Welcome, everyone. It's my pleasure to host this fireside chat with uniQure, and I'm happy to have Matt Kapusta, CEO, with us today for an update. Thanks so much for joining us.
Thanks for having us, Joe.
Maybe we can start by just having you bring us up to date on your latest progress and goals for the year in each of your different areas, and then we'll dive into those.
Yeah, sure. For those that don't know of uniQure, uniQure is one of the pioneers in the gene therapy space. The company was founded more than a quarter of a century ago, currently the only company that has actually brought to the market two approved AAV gene therapies, the first one being in 2012, Glybera for lipoprotein lipase deficiency, and then more recently in 2022 with HEMGENIX, which was the world's first hemophilia B gene therapy. We currently have four clinical programs that we're very excited about. The first one, our lead program, is in Huntington's disease, and that currently has an established accelerated approval pathway based on our conversation with the FDA in November of last year. We're very excited about that program. We have three other clinical programs in temporal lobe epilepsy that are currently in a phase I-II study.
We have a Fabry program, which is also currently in a phase I-II study, and then a SOD1 ALS program that is similarly in a phase I-II study. All three of those programs have initiated dosing. We are in a position now where we think when we look at the next 6 months-15 months or 18 months, we really have a tremendous amount of news flow that we expect to have. We have progression towards a BLA submission for Huntington's disease. We expect to have our initial data for Fabry in the second half of this year, and we expect to have initial data in epilepsy and ALS in the first half of 2026.
We ended last year pro forma with approximately $445 million of cash, so we have the cash resources to generate this news flow and get us into the back half of 2027, which would incorporate not only potential approval of AMT-130, but also the launch in the United States.
Great. AMT-130, it's great you've had a positive set of feedback from CBER so far. Where do we go from here? Can you lay out for us the different steps that remain and where you are in checking off all those boxes?
Yeah, sure. I think we really had an extraordinary year last year for that program. It started with the receipt of RMAT designation in May of last year. We're currently the only program in Huntington's disease to have that designation granted by the FDA. The presentation of what we view as extraordinary data in July was based on a propensity-weighted statistical analysis evaluating the patients that had 21 patients that had achieved two years of follow-up compared to this propensity-weighted natural history that showed a nominally statistically significant slowing of disease progression at two years by approximately 80%. We were very, very excited about that data. That led us to present that data to the FDA and discuss our path forward in November of last year.
It was really quite remarkable that the FDA was able to be very, very clear and unambiguous about our path forward, being able to leverage an accelerated approval pathway. What does that really mean? I mean, that means in essence that we're not required, in order to get accelerated approval, the initiation of a new study, and that we can leverage an external natural history control in order to demonstrate therapeutic benefit, and that we can utilize the Composite Unified Huntington's Disease Rating Scale as what the FDA calls an intermediate clinical endpoint in order to measure therapeutic benefit. All of that, I think, was really, really exciting for us. We are focused now on trying to get to a BLA submission as rapidly as possible.
There's really two elements that we need to further discuss with the FDA, and we expect to do that in the coming months. The first is to align with the FDA on what CMC or manufacturing information is going to be required for the BLA submission. We've guided that we expect to have that meeting with the FDA in the first quarter. That will happen in the coming weeks. Our briefing book has already been submitted to the FDA, and we're very much looking forward to that. Shortly thereafter, in the second quarter, we'll have a discussion with the FDA about the specific statistical analysis plan that we'll use to analyze the data and support the BLA submission. We expect to have that meeting, as I say, in the second quarter.
We would provide a regulatory update to the market that would also incorporate more specific timing of when we expect to submit a BLA.
That's super helpful. How do you feel about the FDA nowadays in the grand scheme of things, I should say?
I love the FDA. No, no, seriously, I think there's a lot. Obviously, you can't go a day without reading in the press about what's going on in Washington, D.C. You know, I think that in any organization, and for those even in biotechnology, where you have tumult, there's going to be a different frame of mind. What I can tell you is that there's no doubt that staff at the FDA, you know, they're going through a lot. There's a lot of uncertainty. As I think about specifically related to our programs, I really don't see any fundamental risk associated with our programs in that regard. The interactions that we've had have not been delayed. Again, we are under RMAT designation, which I think the expectation is that we would go to the top of people's inboxes.
The meeting requests that we've put in have been responded to. The senior officials that we've been dealing with at the FDA continue to be at the FDA. We believe that our accelerated approval path forward, particularly given that we proposed a clinical measure as a primary endpoint, we don't really view that as being terribly controversial. I think we're excited to continue to engage with the FDA. We don't really view the circus that's going around in the background as being something that's going to particularly impact our discussions going forward.
Excellent. Where does the perioperative steroid cohort fit into your overall plan? Does the FDA want to see that and have that be included in the BLA?
Yeah, the FDA is going to get all data that we generated. In fact, prior to the meeting that we had with the FDA in November, all data, including whatever we had for the third cohort, was provided to the FDA, and that will be our tack going forward. The third cohort was just recently completed. There were 12 patients that included six patients in each dose cohort. Really, everything was the same compared to the first two cohorts, but we were evaluating a prophylactic immunosuppression regimen. Where previously we did not immunosuppress patients prior to the procedure or shortly thereafter the procedure, we're now going to be exploring immunosuppression. Really, what we want to get out of this is information to help us define exactly what the immunosuppression regimen is going to be.
We will want to be able to specify that in the BLA submission, but that's largely going to be based on very short-term follow-up perioperative safety, probably looking at 90 days of follow-up from all 12 patients. With the 12 patients treated a couple of weeks ago, we believe we'll have that data in time for the BLA submission.
Okay, great. Can we talk about the actual procedure a little bit?
Sure.
Who will be performing these surgeries? How does it compare to what they currently do in DBS or other procedures? Is there anything that the company needs to do in order to lay the groundwork for successful launch, given how it's administered?
Yeah, so the procedure is an intraparenchymally delivered catheter-infused administration of our drug product. Now, it's very important because you just mentioned this. This is not a completely novel procedure that neurosurgeons don't know how to do. If a neurosurgeon has done deep brain stimulation implants or a neurosurgeon has administered chemotherapy for a glioblastoma, they know how to do this procedure. Most of the time associated with the procedure is actually waiting for the pump to infuse the drug product. That pump rate is very slow, as you might expect. You want to very gently spread the interstitial layers of the brain to deposit the material and ensure that it stays within a relatively local area. It is not a very complex procedure. The neurosurgeon does not have to be in the operating room the entire time.
The great thing about the procedure is that you can see under real-time contrast-enhanced MRI the filling of the key structures that are implicated in the disease. We are administering this directly into the striatum. We know that there is predictable projection of the drug product into the somatomotor cortex, which is also implicated in the disease. The procedure itself can get done. It does take most of the day. I use this as an example. We just had our 45th patient that completed the procedure two weeks ago, as I mentioned, in the third cohort. That patient was administered into the hospital on a Tuesday morning. The procedure was completed later in the afternoon on Tuesday, and the patient was discharged on Wednesday. It's a one-time administered procedure. The patient will come in. Usually, they can get referred from a different site.
They will stay in a hotel. Once they leave, they go back to their home. They go back to their jobs. They can get followed up by their local neurologist. There are some virtues of having a one-time administered surgical procedure where you know that the product is getting into those key areas of the brain because that really, truly is the complexity of treating a deep brain disease, delivery. We can remove that with a one-time procedure that is surgically administered. There will be most likely a center of excellence strategy, but we have identified probably 55-ish sites in the United States that have the neurosurgical expertise and the imaging equipment to actually do the procedure.
When I was looking into how many DBS procedures are done, there's a fair amount. It's over 10,000 a year, I think, at least the data that I saw most recently. Do you have a sense of how many procedures these sites could do for AMT-130? What is the throughput given what you just described about the nature of the process per patient?
Yeah, I mean, it will depend, of course, on the utilization of the operating room. If you have an operating room, or maybe in some cases you have multiple operating rooms, you could do multiple procedures a day. It depends on how many days that a site wants to dedicate for the procedure. We do think deep brain stimulation is a profitable procedure for sites. Our hope would be that that would be the case for our procedure as well.
Okay. Is there anything else the company needs to do in order to ensure a successful launch? There's been a lot of variance in uptake for different gene therapies because of different factors that come into play, which might not apply to more traditional medicines. How is the company thinking about establishing a commercial presence with these sites that you mentioned have the facilities necessary to administer the drug? That way, they're comfortable with contracting and stocking an expensive product and things like that.
Yeah, I mean, that's going to be—I mean, there are two topics that we can talk about with respect to this question. One is, why do we think there are differences in terms of traction that different gene therapy launches have been able to secure? The other is all the legwork that has to be done and the calories that have to be burnt in order to set up the market for the launch of the first disease-modifying product in Huntington's. Just on the first one, I do believe that the severity of the unmet need has been a major determining factor in the success of launches. If you look at spinal muscular atrophy or Duchenne's, these are pretty devastating disorders that impact pediatric populations. The long-term prognosis for those launches and what the potential is for peak sales, I think, is very healthy.
That is because the options for these patients are just extremely limited. We see Huntington's is very similar. There are no disease-modifying treatments for Huntington's. It is an absolutely devastating disease that if you have more than 40 CAG repeats, it's 100% penetrant. You will know based on a simple test whether you will develop Huntington's. If you live long enough, unfortunately, you will die from the disease. Our view is that if we have the first disease-modifying treatment that is available for these patients, there will be substantial demand for it.
Now, in terms of the legwork, the logistical work being done, there's a lot of work that has to be done in terms of educating the market, getting a share of the clinical KOLs and the scientific KOLs, making sure there's adequate patient services to the extent that patients need to be flown into centers of excellence that are doing the procedure, making sure that the reimbursement pathway is known and understood, and that there's an ample amount of support that centers and sites have that are going to be going through that for the first time. We're in the process of mapping all of that out now. By the time that we launch this product, we feel like we're going to be in very good shape.
It's been great to see all the advancement in Huntington's in general. You're not the only ones that are pursuing potential approval. I'd love to get your view on the competitive landscape, given there are some other companies with different approaches. I'm just wondering, how do you see the competitive landscape shaping out if there are a couple of other options as well?
Yeah, I believe, and in speaking with key opinion leaders, I do not think there's going to be a singular silver bullet that is going to win the day in a disorder like Huntington's. I believe that there is ultimately going to be a therapeutic continuum, that there's going to be a place in the market for multiple therapies with multiple modalities. There'll be some determination about what ultimately is first-line therapy, what is second-line therapy. We can debate what the merits are of an oral versus a surgical administration, an oral that is taken chronically for potentially many years versus a one-time surgically administered procedure. In the end, the market will determine that.
I do believe, and you're even seeing this for spinal muscular atrophy, where you have a gene therapy one-time administered approach, and then you also have an intrathecally administered antisense oligo approach, that there are clinicians and patients and even payers that are willing to see a patient take multiple therapeutics in order to manage the disease. I think Huntington's is likely going to be a disease that has to be managed. I think the likelihood that you're going to absolutely cure the disease or completely halt the disease for the rest of the patient's life is unknown. I think if you are able to substantially slow the rate of progression through a therapeutic continuum, that is going to be something that is going to be viewed as very excited by the patients, clinicians.
I think the payers will also, given the fact that this is still, while it is a prolific genetically defined disease, it is still a rare disease. This is still, you're talking about tens of thousands of patients. I think the payer flexibility in covering multiple modalities, I think that's something that will be supported.
Okay, great. You have three other programs in the clinic, so we should touch on each of these real quick. Should we talk about TLE first?
Sure.
I guess update us on the progress in that trial. I know it took a while to treat the first patient, but your enrollment criteria had to be very strict and narrow for the FDA. How does that look now? Yeah, what kind of cadence should we expect in that program?
Yeah, just to step back, this is a very exciting program. It is one where we're not looking at a genetically defined disease and exploring a gene therapy for epilepsy. There are a substantial number of patients, in some estimates, maybe hundreds of thousands of patients that are refractory or resistant to current anti-seizure medicines. Right now, there's a limited number of options for those patients that predominantly is focused on either the resection of tissue in the brain that give rise to these seizures or the ablation or the destruction of those cells. What we're looking to develop is a one-time administered gene therapy that spares that tissue and provides an alternative for patients that have drug-resistant epilepsy. We're currently conducting a phase I-II study in the United States. We're largely looking at seizure frequency.
These patients will normally come in, and they will typically be experiencing multiple debilitating seizures despite being on anti-seizure medicines. Then we will administer our gene therapy once and be able to track their seizure frequency going forward. We were just talking about Huntington's and a slow-progressing disease and the need for multiple years of follow-up. For epilepsy, relatively quickly, we feel we'll be able to develop a clinical proof of concept. In discussing the study with the FDA around the time the IND was cleared, the FDA asked us in the initial patients to have a very narrow criteria for those patients. We treated our first patient, and we've had a number of screening failures because of that criteria. We just recently aligned with the FDA on loosening up that criteria, which we think will help facilitate enrollment.
That criteria now needs to be pushed down into the individual sites. We are very much looking forward to getting through the first dose cohort, which will have about six patients. We anticipate our initial data from the study will be in the first half of next year.
Okay, great. What is the goal here in terms of the clinical profile?
Yeah, I think our goal is to have a meaningful, significant reduction in seizure frequency as low as we possibly can. Certainly, we would want to see the really debilitating seizures go down maybe close to zero or being zero, and that we have a rate of seizure frequency that is at least 50% lower than what it was prior to going into the study.
Okay, that's helpful. This is a slightly different administration procedure. Can you talk about that?
Yeah, this is similar to Huntington's in so much that it is intraparenchymally delivered directly into the hippocampus, which is where these particular patients have lesions. It is much simpler in so much that it is a one catheter direct infusion as opposed to multiple catheter infusions. In Huntington's, you're looking to cover the striatum, which includes the putamen and caudate. You need multiple infusions in a slightly lengthier procedure. For temporal lobe epilepsy, you're really looking at the hippocampus, which is very small, walnut-sized shape. We can do that procedure relatively quickly.
Okay. The patients that you're targeting here are refractory, meaning?
They will be patients that have at least tried two anti-seizure medicines. Despite that, they're still experiencing multiple seizures per month.
Okay. Based on the mechanism, is there any rationale for certain patients to respond more than others? How are you thinking about when you develop this? Are you trying to focus on any particular types of patients?
Yeah, I think ideally, I mean, to the extent that seizures are emanating from multiple loci, we're going in with a very targeted administration of our drug product. Those patients may not be the most suitable. The other thing is that patients that, and this is part of the initial challenges that we had in enrolling, resection works well and is relatively safe if you have a locus of seizure activity emanating from your non-dominant hemisphere. If you have a seizure emanating from your non-dominant hemisphere, removing that tissue doesn't present much of a safety issue. If you have seizures emanating from your dominant hemisphere, that's where there's concerns that removing tissue could create language or developmental concerns. That's precisely where you want to spare tissue. I think ultimately, that is probably like a sweet spot for us.
It doesn't mean that our therapy couldn't work in areas where you have lesions in your non-dominant hemisphere. In terms of its competitive positioning, that's clearly going to be where we would want to focus.
Right. Might be extra compelling there.
Yep.
Okay, interesting. Sticking in CNS, the SOD1 ALS program is very interesting. I'm wondering if you can talk a little bit about how this approach might be differentiated from tofersen, QALSODY.
Yeah, I think that for all of our programs, we're really interested in being best and/or first in class. Obviously, when we get into Fabry and SOD1, there are existing treatments that are available. For SOD1 ALS, there's no doubt this is a devastating disease. Patients that have to take QALSODY are taking monthly intrathecal administrations of the product really for the rest of their lives. For anybody that's gotten a lumbar puncture, it's not something that you want to wake up every morning to have to do or have to do every month. Particularly for ALS patients that are typically immobile, it's not easy for them to have to go do those infusions.
We have been really surprised at, despite the fact that this is a relatively small indication, there is a lot of people that are very interested in a one-time administered procedure, and one where you do not have the kind of peaks and valleys associated with a chronically administered product. We saw this even in hemophilia, that the whole notion of a gene therapy is you administer this once, and then you have a relatively stable production of your therapy. That is obviously happening endogenously. You have relatively stable levels of the antagonist, if you will, that is going to suppress SOD1 protein. Our hope is that this is not only significantly more convenient for patients, but there is the potential that we could have superior efficacy.
What we like about it is for ALS in particular, again, there's an accelerated approval pathway, and there's the ability to collect information about the concentrations of SOD1 in the cerebral spinal fluid, as well as looking at neurofilament light as a surrogate proxy for therapeutic benefit. That data can be collected within the first 6 to 12 months. We think that having data in the first half of next year will enable us on the first handful of patients that we treated to get a sense of whether or not we're seeing signals of potential clinical proof of concept.
Okay, great. A couple of words on the Fabry program. How is 191 differentiated from what's currently available? What do you think the appetite for gene therapy is in that setting?
Yeah, I think what's really interesting about Fabry is the recent data from one of our competitors has actually suggested that when you look at kidney function, that there's the potential to not only stabilize kidney function, but maybe even to somewhat improve kidney function. This is something that you just don't see with enzyme replacement therapy. There is the potential that a one-time administered gene therapy where you're teaching the body to produce GLA protein by itself. This is not some exogenous replacement therapy that you're putting in that has limited potential benefit. The glycosylation process of having the body's own cells express this protein actually may make the protein more potent and have a meaningful or potentially superior therapeutic benefit. That goes towards gene therapies and the potential appetite.
If that is true, I think there'd be significant appetite in the clinical community and the patient community for a gene therapy. What we're trying to do with our gene therapy is leverage the expertise and the validated components that we used for HEMGENIX. We can deliver this with an AAV5 serotype that we think is immunologically favorable. We think that we can treat patients irrespective of pre-existing neutralizing antibodies, which means that we potentially can treat a broader swath of patients with Fabry. What we're also looking to do is have higher levels of GLA activity because we're also incorporating a special promoter, which potentially can lead to super physiological expression of GLA activity.
We would be aiming for higher levels of GLA activity, higher substrate reduction, and potentially greater therapeutic benefit with an immunologically favorable AAV capsid that has the potential to have broader patient access to treating more patients with Fabry. We expect to have our initial data from this program in the second half of this year.
Very interesting. Thank you so much for the update.
Joe, thanks for having us. Appreciate it.