All right. Thanks so much. It's always a pleasure to be sitting on a panel with Matt Kapusta, CEO of uniQure. I'll kick it over to Matt just to give a kind of quick update and snapshot of the company, where you're at with 130, the rest of the pipeline, and then we'll do Q&A. So thanks.
Yeah. No, thanks for having us, Paul. It's always great to be here at the Stifel Conference. So yeah, so this has been a really busy year for us. We started this year really with three strategic imperatives. One was to advance HD closer to regulatory clarity on our path forward. The second was to initiate three additional clinical studies across our pipeline. And the third was to really make decisions to ensure that we're allocating capital appropriately. And I think we've made tremendous progress thus far on all those fronts during the year, just to frame HD, and we can go into it in a little bit more detail. We achieved our RMAT designation in the second quarter of this year, which we were very excited about. And then we presented updated data from our first two dose cohorts in AMT-130 in the summertime.
And that included two years of follow-up data on 21 patients from those first two dose cohorts compared to a propensity-weighted natural history, where we demonstrated meaningful evidence of slowing of progression of disease. We've initiated three other clinical studies in epilepsy, ALS, and Fabry disease. And we've made substantial changes to our spending that will lead to a 40% reduction in our cash burn rate. So that's just at a high level where we are, and very excited about the progress we're making, and excited for a great next year, too.
Yeah. So before we talk about the FDA dynamics of 130, maybe just take a step back, right? It's been a long road of data disclosure in this program, right? You've learned a lot about measuring target engagement. You've learned a lot about the pace of progression. As you sort of look back now, and you're making the case to the street, to KOLs, what are the couple data points you'd point to with this study that give you conviction there's a real clinical signal here?
Yeah, I think there's really two at a high level. One is the Composite Unified Huntington's Disease Rating Scale. And the second is the neurofilament light chain. And I'll go through those just very quickly. So we're in this fortunate position, having a one-time administered gene therapy, that we initiated a phase one two study five years ago. And we now have multi-years of follow-up data where the clinical outcomes and the functional data become more important. So remember, this is a very, very slow progressing disease. And in order to really demonstrate the slowing of that progression of disease, you really do require a substantial amount of follow-up. So the Composite Unified Huntington's Disease Rating Scale is not a measure we came up with. It's a measure that has been evaluated and studied independently for many, many years.
There's been independent research that suggests that it's probably one of the most sensitive measures of progression of disease and has one of the highest signal-to-noise ratios, which is going to be important for demonstrating therapeutic benefit in relatively small patient numbers. So that's a really important measure that we showed dose-dependent slowing of progression of disease in just 21 patients at a statistically significant level. So that's number one. And number two is the CSF NfL. So CSF NfL is a validated measure of neurodegeneration. We know that it is highly associated with the progression of Huntington's and the stage of Huntington's. And the KOLs that looked at this data, where we showed a statistically significant reduction in CSF NfL at two years from baseline, were really floored by this. It's just something that they have not seen out to two years.
And the natural history data that we have available suggests that it would increase 25%. We demonstrated a double-digit decline. So those are the two measures that I think are probably most impressive to the KOL community.
Yeah. OK. So maybe talk about your FDA engagement strategy and also cadence, right? And you've talked about this being a series of conversations. So where does all that stand?
Yeah. So we got our RMAT designation in the second quarter. They requested that we schedule a type B multidisciplinary meeting. That meeting is now on the books for the end of this month. That meeting is typically a kickoff meeting where you'll have a number of people from the FDA across clinical, nonclinical, safety, toxicology, et cetera. And we submitted several weeks ago a very extensive briefing book or briefing package that includes substantial clinical data and preclinical data, as well as a series of questions that we're posing to the FDA and position statements on those. Obviously, one of the things that we want to do is be very clear with what our positions are about how we would develop this product going forward.
We want to make sure that we can elucidate out of the FDA what their feedback is and what their sensitivities may be, what their concerns are, so that when we set up individual meetings with their subgroups, we can incorporate that feedback into advancing the discussion.
What are some examples of those questions? Or what's a hypothetical example, just to kind of give us?
Well, yeah. So as a hypothetical example, I think we want to understand what the FDA's viewpoints are on utilizing an external comparator.
Right.
Right? So I think in order to get expedited approval, the whole point there is we don't think it's necessarily required or appropriate in light of Huntington's being a very slow progressing disease, genetically defined.
You don't want to put people on a placebo or a sham for years.
Yeah, so we want to know. We want to pose a question to the FDA. Do you believe that a propensity-weighted external comparator could be acceptable in being able to demonstrate therapeutic benefit?
Yeah. OK. What are some of the other questions?
No. I mean, look, let me tell you, let me instead define what success looks like. Success, in my mind, when I think about an accelerated approval pathway or expedited approval pathway, it's really based on two things. One, as I said, is being able to utilize an external control.
Yeah.
The second is to be able to leverage long-term outcomes from our phase 1/2 study. I think that being in a situation where by the end of this year, we'll have 45 patients treated with AMT-130, with the overwhelming majority of them treated several years ago, we'll be in a situation by next year where we'll have a minimum of two years of follow-up data on all 33 patients from the first two cohorts. 24 of those patients will have three years of follow-up data. I want to be able to leverage long-term outcomes from this study, looking at potentially functional-oriented endpoints, and compare that to a robust natural history comparator in order to be able to demonstrate therapeutic benefit. My questions are going to be oriented around those.
Right. Maybe oriented around endpoints, duration of follow-up, things like that.
Yeah. Specifically, what is the endpoint? Specifically, what's the follow-up period?
Yeah. Yeah, yeah, yeah.
The ability to pool data, things like that.
Right. Yep. OK. So I think we've talked about this before, right? There are two very extreme ends of the spectrum. One is that you actually have enough data right now to file. The other one is that the FDA is like, you know what? We're not comfortable with this. Run a two-year placebo-controlled phase three. Those are obviously incredible and obviously really, really challenging. What are the other sort of scenarios that are in between in your mind?
Yeah. So there are gradients, right? And there's so many of them. It's not worth going through all of them individually. But what I can talk about is different flavors. So obviously, one flavor would be the ability to utilize an accelerated approval pathway where I can predominantly pool data and utilize long-term outcomes from the phase 1/2 study. But perhaps two years isn't sufficient follow-up. It's possible that the FDA may want there to be some prospectively defined element associated with it. And maybe they suggest three years of follow-up data. And there's analogs for this.
Like creating a primary endpoint for the three-year data?
Creating a primary endpoint, creating a statistical analysis plan.
Yeah.
You saw this with, I don't know if you followed the Biohaven story.
It's actually happened recently with Vigil, too, potentially. Or at least they have discussions around this in ALSP, another rare neurological disease.
Yeah. And Biohaven is developing, and this is all public.
SCOTHRY.
They're developing a spinocerebellar ataxia type 3, which is an interesting analog because it's another very slow progressing genetically defined disease where.
With negative placebo-controlled data in that case.
Yes. Exactly. Where the FDA has said, look, the practicality of running a randomized blinded control data doesn't make a lot of sense. You're looking at a functional endpoint. And there, I think they're potentially even pursuing a full approval, right?
Right.
There's the ability to look at the prospectively defined nature, the length of the follow-up. There's the potential, and I think Rocket Pharmaceuticals was a company that has alignment on an accelerated approval pathway. I think the FDA asked for some concurrent natural history data, so the potential to possibly enroll some patients that could supplement a retrospective natural history. The FDA may want to get some additional safety data. There could be so many different permutations where possibly some additional data is required, but not randomized placebo-controlled brand new study is required. And then there's the possibility that the FDA says, yeah, you may need to do a new study, but it doesn't need to be blinded. You can do a concurrent natural history. And all of these things have different impact on timelines.
Right. Yep. Yep. OK. That makes sense. When you're engaging with CBER, to what degree are there groups within CBER that have true subject matter expertise in neurology? Maybe that's a silly question, but I feel like in the investor community, when we look at stuff at CDER, we look at precedent at the neuro division, and when we look at stuff at CBER, everyone talks about what is Peter Marks doing. There's got to be an in between, right? Is there coordination with the actual CDER group of the neurologists who are giving feedback to companies like PTC, Biohaven, Wave? Or maybe just help demystify that whole dynamic of who you're engaging with.
Yeah. I think, I mean, look, I wouldn't look at CNS any different than something else. I mean, we went through this whole rodeo with HEMGENIX, right? So what I think you do have with CBER is you have cell and gene therapy expertise. And then they do bring in the domain expertise that they need from a scientific and clinical standpoint to supplement. But I don't believe.
People from CDER.
It could be people from CDER. It can be external experts. But yeah, I mean, there are people from CBER that have neurology expertise.
Part of the reason why I ask this is we'd seen, and now some of these are being reconciled, but we'd seen a number of really interesting examples where in the same indication, the CBER company was getting more flexibility than the CDER company, like in Hunter syndrome and a number. And so that's where I'm just trying to better understand, are there analogs with some of the regulatory feedback that CDER has given in Huntington's? Or are we talking about different people that you're dealing with?
Yeah. No. I do think, so there's going to be definitely, so I think a lot of that flexibility is directed at the senior levels. And it doesn't mean that it's Peter Marks is the one that's directing all this. But I do think you have directors. I mean, you have a clinical reviewer, and then you have a director, right, of the clinical review. And so those directors aren't going to have neurology experience. But that staff reviewer is probably going to be on every single Huntington's review team. So that person is going to develop a very substantial amount of experience.
But the determination as to what risk-benefit is appropriate and what is the registrational pathway and how is therapeutic benefit going to be demonstrated, I think those do happen at levels in CBER or levels in CDRH where they are not going to be domain-specific but be more branch-specific.
Yep. OK. So I don't know if you're comfortable saying this, but I would just be curious, based on everything you've learned about endpoints and biomarkers, what do you think would be some of the examples that would be more favorable to uniQure on some sort of analysis? I guess cUHDRS.
Yeah. I think obviously we would view the Composite Unified Huntington's Disease Rating Scale as a really strong surrogate biomarker or surrogate marker, right?
Why wouldn't that even be an approval?
It could be an approval endpoint. But you have to keep in mind that we didn't necessarily pre-specify the statistical analysis plan and the formation of the natural history at the beginning of this study. While cUHDRS, in my mind, could be a very meaningful full approval endpoint, there are obviously limitations to how this protocol was set up and its intended objective of this study. I do think that when you look at whatever it might be, mutant huntingtin, caudate volume, whatever else you want to look at, expression of a protein or suppression of an enzyme, actually having a functional endpoint as a surrogate, in my mind, is a powerful surrogate endpoint. I think that that can be supported by more objective neurofilament light data that is also a very well-characterized, validated endpoint that demonstrates the level of neurodegeneration.
So for me, I think the ability to look at the totality of data that has been demonstrated in the phase one two program, whether it's out 2 years or 3 years, and to look at those key components of data and suggest that there is a more than reasonable chance of therapeutic benefit that has been demonstrated that meets a particular bar for this very high unmet need. I think that, in my mind, would be a real win for us if we're able to do that or secure that kind of pathway.
Yep. OK. So it sounds like we're going to have to be a little patient as you have multiple interactions with the FDA. How would you guide, ballpark, for sort of a reasonable time frame where we could get some better clarity?
Yeah. And it's not a lot of patience. And I know that, I mean, it is any time you ask investors or analysts to wait for something. I understand there's patience required. But what I can tell you is I've spoken with these management teams. I've spoken with these head of regulators. These are people that have successfully navigated accelerated approval pathways. And it is pretty standard that you are going to require multiple interactions to really be able to have meaningful feedback. The great news is we're starting it by the end of this month. And we're already past the midway point in November. And I think under RMAT, we would expect to have more frequent expedited interactions with the FDA. So I think we expect to make really good advancements and progress in the first half of next year.
I think in terms of our communication, we will plan on confirming to people that we've had a meeting. We will probably limit our comments to focus on procedural next steps. So we'll talk about the timing of interactions, the groups within the FDA we're meeting, the agenda topics that we're going to be focused on, and wait until we align with the FDA until we provide really substantive feedback about our path forward.
Yeah. OK. Fair enough. Let's just talk briefly commercially, right? So this is the administration of this gene therapy is not trivial. Can you talk a little bit about if this were approved, how many centers are there in the U.S. that can kind of easily give this? How many patients can be accessed by those centers? And how would you envision, I guess, a rollout actually looking like?
Yeah. I mean, look, this is a surgical procedure, right? But it's not any meaningfully different than the deep brain administration of chemotherapy or the administration of deep brain stimulation. So there are precedents for a procedure like this. But it obviously does require a level of expertise. It requires a level of imaging diagnostic equipment associated with a Tesla MRI. But none of this is rate limiting. I do think it's likely that there would be some level of centers of excellence. Those centers of excellence would develop an expertise in administering the procedure and a level of efficiency that can be achieved. I do think that there's every possibility that this could be actually reimbursed on an outpatient basis, that the procedure can be done within a period of time, and the patient could be discharged within 24 hours commercially.
I think it is important to recognize that it's a surgical procedure and is going to require some level of expertise. Remember, it's one time. As I said, I don't think that this is going to be a rate-limiting step.
Yep. OK. And from a data perspective, right, let's talk about that accelerated scenario where you can compare to natural history. What's your level of confidence that that kind of data would be enough to justify gene therapy-like pricing and get payers on board?
Yeah. I mean, I think that there's, I mean, our approach, right, is that we believe by the time that this is approved, we're going to be armed with some patients will be out to five years of data. We're probably going to wind up doing our analysis on multiple years of data looking at functional progression associated with the disease. And the hope is that at the time we read out pivotal data that we have demonstrated a meaningful, clinically relevant, clinically meaningful slowing of progression of the disease. So I think that's a very different substantiation than if we just had some biomarker data where the correlation with progression of disease or clinical functional endpoints is less validated, if you will. But yeah, there's going to have to be some understanding that this is a rare genetically defined disease, that these patients have no disease-modifying alternatives.
There are plenty of different cases that exist today, whether it's in Duchenne's or it's in spinal muscular atrophy. These are very high unmet needs where the payers in the United States have expressed a willingness to pay for these treatments. In some cases in spinal muscular atrophy, they're reimbursing for multiple treatments at the same time.
Right.
So I do think it's going to be a lot of work and evidence to justify that reimbursement. But I do believe that this is an unmet need and that we would ultimately get approved on a set of data that would justify premium pricing.
Yep. OK. And in the meantime, when is the next data cut that we'll see?
We expect to have two different data sets that we'll talk about next year. One is going to be from our third cohort. Our third cohort, which we expect to complete by the end of this year, will include 12 patients across both those cohorts where we're going to be evaluating an optimized immunosuppression regimen. We will have an overview of the impact on perioperative safety that we'll discuss in the first half of next year. Then we've guided that we'll have the next update on cohorts one and two, where we would include 21 patients with 3 years of data compared to a propensity-weighted natural history by the middle of next year.
Yep. OK. Great. Anything else to add on Huntington's?
No. Just that we feel really prepared. We feel really encouraged about our data, and I think our team is incredibly excited to start our interactions with the FDA.
OK. All right. I look forward to seeing that briefing book you're giving the FDA.
Of course. Later tonight.
Yeah. OK. All right. In the meantime, do you want to talk about the couple other programs you're pursuing that get less attention, maybe give an intro and maybe a few questions?
Yeah. So I talked about our three goals: HD, initiating these other studies, and then cost containment. So this year, we've initiated three studies: epilepsy, Fabry disease, ALS. Epilepsy, we're focused on drug-resistant epilepsy. More than a third of patients with focal onset seizures are drug-resistant to anti-seizure medication. Really, the only thing that's available for these patients is ablation surgery or resection surgery, where they're actually removing part of a patient's lobe. So what we're hoping to develop is a one-time-administered, intraparenchymally delivered gene therapy that can reduce onset of seizure activity within mesial temporal lobe epilepsy patients. So we're focused initially on hippocampal lesions. But the beauty of this indication we're talking about Huntington's is that the hope is that we can demonstrate a clinical proof of concept relatively quickly by looking at seizure frequency. So that's a really exciting study.
It's not a genetically defined disease, but the neuroexcitatory pathways are very well characterized and understood. And this is the kind of indication that if we can get even low penetration percentage, this could be one of the largest opportunities within the gene therapy space. So that study, we have our first patient enrolled into the observational stage of the phase one two study. And we expect that patient to be treated shortly.
Can you put into context just in this condition and in the trial specifically the degree of refractoriness of these patients and what a baseline seizure burden might look like, ballpark?
Yeah. So just like in hemophilia, right, there's going to be a variability of severity of, call it, uncontrolled for hemophilia patients' bleeding. For epilepsy patients, it's uncontrolled seizures. What I would tell you is that many of these patients let me just give you a sense if you look at this as a competitor program with a cell therapy, their patients were seizing somewhere between 10-30 times a month, right, despite being on different kinds of anti-seizure medication. So that wouldn't be unusual. Now, not all of those are what we would call impaired awareness seizures. So these aren't necessarily what you would call grand mal seizures. But these are documented seizure activity that can actually be measured on EEG that is happening at some level in these patients.
OK. OK.
So in any event, you asked me about these other studies. I'll try to be really brief.
Yeah.
That one is on its way. We have a Fabry disease program where we hope to have a better mouse trap. We're using a highly potent liver-specific promoter, which we hope leads to higher GLA expression. We're leveraging AAV5, which was part of the approved HEMGENIX product portfolio where we demonstrated the ability to treat patients irrespective of pre-existing neutralizing antibodies. That patient, that study is underway. We potentially could have data on that next year. We know there's an accelerated approval pathway. SOD1-ALS is a more modest ultraorphan disease. Unlike these other rare diseases, there's a meaningful incidence rate. Because of the aggressive nature of the disease, there may only be 300, 400 patients in the United States. There are probably 200 patients diagnosed every year.
So this could be a chronic peak sales opportunity of several hundred million dollars. And our view is that we potentially, with a gene therapy approach, can be best in class, certainly, but even better than QALSODY. And certainly, the one-time-administered approach is certainly more convenient for these patients as well.
Right. OK. Great. So timing of data from the pipeline?
We'll talk more about it early next year at J.P. Morgan, but our hope is that a year from now, we're going to be in a position where hopefully we have an expedited approval pathway for HD, and we have three other clinical programs that are either in the process of reading out data or will shortly be reading out data.
OK. Great. And cash runway, Matt?
So cash runway, as I said, we made some significant changes to our burn profile that will reduce our burn rate about 40%. And we expect to have cash runway through the end of 2027.
OK. Great. Looking forward to next year. Thank you.
Thanks, Paul.
Appreciate it.
Appreciate it.