Good afternoon, and thank you for joining the Guggenheim Securities Healthcare team at our sixth annual conference. I am Debjit, and joining us from uniQure is President and CEO Matt Kapusta. Thank you for your time, Matt, and before we get to the Q&A, a very quick introduction of uniQure.
Yeah, sure. By the way, thanks for having us. So uniQure, for those that don't know us, has been one of the pioneers in the gene therapy space. The company was founded actually more than a quarter of a century ago, was the sponsor of the first approved gene therapy in the world. It was a product called Glybera, and is one of the few with multiple approvals, including an approval last year of the first hemophilia B gene therapy with HEMGENIX, which is now being commercialized by CSL. We, I think, over the years have really differentiated ourselves in our manufacturing platform, and I think today have in the Boston area an 80,000-sq-ft facility that has the ability to produce commercial quantities of gene therapy.
I think has been a significant asset for us in terms of being able to navigate the clinical regulatory pathway in terms of CMC. We have a pipeline now, I think a pretty robust pipeline, that includes four clinical stage programs, that we believe are in a position to produce and generate data with reasonably modest investments, to provide at the very least early proof of concept within the next 12-18 months. That's what we're focused on. We have a good cash position, and we're locked in on ensuring that we allocate capital appropriately and make sure that we have runway to generate value for our shareholders.
Thank you for that, Matt. I don't think you get asked this question by sell-siders, but the stock has underperformed miserably over the last couple of years.
What are you talking about?
So what can you do, or what are you doing, to turn this around?
Yeah, I mean, we're, you know, I can't tell you how pissed off I am, and we all are extremely disappointed with the stock price performance. Obviously, a lot of the underperformance has happened in the last six months post the latest HD data update, and we can talk more about that. But I think, you know, that really gets to what our focus is for 2024, which is really three things that I had kind of alluded to in my opening remarks. One is really getting regulatory clarity in terms of our HD program so that we can understand our path forward. Number two is clinical and operational execution excellence, so really working hard on site activation and trying to expedite patient enrollment because, in the end, that's what enables us to generate data.
And then the third is, really making sure we prioritize our spending, focus our investments on things that can drive value, and make sure that we preserve as much cash runway as possible. That's what we're focused on to try to turn things around.
Have you calendared a meeting with or requested a meeting with the FDA to date on AMT-130? And, you know, what kind of feedback do you really expect to hear from the agency?
Yeah, so what we've guided to is that we expect to have the first interaction with the FDA in the second quarter. I think that there's going to be a number of topics that we're going to be focused on. Remember, we started enrolling this study almost four years ago, so we have not yet shared any data with the FDA. So our first order of business is to share the data with the FDA, our interpretation of the data, particularly as it relates to the safety profile and the efficacy profile, and understand, you know, how the FDA views the data and are they aligned in their interpretations of the data. That's going to be the first order of business that we're going to do.
As part of that discussion, but also, possibly in further interactions with them, we want to have an understanding of their views on natural history, both in terms of, how to utilize natural history to interpret the data, but also, how we might be able to utilize natural history in terms of late-stage development or possibly registration. And then I think another area that we're going to want to be focused on is how the FDA is thinking about our Phase I-II data and the ability to leverage the long-term follow-up from that Phase I-II data as part of a registration package.
So one of the benefits of being a gene therapy and having a one-time administration is that even in early studies where traditionally you have very discrete follow-up periods, in a gene therapy you can actually collect long-term follow-up data, which is going to be critically important for HD where it's slow progressing. So we are collecting and aggregating long-term follow-up data on clinical outcomes, and we think that that is going to be potentially important, and the ability to leverage that, I think, you know, has the potential to be a key advantage for us as we think about late-stage development and registration.
Is the discussion with CBER and Peter Marks, or is this with the neurology division?
We would expect it would be with CBER.
So CBER has been very flexible with neuromuscular diseases, but we haven't seen that translate into neurodegenerative diseases. What gives there? Is it that natural history that the FDA is not buying into?
It's an interesting question. I don't know, I mean, obviously, you know, they just approved tofersen on an accelerated basis relying on neurofilament light as a surrogate endpoint. And of course, you know, the story has been written to a large degree in Alzheimer's disease looking at, you know, you know, the potential for accelerated approval there. I do think that the FDA is probably more focused on unmet need, severe unmet needs, areas that are rare in nature, where there's no disease-modifying treatments that are available. I do think it is a picture. It's not. There's not one factor, I think, that the FDA says we're going to be more flexible or less flexible. They look at a number of things, including the clinical data itself.
But I do believe that the availability of natural history data and the robustness of that natural history data, I think, is critically important. One of the benefits in HD is that you have a very robust set of natural history data. In many cases, it's collected in a regulatory-compliant manner. And so I think that is a benefit that we have that many other rare diseases don't have.
So if the feedback from the agency is this is our AMT-130 data do not support an accelerated approval and you need to run a randomized study, are you willing to commit capital to that, or, you know, you sort of fold the program?
Yeah, I mean, so I think when we think about a go-no-go decision, I think there's going to be a few key factors. I think one is obviously we're going to have more data in the middle of this year where we'll have up to three years of follow-up data now on patients in the low-dose cohort and two years of follow-up on patients in the high-dose cohort. We're very encouraged by the functional trends that we're seeing and even what we're seeing in the neurofilament light. And I think, you know, so we want to see those trends generally continue in the next data readout. So that's going to be an important point. The second is going to be the regulatory interactions that you just mentioned.
I think if the data supports bringing this program forward, it then comes down to what's the funding required, whether it's accelerated or not, what's the funding required, and what is our ability to fund this ourselves versus the potential need to partner. So there's always the potential, if we have a path forward and if the data is conducive, to find a partner that is willing to share in the risk and the investment within the program. And that is an option that we would, of course, explore if we had to.
I mean, the data to date, it's taken a real long time to separate, not surprising given the baseline characteristics of these patients. The duration of any Phase III, assuming that you enroll a similar patient population, will probably be five years, right? So do you think, you know, the S treet will give you any credit even if you partner it out?
Well, so what I would tell you is one of the questions that I asked is how can we leverage the Phase I-II data? If AMT-130 has a transformative effect on the disease progression, we will know that, potentially with statistical significance, from our Phase I-II study. Now, the study was not designed right in that way, wasn't powered in that way, but with long enough follow-up, we will know that. We're at a stage now where we're getting into the two to three year period of follow-up. And so, yeah, if you're thinking about five years, we'll have five years of data on more than 30 patients from the Phase I-II study.
I would submit to you that if we do see meaningful improvement from these treated patients, that you could go into the FDA and have a very meaningful discussion about the possibility of accelerated approval. Now, that's not the traditional accelerated approval that we're used to thinking about. The traditional accelerated approval is to march into the FDA with some surrogate biomarker and say, "Hey, FDA, this is correlated with efficacy," and then they say, "Well, how do you know that?" Here, we'd be marching in with actually the clinical outcomes that are most important to them. I think that's always an option for us.
I don't know what investors will give us credit for, but I would say that if we're beginning to see separation out two to three years that is clearly exciting the clinical community and clearly exciting the patient community, that there'll be some investors or a partner that say, you know, "This is we're willing to do this because of the unmet need here and the size of the opportunity.
Got it. So if the FDA were to say, you know, "We don't know if this is conclusive enough, go ahead and submit. We'll evaluate, but in the meantime, you need to start a randomized study," are you willing to do that?
Again, when I say willing, right, I think what you're meaning is, are you willing to commit funds to do that?
Yep.
You know, I, you know, nobody loves committing funds to a study that they don't have the ability or the wherewithal to complete it. So I think, you know, we'd have to look at where what our value is, what our ability is to raise capital, how much of it we think we can fund. Is that dilution worthy? And if not, we'd have to have partnering discussions.
So, I think, you know, let's say six months back or even a year back, the thought process was maybe a 150-patient study would be enough for a randomized study in a randomized setting. Do you think that's still feasible, or you would definitely need more patients given the slow progress you know, the rate of progression in these early-stage Huntington's patients?
Yeah, we've obviously done work around powering. It's maybe a little too early for me to talk about that, but obviously, as you know, there's going to be a yin-yang between the number of patients and how long a follow-up that you're targeting. What I would say to you is there you know, at least given the trends that we're seeing thus far, I would say there you know, is, you know, a real possibility that we would not need that many patients.
Got it. And you guys were thinking of another cohort, exploring a different route of administration. Is that up and running, and would that change anything, or it's just more it simplifies the procedure?
Yeah, let me be clear with this. So yes, it's true that originally when we were contemplating a third cohort, we were contemplating that third cohort to look at surgical adaptations to reduce the time that the procedure takes, really to make it more efficient and to provide more automation. We do not believe at this juncture that that is something we need to do in advance of a pivotal study. That is something that we could potentially explore in parallel to make the procedure more efficient and commercially acceptable, but that we can take the current procedure, you know, into a registrational study. The third cohort, as it's designed right now, is really focused on looking at variations or alternatives around immunosuppression.
Now, we believe that the safety profile is generally safe and well-tolerated, and we don't think the data from this cohort three is required in order to make a dose decision. But we do see inflammation associated with the procedure in AMT-130 tends to be a little higher in the high dose, and we do believe that we can optimize the immunosuppression. That is what we're focused on and would only require probably maybe 90 days of perioperative follow-up in order to answer some of those questions around the immunosuppression regimen.
Got it. And if you were to take anything forward, it would be the high dose, given that at least you're seeing some trends with the high dose and not so much?
We're going to take forward, you know, the highest well-tolerated dose. And particularly now that we're beginning to see, I think, signals of dose dependency and separation, I mean, you know, I think all else being equal, our preference would be taking forward the higher dose. You know, but we haven't officially or formally made that decision.
Got it. When I look at the gene therapy landscape, some of your sort of peers have had reasonable success investing in novel serotypes. Is that an area that you guys are, you know, contemplating going into, or you're stuck with more of these natural serotypes?
No, I mean, we've actually been one of the pioneers within the next-generation capsid landscape. And we have a number of efforts going in, particularly on the CNS side. I will tell you, on the liver side, we have a really high bar. We really do believe that AAV5 is the least immunogenic naturally occurring serotype with demonstrated efficacy in liver transduction, with demonstrated ability to transduce hepatocytes irrespective of preexisting neutralizing antibodies. So there's a very high bar. We've also obviously gathered a lot of experience with AAV5 for CNS applications, but we also use AAV9. For CNS, I do think there's potential for innovation associated with delivery, less invasive delivery, blood-brain barrier penetration, greater biodistribution, liver detargeting. I mean, there's all sorts of things that we can look at, and we are looking at.
So there is an effort that's going into that. There is investment dollars going in.
Got it. So, you know, second half of the year, you're expecting data from the TLE, SOD1 and the Fabry program, right?
Yeah, I don't think we've guided specifically to it being the second half of the year. I think we've said that we'd provide more guidance on the timing of that. We will be accumulating data in the second half of the year. The question is, at what point do we have the initial presentation of the data? We'll provide more color on that when we, you know, initiate patient enrollment.
So how quickly can you get to, you know, getting the patients enrolled and dosed? I think the TLE program is front and center for everybody.
Yeah, I mean, we're, we've got a tremendous amount of effort going into it and, you know, and I think we've guided that our hope is that within the next six months we'll be able to get patients across all of these studies. There is a little bit of a staggering between patients in the TLE study, particularly I think there's a stagger between the first patient and the second patient. Then we can immediately do the third patient, and then we can do the remaining three. So there's it's only a 30-day staggering period, but we have to have DSMB meetings. So the point is, you know, we're fast and furious working on site activation, working on patient identification, trying to get the study enrolled as fast as possible.
From a readout perspective, the TLE readout should be much more rapid and cleaner than Huntington's seizures are not?
All these next three programs, it should be a lot cleaner.
Is that a six-month kind of a time frame that you think is good enough, or, can three months suffice?
I think we have, for the TLE study, I think we have a four-month interim analysis and then an eight-month interim analysis. So I think it could be as, as early as four months of follow-up. And then again, the question becomes, how many patients do we want to, you know, to have at minimum of four months?
Got it. And the C9orf72 program, you know, do you target both the sense and the antisense transcript? Because obviously there have been a bunch of ASO failures, primarily because they could not, you know, target the sense.
Yeah, we're very well aware of those failures, and our construct targets both sense and antisense.
But I mean, again, is that sort of I mean, it's a hypothesis, right? We don't really know why they failed, but you guys are confident and there is an animal model which, you know, clearly gives you that answer?
Yeah, I mean, the animal models are not. They have limitations. But I think, you know, I think we believe in genetics in terms of the C9orf72 mutation, and we do very much believe that some of those failures are driven by the fact that they were not both sense and antisense targeting. And that would be, you know, that is the current focus of that program.
Got it. And any updates from your partner on the launch of HEMGENIX, rather?
Well, I mean, you know, it's, we're not in the trenches. You know, you know, part of why we monetize that is because we have limited control and limited ability to talk about it. But I would say that, you know, it's, it's really what I said even I think the last time we were together. Every time I speak to CSL, they continue to be very enthusiastic by the clinical and patient demand and continue to be very frustrated by the time that it's taking to navigate administratively through the payers. That those discussions are largely happening between each of the individual hemophilia treatment centers and the payers. And I think, you know, they were, I think maybe caught by surprise, but certainly frustrated by the time that it's taking.
There's a growing backlog of demand for HEMGENIX, and in my view, I think it's a question of time, you know, before that log jam clears. The reality is, you know, for a company the size of CSL and the fact that I think they're Australian domiciled and only report earnings twice a year, there's not a lot of public commentary, but that's, I think the gestalt of how they're feeling about the opportunity.
But you still are manufacturing it for them, right?
We are still manufacturing it.
What does that order book look like from on your side?
The order book looks still healthy. I mean, you know, obviously I can't give details, but there's still, you know, they're still enthusiastic about the ramping of the product.
Got it. So, we are roughly toward right in the middle of the first quarter. By end of the year, you know, where do you think you can take the company to?
Well, I talked about this. I think, by the end of this year, number one, we want to have as much clarity as possible about the path forward for HD, and be making decisions about how we're going to be moving the program forward, funding it, and what that pathway looks like. Secondly, we want to be in a position where we are already underway in enrolling patients across three additional clinical studies with a near-term expectation for initial clinical data from those programs. So you would have potentially a lead program in a highly attractive market opportunity, potentially moving forward into late-stage development, and three additional clinical studies reading out potentially proof of early proof of concept data within a you know several months or whatever it might be window.
and to be demonstrating adequate capital allocation where we continue to have funding to be able to get to these value-driving points.
One last question. FDA's guidance to Sangamo on their Fabry program has not been well-received. So that's another program where I don't think you're going to get credit over the near term. How good does the data have to be that Fabry becomes a meaningful program for you?
Yeah, I mean, I think we want to be able to feel that we are. I think initially we want to be able to see increases in plasma GLA levels that we believe have the potential to translate into meaningful reductions of lyso-Gb3, right, and to be able to see those reductions at least based on plasma. I mean, if we can't demonstrate that, then, you know, then I think, you know, we have to really figure out where we're going to go with that program.
All right, Matt. Good luck for going forward, and really appreciate your time and candor here.
Yeah, thanks for having me.
Thank you so much, Matt.