority for me at uniQure, for our board, and we are continually evaluating ways that we can manage, reduce burn, to ensure that we have sufficient runway to generate data from these new programs.
Sounds good. Good luck.
Thank you!
Thank you for the update, Matt.
Yeah, appreciate you having us here in Miami.