Alrighty, I think we'll go ahead and get started here. Thank you all for joining us at TD Cowen's 45th Annual Healthcare Conference. I'm Joe Thome, one of the senior biotech analysts here on the team at TD Cowen, and it is my pleasure to have with us today the team from uniQure. On the fireside chat with me today will be CEO Matt Kapusta. Matt, obviously a lot has changed in the past 12 months at uniQure. Maybe before we dive into some of the specific questions, including AMT-130, if you want to just give us a brief kind of state of the business, what's happened over the last six months and what should investors expect over the next six?
Yeah, sure. By the way, thank you for having us here. It's always a great conference, and we're excited to be here. Last year was a transformational year for uniQure. We started the year making some difficult but necessary decisions, really to streamline the organization, make it simpler to operate, and substantially reduce our operating burn. We did that particularly because what happened in the back half of the year, we were planning for success. For HD, we made really a tremendous amount of progress in that very important program. That started with getting RMAT designation in May. We currently are the only HD program with that designation.
In July, we presented for the first time, two-year data on 21 patients, compared to a propensity-weighted natural history that demonstrated nominal statistical significance in looking at the composite unified Huntington's disease rating scale, which is an important clinical outcome measure for these patients. In November, we had an important interaction with the FDA under our RMAT designation to talk about the regulatory path going forward. In that meeting, the agency agreed that the composite UHDRS can serve as an approvable endpoint under accelerated approval, that we did not require a new registrational study, and that we can utilize an external control group, comprised of natural history data to demonstrate therapeutic benefit. I think now we are obviously really excited. We are envisioning us to launch AMT-130 in the United States.
We've already greenlighted a number of investments on CMC and are in the early stages of commercial planning. Very exciting time. The one other thing I'll say is that, you know, this company is not just an HD company, and we're very excited that last year we started three additional clinical trials, one that is in Fabry disease, one that is in temporal lobe epilepsy, and the third one is in SOD1 mutations of ALS.
Perfect. You are slated to meet with the FDA a couple of times in the first half of the year. Maybe we'll break them into two component parts. The first quarter, you're going to meet on CMC. I guess, what are you hoping to gain from that meeting? Maybe if you want to just loop in sort of your overall CMC readiness. Obviously, you've launched Hemgenix and did all that. Any context around that?
Yeah, so the, you know, the CMC piece, when you really think about the cell and gene therapy space, the CMC part of this has always been the, the tricky area. That's where complete response letters and clinical holds and comparability issues have come out. We believe at uniQure that we are in a very good position in that regard. And there's a number of reasons why. One is, we ourselves have been deeply involved in doing this. This would be our third approved AAV gene therapy. So just as a company, we have a very deep understanding of CMC and the critical success factors associated with that. More importantly, the Hemgenix process of manufacturing is highly consistent with what we do for AMT-130. Not only that, but it utilizes largely the same AAV serotype.
It's produced at the same scale, and it is produced at the same facility by the same people that know how to manufacture Hemgenix. I think we feel that we are in a good position to do what's needed on CMC. The key thing that we have to discuss with the FDA is, what is the specific protocol to validate manufacturing in the mind's eye of the FDA? Everybody has to go through manufacturing process validation. Typically, that incorporates doing multiple manufacturing batches consecutively to demonstrate that you can do this within the specification set for your critical quality attributes. The specific protocol, that's what we want to discuss with the FDA, and we expect to do that this quarter.
Perfect. Obviously we're going to get an update on overall BLA timing, but I guess as much as you are able to provide, is the manufacturing kind of readiness going to be the thing that is most gating for the submission? Can you kind of give us an outline in terms of how long it takes to, you know, make and follow these batches?
Yeah, I mean, it is the gating item, but not, it's, it's just because, I mean, I, it's a terrible analogy, but it's just like, it's like a pregnancy, right? It's, you know, it, it, it just, it's going to take nine months, no matter, no matter how much prep you do. For manufacturing process validation, you know, there's a certain amount of time that it takes to produce drug product, and then there's a certain amount of time that it takes to actually do all the individual tests that are required to produce the data. And so, that, that just takes time. I think it's likely that it will, it will take more time than it will be to generate the clinical data from, from the study, but not substantially longer time.
For the reasons that I just mentioned, you know, more time does not mean more risk. It just, it's just the blocking and tackling.
Perfect. We are going to dive into the second meeting on the statistical analysis plan. Maybe before we dive into the specifics on that, just for the people in the room, can you hit us with the high-level takeaways from the two-year update that you saw last year, maybe specifically on the UHDRS that the FDA is looking for, but also on any other supportive measures or biomarkers?
Yeah, I mean, the most impressive thing, I mean, it's very simple. The most impressive thing is that, on just nine patients that we had tracked, for two years from the, from the time that they received, a single dose of AMT-130, these patients were showing approximately 80% slower rate of progression compared to a propensity-weighted natural history. You know, that is important because number one, it's a clinical outcome measure. Number two, it is a meaningful amount of follow-up in two years, particularly with a slow progressing disease. I mean, that's, you kind of need to wait almost a minimum of two years given the slow progressing nature of the disease. Number three is that, you know, we also saw, what appeared to be trends of a dose-dependent impact on the composite UHDRS.
I think that was very compelling and that therapeutic benefit is being derived from a propensity-weighted natural history that was calculated using eight specific prognostic factors. When you compare the natural history, the propensity-weighted natural history to our treated patients across all these factors, they're almost nearly identical. It's almost like a digital set of twins. A very strong, robust analysis that shows a meaningful, slowing of disease progression. That is very exciting. We also saw, on the neurofilament light data, that when you pull the neurofilament light data, we saw approximately 10% reduction in neurofilament light compared to the natural history, which shows about a 25% increase at year two. I mean, that's very exciting data. That's what got people all jazzed up back in July.
Perfect. When you think about the statistical analysis plan alignment, that's scheduled for Q2, what are the remaining questions that you'll be looking for from the FDA? Is this two-year data, three-year data, making sure the natural history is in alignment? Anything else?
Yeah, I mean, those are literally, those are all the things that we'll have to determine. I mean, we're going to need to, ultimately identify a dose. We're going to have to identify, a cutoff. We're going to have to identify a number of years of follow-up. And then we're going to have to identify, the specific protocol to generate the natural history comparator. Now all of that, you know, we've, we've done in the past, but it needs to be, discussed and reviewed with the FDA. Keep in mind that the, you know, when, when you're doing an, when you're, when you're thinking about an accelerated approval, the biggest thing here is that you're utilizing an open label study and an external control. The key things that the FDA wants to understand is how do you control for biases, right?
Those are things that we've thought through. We did not go through our rationale and, you know, go through a specific list of potential biases and how we're mitigating those risks of biases. We didn't go through that in our November meeting, but that's precisely what we want to go through with the FDA, make sure they're comfortable with it, make sure they understand our hierarchy of endpoints, how alpha is going to be spent over those endpoints. Those are the things that we want to go through in detail with them, and we expect to do that in the second quarter.
Perfect. We are going to see the update on the phase I/II in the third quarter of this year. I guess, what are your expectations for that readout? What's going to be most important? The study is open label. I guess, how often are you able to look at the data?
Yeah, I mean, we're obviously being, just on the last piece, we're obviously being careful. The FDA, I mean, the FDA understands that this is an open label study, but they do want the statistical analysis plan to be prospectively defined. And so, bless you, we should not be, you know, continually doing comparisons against our proposed natural history to the actual data. Obviously, we are collecting data on an ongoing basis. Although the patient follow-up visits, when you start to get to three years of follow-up, I mean, they're twice a year. It's not like the data set is moving in a meaningful way on a week-to-week basis. Yeah, in terms of expectations, I mean, we're going to be, it's all laid out. The outline is here, right? We're going to be focused on the composite UHDRS.
We know that's a very compelling primary endpoint because it has, of all the things you can look at, probably the highest signal to noise ratio, which lends itself to a small patient set. We're going to continue to want to see meaningful slowing of progression of disease as defined by that. We'll obviously also be looking at the subdomains, total functional capacity, total motor score, as well as a couple of cognitive measures. We'll be looking at neurofilament light where, you know, ideally you want to see relatively stable neurofilament light that continues to be meaningfully below the natural history.
Perfect. Maybe can you comment a little bit about what you're seeing from a safety perspective? The company is going to have some data from a group of patients that were dosed with the perioperative immunosuppression. Maybe why did you do that? Will all that be wrapped up, and you'll have a good answer by the time of the BLA submission?
Yeah. So, obviously with a one-time administration, you're really talking about the tolerability of the procedure itself. And then, you know, obviously you're going to be continuing to follow up patients over the long run. So safety is always going to be something that you're evaluating. What we did see, as is not really that unexpected, is we did see some infusion reactions, particularly at the higher dose. And that was manifesting in CNS inflammation. Most of these events happen within days or weeks of the procedure. And, to the extent that intervention was required, the CNS inflammation was highly reactive very quickly to steroid infusion. So our original protocol, we did not prophylactically administer immunosuppression. And what we wanted to explore in this third cohort at both doses is the impact on CNS inflammation or the adverse event profile, to administering prophylactic immunosuppression.
The purpose of that third cohort is largely to look at the perioperative safety. It is not a gating item on the BLA. We just announced recently that we completed the dosing of that cohort. In the second quarter, we can review what is most likely to be focused on the 90-day safety data from those 12 patients.
Perfect. And we do, you know, still get the question that, you know, this is a brain intervention. If you can kind of put that into context, I know at the breakfast this morning, you indicated that essentially the patient can have the surgery and recently one was able to discharge basically the next day. Can you touch a little bit about physician-patient ease of administration here and kind of what we're seeing overall in terms of just the ability of physicians to do this?
Yeah. I did make the point that I think sometimes when we think about surgery, we think about that in a different way than, let's say, you know, an intrathecal administration, which a lot of gene therapies are intrathecally administered and they are different procedures, right? But, you know, many, you know, as an example, anti-sense oligos, right, are administered on a monthly basis in some cases or quarterly basis. These are not surgery, but if anybody's ever had a, had a spinal tap or lumbar puncture, they're not pleasant and have to, have to endure that, repeatedly for, for potentially years or the rest of your life is, is not a fun proposition. While we are a surgical administration, it is once we talked about, the last patient in our third cohort, that patient was enrolled.
They came in in the morning, and they were discharged the next day. You know, this is not, I mean, that's not unusual. The patient will go home and then they go on with their life. They don't have to come back to the hospital to keep getting chronic administration. I, you know, this is a procedure, where we absolutely know for sure, because we can see under real-time contrast-enhanced MRI, we can see the filling of the structures. Those structures are very important to make sure that any therapeutic is bioavailable. We know it is. You know, again, as I say, once the procedure is done, the therapeutic intervention is over. We are doing some work to try to make that procedure as fast as possible.
We think given that it's one-time administered, the importance of the disease, the importance of getting into those deep structures, that this could potentially be a best or first-in-class.
Perfect. As gene therapy launches have progressed, we've seen a little bit of variance in terms of patient willingness to adopt and also on the other side, getting these effectively reimbursed. The success story is obviously on the Zolgensma side and, you know, the hemophilia therapies have had a little bit of a slower start. What can you do now as a company to make sure that you have that interest there and you have the reimbursement dynamic set up? Are any of these existing launches a fair-ish comp, I guess?
Yeah, I mean, there's, I think this goes for any novel therapy, but there's no doubt, it's the case in gene therapy. The severity of the unmet need matters a lot. You know, it's a very different situation when you have either a pediatric disorder, or even in Huntington's where it's an adult disorder, but if you have very limited options to therapeutically intervene on a genetic disease, and the patient is going to worsen over time, there's going to be a high urgency from the clinician, the patient, the patient's family, to conduct that procedure. You know, you take hemophilia A or hemophilia B, these are meaningful unmet needs, but they're certainly more modest. Nobody would disagree with that. I mean, there's a number of different exogenous treatments for replacing factor nine or factor eight.
If that patient takes 18 months to get reimbursement, you know, then that patient's not going to be in a lurch. If you take Duchenne's or you take spinal muscular atrophy or you take a neurodegenerative disease like Huntington's, if you wait a year and a half, that patient may no longer be eligible for therapy. There is going to be a much higher urgency for, I think for payers and caregivers to administer even, even, you know, conditionally approved therapeutics. There is just no disease-modifying therapy for patients with HD. We do think that's going to be important, but building that value proposition, you know, that's what we have to do, right? Thinking about market access, right? Making sure clinicians understand the biology of our therapy, what differentiates our therapy, what's the safety profile.
you know, all of that is going to be important in terms of laying a groundwork for a successful commercial launch.
Perfect. All those factors that you just mentioned kind of all factor in together, but how is the company thinking about how big the opportunity could be for AMT-130? How big of a drug could this be? And are there any, when you look at the patient population overall, obviously you have the enrollment criteria that you're using, but what proportion of the population do you think is sort of an easier get for you?
Yeah, I think, I would say I believe this has the potential to be the largest opportunity for gene therapy of this era. I think it has a potential to be larger, you know, than a Duchenne's, larger than a spinal muscular atrophy. You know, that is just based on even just sheer prevalence numbers. I mean, there's probably 70,000 patients that are sequenced, confirmed to have Huntington's in the United States and Europe, but potentially hundreds of thousands more that are at risk, and they just haven't gotten tested because there's nothing for them. I do think this has the potential to be very large. I think my view is that the lowest hanging fruit are likely going to be the patients that are very recently manifesting of symptoms.
You know, these are people that, they know that they're obviously confirmed to have Huntington's, but now they know that symptoms have started. They have the ability to look into their future and see where they're headed, but they haven't progressed so far where they're potentially beyond, you know, what could be rescued from therapy. I think those are the lowest hanging fruit. I would then say beyond that, there are patients that are what I would consider to be prodromal. These are patients that have not yet manifested symptoms, but when they look at their parent, right, that had HD, maybe they're three or five years away from when their parent began to manifest symptoms. Those are people that want to get ahead of it because even if you're not symptomatic, right, the atrophy process has already started.
I think you ideally want to be able to therapeutically intervene even in those patients. I think those are probably the areas where I would say is the lowest hanging fruit.
Perfect. What do we know from the FDA thus far in terms of the need for a confirmatory study or what that would look like? Is that going to come up at all in any of these upcoming H1 meetings? Do you expect?
I mean, we'll, I mean, we raised it in our, it's not just to be clear, it, it, it has come up already. We raised it in our November meeting. We actually proposed an outline of a confirmatory study. I think the FDA, you know, was not at that moment ready to talk about it. We did, we did raise to them our awareness that, you know, the FDA has put guidelines out that they want confirmatory trials to be initiated. They appreciated the fact that we were, were conscious of that and, and told us, you know, it's okay. We'll, we'll raise that. We'll talk about this at another point in time.
Our view is based on the conversation and the written feedback, that we think all options are on the table and that could be, you know, it could require a new study. We think it would be very high likelihood to be an open label study that would be conducted post-approval, to look at maybe, maybe a primary endpoint like total functional capacity. Or it could be, you know, the existing patients in the phase I/II trial could suffice to produce confirmatory evidence, but, but looking at longer-term follow-up. It can run the gamut of those alternatives.
Perfect. When you think about the launch, you know, historically when maybe a phase three was sort of the base case and all of the changes you were doing to kind of ensure financial success last year, you were looking for a partner for this program. Now that accelerated approval's on the table, how are you thinking about either the desire or the need for partnering?
Yeah, I think we have a strong desire to want to launch this ourselves in the United States. We have the financial wherewithal, you know, without raising additional capital to get AMT-130 to BLA submission, approval, and commercial launch. You know, we view this opportunity, as I had alluded to before, as very different than in hemophilia. We think this is leverageable across our pipeline. We think we can do it without building a huge commercial infrastructure. Obviously, it's going to require meaningful investment in a transition for any biotech company, but we have a high degree of confidence that we can win at this and that we can build tremendous amount of value, not only for patients and their families, but for shareholders, in doing this ourselves.
Great. Maybe turning to the pipeline, you do have three other gene therapies in the clinic. Maybe we'll start with the temporal lobe epilepsy program. Maybe can you just remind us where you're at in terms of that trial, enrollment, MOMLC data, and just the overall size of this potential opportunity?
Yeah, I mean, this is, epilepsy is at least the, the temporal lobe epilepsy that we're looking at is, is not a genetically defined disease, but it is a very substantial disease where a lot is understood about the neuroexcitatory pathways. We're exploring again, a one-time administered gene therapy in these patients. These would be patients that are treatment resistant to the standard anti-seizure medication. They don't have a lot of alternatives, particularly if they have seizures in their dominant hemisphere. We would be offering one of the, one of the only, if not the only, tissue sparing methodology for treatment of treatment resistant epilepsy, because the only other things you can do is actually resect the lobe or the lesion or ablate it. It's very exciting.
The way our study was designed was the initial patients had a, had a much more narrow inclusion criteria than the later patients in each cohort. We treated the first patient, but, you know, there are a number of screening failures in meeting that inclusion criteria. We did discuss this with the FDA. They agreed to some protocol amendments to relax that criteria. We're hoping that we can make continued progress, you know, later on this year in enrolling the study.
Perfect. Maybe touching on that target population or I guess the options that are available right now, I guess, what are some of the most worrisome side effects when you do have to do tissue resection and, I guess, how much could a gene therapy improve upon that?
Yeah, I mean, the biggest thing is, if you have a lesion in the dominant hemisphere, that hemisphere is going to control, let's say, language. If you're now ablating a section of the brain or resecting it, there's a meaningfully higher risk of comorbidities associated with that treatment. If you have a therapy that keeps intact the cells but is really trying to quiet the neuroexcitatory pathway, I think that potentially provides an attractive first-line therapy. You can always preserve those other treatments as second or third line if it doesn't work. I think that's what's pretty compelling.
Perfect. Your Fabry program, 191, you've guided to initial data before the end of this year in the second half. I guess what, what's going to be included in that, in that update? Is it mostly going to be safety or are there some efficacy measures that we should be looking at?
I think it's going to include to be focused on safety, but we will also be looking at plasma levels of GLA, the GLA enzyme, which I think is a pretty compelling biomarker, that at least we can compare that to enzyme replacement therapy or some of the other product candidates that are currently in investigation now to see if we have the potential to be just as good or, or if not better, which is really where we're aiming to be better.
Some other companies have seen some success also accelerating their products through the Fabry side of things. Do you believe that you'll fit in that same bucket, that accelerated approval is kind of on the table here? And is there a pretty clear path to doing that?
Yeah, I do. I do believe so. I do believe that's going to be available to us, and I think what is attractive to it with the FDA and for us is that you can look at, again, you're not just looking at biomarker data, which is very useful, but you're going to be looking at, potentially, an intermediate clinical endpoint based on kidney function, you know, and that can be as quickly as one year follow-up on maybe 25 patients or so.
Perfect. The last program we'll touch on in the last minute here, you do have the SOD1 program. I guess what sort of this overall opportunity feels like, maybe not as many patients in the U.S., but maybe high unmet need. Can you just kind of put that in context?
Yeah, it is a far smaller prevalence, but one of the things we talked about this morning is that it could be deceptive because the reason why it's so small prevalence is because it's an extremely high unmet need and patients that have ALS, many of them are dying within a matter of a couple of years. For those kinds of indications, you're always going to be looking at something that is more akin to an incidence. You know, there are probably several hundred patients just in the U.S. alone that are diagnosed with SOD1 mutations of ALS. It is a high unmet need. You know, we think that, you know, there's very limited treatments available that have their own complexities associated with it.
One-time administered gene therapy that treats a validated target like SOD1 we think is low hanging fruit. Again, there's another accelerated, another situation where there's an accelerated approval pathway, which means faster times to the market with more expedited clinical trial design.
Perfect. With that, we are out of time. Thank you all for joining us, and thank you, Matt, for a great discussion.
Thanks for having me. Bye-bye.