Okay. Hi, good afternoon, everybody. I'm Kristen Kluska. I'm one of the biotech analysts at Cantor. Very happy to be hosting a company that I cover, uniQure. Joining me is the CEO, Matt Kapusta. Thanks so much for coming.
Thanks for having us, Kristen.
Great to see you. So following the success in hemophilia B, by next year, you're largely gonna be a CNS-focused company with four programs in the clinic. How has your expertise and knowledge around both AAV5 and AAV9 led you to your confidence to move forward in this space and help de-risk some potential?
Yeah, that's a, that's a great question. I think, you know, we, we do look at AAV as a core component to what we do. It's obviously the way in which we, we deliver the cargo, the constructs, to the cells that, that we're targeting. So, being able to rely on serotypes or capsids, where we have not only a tremendous amount of knowledge about how they behave, how they're manufactured, but also the, safety profile associated with those capsids, and the, ability to transduce and generate expression of whatever the cargo is, is critically important. You know, and I would say that, in a number of the disorders where, we're looking at, like, as an example, ALS or in Huntington's, and even epilepsy, as we'll get into, it's critically important that we're able to optimize efficacy.
So in those situations, you know, not only do we do surgical implantation of the therapy, but we want to really make sure that we understand exactly how much we're gonna get in what areas of the brain. So, you know, there is the ability, of course, I think, to optimize AAVs, to go towards next generation capsids, and of course, those are things that we're looking at to solve specific problems. But in many cases, you really want to optimize efficacy before you think about a less invasive administration with a novel capsid. So having focused on AAV and AAV9, which are two capsids where there's a tremendous amount of scientific and clinical understanding, I think is a benefit for the programs that we're looking at.
Okay, thank you for that. And then beyond capsids, there are a lot of platform technologies that you're building that are critical for your lead program, but also may have potential down the road as well. One of those is the miRNA silencing technology, which you established some proof of concept for recently in the Huntington's model. So same question, but now more on the platform side, how is this kind of directing the next stage at uniQure?
Yeah. So I think that one of the reasons that we are focused on CNS disorders is that these are disorders that have critically high unmet needs, and in my mind, the delivery for CNS disorders is more complicated and lends itself more to adeno-associated viruses. Obviously, with things associated with the liver, everything gets to the liver. There's a lot of different delivery modalities. And so we're focused on CNS disorders. The ability to suppress something was really a driver of our strategy for quite some time. It's very easy to replace a missing gene like we're doing with hemophilia, but a lot of disorders, particularly neurological disorders, you have a gain-of-function mutation. So for epilepsy, we're looking to suppress a neuroexcitatory pathway. For Huntington's, we're looking to suppress a mutated protein. That seems really easy to do.
MicroRNAs have been around a long time. Antisense oligos have been around a long time. What I will tell you is that five or six years of research have gone into exactly how you design these constructs. So it is very easy, as an example, for microRNAs to overwhelm the microRNA machinery that are in cells. That could be toxic. It's been demonstrated to be toxic. There's also the ability, when you have microRNAs, for there to be off-target effects, to suppress certain things that you're not directly looking to suppress. We've put a lot of research and development into the scaffold that we comprise our microRNA constructs in, in order to not overwhelm that machinery and in order to reduce to close to zero the off-target effects. So the bottom line is, these cargo technologies are important.
They're not gonna end with microRNAs, but we do have a lot of know-how, and that's why we deploy it in a number of our programs.
Okay. I'd love to actually start digging more into your temporal lobe epilepsy program. I don't think you get much credit for it, and it's very interesting, in my opinion. So it's a pretty substantial market opportunity. Why don't anti-seizure medications work for the majority of these patients? Do we have, like, a biologic understanding of some of the limitations?
Yeah, it's a great question, and obviously, the, there are theories on this. What I can tell you is that anti-seizure medications have been around for decades, and that when you look at the number of epileptic patients that are refractory to anti-seizure medicines, it really hasn't changed much over that period of time. There is a variety of different targets and methodologies. I think the biggest issue with anti-seizure medication is that they are typically non-specific.
Mm-hmm.
So they're systemic, and as a result of that, there are toxicities that can impact efficacy. I think it comes down to the delivery, the non-specific nature of it, and the fact that the level of innovation or transformational innovation that has happened with anti-seizure medications has been more incremental than substantial.
Okay, thanks for that. So what evidence do we have that a gene therapy like AMT-260 might be able to break this cycle?
Yeah, I mean, of course, we have substantial evidence from a preclinical standpoint.
Mm-hmm.
So, we've looked at AMT-260 in pilocarpine mice, which is probably the gold standard in terms of evaluating anti-seizure medicine. So these are heavily epileptic disease model mice, where we've seen highly substantial reduction of seizures. We've also looked at the impact on neuroexcitatory function in actual slices of brain tissue from epilepsy patients. So I think we generated as much preclinical data that gives us substantial encouragement with the approach. The other piece of this is that effectively, we are able to administer, on a one-time basis, in a very selective manner, the therapy to the specific lesion of the brain where the seizures are emanating. So of course, everybody would like a pill. We know that there's about 30%-40% of the population that are refractory to that. They still seize heavily.
We have the ability, with a different mechanism, to locally implant the therapy once into the area of the brain that is diseased, to reduce or eliminate the seizures, and I think that's what makes us excited about the approach.
Is the secret sauce here that you're targeting the underlying problem of GluK2 expression?
Yeah, I think the secret sauce is that it is a, it is a novel, well-characterized neuroexcitatory pathway-
Mm.
That is not targeted by anti-seizure medication, so if anything, it could be additive. The second is that it's one time administered. The third is that it spares brain tissue because, quite frankly, the only alternative for refractory epilepsy patients is to remove the lobe or to implant something that requires maintenance in the lobe. So here we have a one-time procedure that can be administered locally. It can spare the healthy tissue, and it's a novel mechanism, and if for whatever reason it fails, you can still do either, you know, ablation, or you can do resection. So I think that offers, you know, a really encouraging and impactful alternative for these patients where anti-seizure medication is failing.
Would you say that this is a neurological condition that's perhaps a little bit more understood than something like Huntington's disease, for example, in terms of pathophysiology?
Yes, I think it's under... It's certainly, I think, understood. You know, folks that have temporal lobe epilepsy, many of them, you know, you understand, you can see a lesion.
Right.
You know, it often happens with head trauma. You know, you can electronically map the physiology. You can see it on an MRI. So I think there's an understanding of it. Now, it is a complicated pathway.
Okay.
There's a lot of factors that can enhance seizure activity, and then there are also factors that can suppress seizure activity. So in some respects, it's more complicated than Huntington's, where we know-
Yeah
It's a monogenic disorder.
Yeah.
I think where Huntington's, of course, gets more complex is in the clinical setting.
Yeah.
Right? It's in biomarkers. It's in measuring therapeutic benefit. That is far easier with epilepsy, just as it was with hemophilia, right? In the end, you have therapeutic benefit if you can measurably eliminate, you know, severe seizures for patients that really have no other alternatives, and obviously, demonstrating that with Huntington's is a little bit more complicated.
Okay, thanks for that. So in terms of the clinical development, obviously, first and foremost, the goal is to establish safety, but beyond this, what's gonna give you a good early signal that the therapy's working?
The most important thing is reduction in debilitating seizures. Like, in my mind, that is, you know, the most important thing. We obviously can look at interictal discharge, where we can evaluate the electrical firing-
Yeah
Inside the brain. That can give us some early biomarker evidence, but the reality is that, you know, within four to eight to twelve months, that is sufficient follow-up to understand, are we, you know, radically reducing debilitating seizure frequency? And that's really what we would be aiming to do with this therapy. So, you know, I think even from an open-label phase I/II study, which is what we're conducting, that is what we're going to be mostly interested in capturing.
Okay, so it's not going to take a whole lot of follow-up to tell the Street, "We think we have something," or, "We want to explore this further." It should be a lot more straightforward than something like, again, Huntington's, where, you know, it's kind of taken a couple of years to see a lot of these pinpointed differences.
Yeah. I mean, there's a competitive company that has a program that I think created a huge amount of excitement, I think, within the investor field, the treating clinicians, and in the patient community from just a few patients of data.
Okay.
So I think that to us, when we acquired Corlieve, which got us this program, I think not only did we see a large market opportunity, we saw in refractory patients a high unmet need, but the clinical proof of concept pathway of demonstrating that, you know, was, you know, fairly black and white and fairly expeditious. So I think those are attractive when we look at the kinds of investment opportunities we're going to be focused on.
Yeah. Let's dig into that a little bit more. So when I think about uniQure as a whole, your valuation not getting credit for much, but if, as we sit in this room here today, we're talking about a massive market indication. Standard of care is not effective for a lot of patients. You have some preclinical data that's pretty validating from an early stage. Investors aren't going to have to wait years and years to see if your therapy works. Like, why should they be buying the stock today versus, say, "You know, we're just going to wait to see if there's proof of concept first?
Yeah, I mean, look, I think, I think with that, you have to look at the entire company.
Yeah.
It's obviously hard to get into the mind's eye of investors, but I think, you know, uniQure as a company, you know, we have $525 million of cash as of June 30. We've taken very difficult steps to substantially reduce our burn. We have runway through the end of 2027. We have a lead program in Huntington's that I think we have a very significant potential value inflection point in the near term in providing regulatory clarity. And we have three other clinical programs, with temporal lobe epilepsy being a substantial opportunity-
Yeah
Where there's a potential on a modest, the number of patients with not significant follow-up to demonstrate a meaningful clinical proof of concept. So at some point, if we're right, there's going to be a significant value inflection, and if you wait for that, then, you know, you you've missed the boat, or at least in part. I think now is an attractive opportunity with more limited downside and a substantial amount of upside, you know, but I'm not, I'm not an investor. I do think that in today's environment, that as we get closer. Let's talk about temporal lobe epilepsy. As we get closer and we know that, you know, maybe six months is kind of the sweet spot when people look at inflection.
As we get to that point where we're that proximal to data, I think people will switch on, and maybe in today's environment, it's just going to be a little bit more time. I don't know.
You've been notorious for sneaking great things on us. I still remember one of the first things you did as CEO was the new hemophilia construct, and the stock did so well, and I know a lot of people kicked themselves for missing that. Maybe they should do their homework now, so they're not beating themselves up again, right?
Absolutely.
So with Huntington's disease, you surprised the Street with better-than-expected data this summer. Maybe just recap for us the findings, but I think the big question now in everybody's mind is: What's next in terms of FDA?
Yeah. So I think, I mean, look, we've always been very encouraged by the data. I do think, though, we got to a tipping point in the July update, where we had a real critical mass of patients with meaningful long-term follow-up. So for the first time, we had more than 20 patients where we had twenty-four months of follow-up, and for a slow-progressing disease like Huntington's, that's really the level of follow-up that's required to really understand whether or not you're impacting the progression of the disease. The other aspect where the follow-up became important is that because we are an intraparenchymally delivered therapy, some of the biomarkers, like neurofilament light, the near-term data are impacted by the procedure itself.
Mm-hmm.
At two years, we've gotten to a point where a lot of that noise has been washed out, and we have a critical mass of number of patients with enough follow-up, where the picture is becoming more in focus. I think what we've been able to demonstrate is a statistically significant slowing of the progression of disease, as measured by a well-characterized composite endpoint that looks at motor factors, behavioral, psychiatric, and cognitive factors. You know, that is demonstrating more or less stability in how these patients are behaving or progressing over that two-year period of time. We compared that, most importantly, to a propensity-weighted natural history.
We do not have an internal control that goes out that far, so we took great care to get access to registry data and to develop a comparator that essentially comprises of digital twins. So if you look at a whole host of prognostic factors and you compare the treated patients to the natural history, they are nearly identical. And again, important because there's a high degree of variability from patient to patient. So we were able to demonstrate this with really compelling data on the Composite Unified Huntington's Disease Rating Scale. But more importantly, for the first time ever, we've seen a reduction in neurofilament light assessed in the cerebrospinal fluid. The neurofilament light is probably one of the most well-characterized biomarkers or measures of neurodegeneration, and to our knowledge, it has never been demonstrated clinically, with two years of follow-up, to see a reduction of neurofilament light.
We have natural history data that suggests that untreated patients normally would have about a 25% increase in neurofilament light over two years. We saw an 11% decrease.
Okay, thank you for that. And then just in terms of regulatory path, I know it's not cemented yet, but maybe you could tell us what the next steps are in terms of meeting with the FDA?
Yeah, so we received RMAT designation in-
Yeah
in May of this year. Two important parts about RMAT. One is that as part of achieving RMAT, there has to be a reasonable basis or a reasonable probability of therapeutic benefit that is supported by clinical data, and the second is that under RMAT, there is the possibility or potential for accelerated approval. So I think those are really the important elements. I think the third, and arguably most important, you can debate, is that it allows for us to earlier and more frequently interact with the FDA about how to define an approval path forward. So we expect to kick off those RMAT interactions with the FDA in the H2 of this year. We will conduct a Type B multidisciplinary meeting with the FDA.
That will be a first step, and then after that, there will be more specific topical meetings with the disciplines like CMC and Clinical Statistics, with those particular departments of the FDA shortly thereafter to get into deeper topics, and really, what we're gonna be focused on is defining that path forward as expeditiously as possible, utilizing a natural history comparator and leveraging long-term outcomes from our phase I/II data as best we can.
Okay. I think something that's been really unique and special here is there's a couple companies in this space, and you all take the responsibility of the patients most seriously. I don't see this as companies speaking negatively about each other. I see this as a few companies that genuinely all wanna come together and support, that these patients really need therapies, and they're all clearly working with the FDA to maybe change the tune of things in the past. You've all brought up the example of ALS in the past in terms of the flexibility there and what the FDA has done to really help bring treatments on board. How does this work for Huntington's disease? Do you see the FDA kind of willingness to hear you all out in terms of this disease?
I mean, the way it, it's described as a combination, right, of like Alzheimer's, Parkinson's all at once. It's a terrible disorder.
It would not surprise everybody here to, you know, to hear me say that, you know, at uniQure, we're obviously a patient-driven organization.
Yeah.
You know, I think we got a huge amount of pride and delight in seeing Hemgenix get approved for patients.
Yeah
With hemophilia B, and we do believe in the transformative value of that therapy, but Huntington's is a completely different-
Yeah
Ball of wax and it doesn't take meeting probably more than one patient.
Yeah
One family member to understand, how it's basically living torture. So, you know, there are no disease-modifying treatments for Huntington's, and I think that the FDA, in particular, CBER, is no doubt leaning into, in a very substantial way, trying to collaborate with sponsors in these areas of very high unmet need, where you're dealing with one-time administered therapies, to find to work and find expedited approval pathways.
Yeah.
Even as Peter Marks has said, understanding that mistakes may be made, and things may get approved that ultimately can't be confirmed. I do think with ALS, it's really important. You know, the FDA approved Amylyx's therapy, and the product didn't work, as has been evidenced with a confirmatory study, and the product is gonna be pulled, and I don't think there's anything wrong with that, particularly with rare diseases, monogenic diseases, where you're dealing with, you know, relatively small populations.
Right.
So there's no doubt that, you know, the competitive landscape, there are folks with different approaches. I do think we all want to find an appropriate way to get on the market.
Yeah.
I think we all could enjoy the ability to leverage the natural history data in Huntington's, where there's, like, sixty thousand patients of data, so to be able to leverage that in order to demonstrate efficacy faster than would otherwise be we deem necessary in a traditional basis. I think we would all benefit from that.
Yeah. No, props to you guys for all putting the patients and their needs above anything else. That goes forgotten about sometimes, right?
Yeah, yeah, yeah. No doubt.
So maybe to close, I mean, we only really got to touch on two products. There's a lot more going, but I did wanna open the floor to you, see if there were any other programs or opportunities that investors should really be keeping on their radars.
Yeah, look, I think the key thing for uniQure, as you think about it, I do think that there's a huge amount of potential left in gene therapy. We're at a stage now with four programs, where over the course of the next year or so, we're gonna be generating potentially meaningful data across a number of programs, where, in my mind, the clinical proof of concept is relatively rapid. We have a focus on a number of markets where these could be perhaps, you know, the biggest opportunities within the gene and cell therapy space. We have a substantial amount of cash on our balance sheet. We've taken steps to really focus our investments.
Yeah.
We have adequate runway to get to data generation and value inflection points, and, you know, we're gonna be focused on execution, as we always are. But we're very much encouraged with the data from our Huntington's program. We're really looking forward to engaging with the FDA on a really exciting opportunity, and continuing to execute on the new clinical studies and the generation of data as quickly as possible.
Yeah. Sounds like it'll be an exciting 2025 , and I, I bet you'll be getting a lot more questions beyond just Huntington's, and people will be focusing on the pipeline holistically then.
Yeah, absolutely. We're looking forward to it.
Thank you so much, Matt. Really appreciate it.
Thanks, Kristin.