uniQure N.V. (QURE) Earnings Call Transcript & Summary

Good day, and thank you for standing by. Welcome to uniQure's AMT-130 Huntington's Disease Program Update. [Operator Instructions] Please be advised that today's conference is being recorded. [Operator Instructions] I would now like to hand the conference over to your speaker to Maria Cantor, Chief Corporate Affairs Officer. Please go ahead.

Good morning, and thank you for joining us. This morning, uniQure announced safety and biomarker data on 10 patients enrolled in the low-dose cohort of the ongoing Phase I/II clinical trial of AMT-130 in Huntington's disease. 6 of these 10 patients received AMT-130 and 4 patients experienced an imitation surgical procedure in this randomized blinded study being conducted in the United States. Observations shared today pertain to safety, tolerability and biomarker data at 12 months following AMT-130 administration. Joining me for this investor event and webcast are Matt Kapusta, our Chief Executive Officer; and Dr. Ricardo Dolmetsch, our President of Research and Development. Please note that we'll be making forward-looking statements during this investor call. All statements other than the statements of historical facts are forward-looking statements. They are based on management's beliefs and assumptions and on information available to management only as of the date of this conference call. Our actual results could differ materially from those anticipated in these forward-looking statements for many reasons, including without limitation, the factors described in uniQure's quarterly report filed on May 2, 2022, and other securities filings. Given these risks, uncertainties and other factors, you should not place undue reliance on these forward-looking statements, and we assume no obligation to update these statements even if new information becomes available in the future. Now let me introduce Matt Kapusta, uniQure's CEO.

Thank you, Maria, and good morning, everyone. We're delighted to share with you today encouraging 12-month data from the low-dose cohort in our U.S. Phase I/II study of AMT-130 for Huntington's disease. This new data builds on the clinical observations shared last year, further underscoring the tolerability of AMT-130 and for the first time, providing early indications of target engagement. AMT-130 is our first gene therapy candidate leveraging our miQURE platform, a proprietary technology to deliver onetime administered gene silencing constructs to patients. We're currently applying this innovative approach to numerous other genetic disorders, including temporal lobe epilepsy, ALS, Alzheimer's and other indications. As many of you know, Huntington's disease is a progressive neurological disorder that represents one of the most devastating and prevalent monogenic diseases. It is caused by a triplet nucleotide repeat within a single mutated gene called Huntington that leads to a toxic gain of function. There are estimated 72,000 diagnosed patients with manifest Huntington's disease in the United States and EU5. And in the U.S., more than 200,000 written risk of inheriting the disease. The belief that Huntington's disease is untreatable is one of the factors prevent people at risk who may be symptomatic for discussing possible diagnosis with health care practitioners, families, friends and loved ones. I'd like to revisit the reasons why we believe AMT-130 has the potential to be not only a first, but best-in-class approach for the treatment of Huntington's disease. First, AMT-130 is designed to be administered once with potential for long-term therapeutic effect. This is facilitated by our AAV constructs, which delivered genetic material capable of long-term expression of proprietary MicroRNAs specially designed to suppress the expression of Huntington protein. Secondly, AMT-130 is administered directly to the areas of the brain that are implicated into early manifest Huntington's disease. During the procedure using MRI guidance, we can see real time the infusion of AMT-130 filling these key brain structures. We believe this is absolutely crucial as no matter how effective a drug might be, it simply won't be therapeutic if it can't reach the diseased areas of the brain. Yet at the same time, Huntington doesn't necessarily affect all cells in the body, so sparing healthy tissue is also desirable. Third, AMT-130 delivers a MicroRNA that was specifically designed to suppress not just the full length of mutant protein but also a highly toxic protein species called exon-1. That may also be associated with disease pathology. And lastly, AMT-130 leverages our AAV5 capsid which we have shown to be well tolerated in 6 different clinical studies in more than 80 patients. Additionally, AMT-130 employs a [indiscernible] and a MicroRNA without a passenger strand, which is designed to mitigate all target effects and other potential toxicity. In March of this year, we completed enrollment of 2 dose-escalating cohorts of 26 patients in a multicenter Phase I/II trial to evaluate the safety and tolerability of AMT-130 and explore potential efficacy at 2 different doses. Based on the recommendation from the FDA, the study is conducted as a double blinded and randomized trial, including an imitation surgical control. We believe this approach will produce the most robust data and has the potential to provide a faster pathway to registration. In a [indiscernible] study, we specifically screened for early manifest Huntington patients with a defined minimum striatum volume. We believe these patients have greater potential to demonstrate a therapeutic effect on meaningful clinical outcome measures. Moreover, because AMT-130 is a onetime administered therapy, and we have a requirement to follow patients for 5 years. we have a unique ability to evaluate long-term clinical outcomes that distinguishes our clinical program from chronically administered approaches where long-term follow-up of compliance are more challenging. In addition to the U.S. Phase I/II study, we are also in the process of enrolling a 15-patient open-label European study evaluating the same 2 doses. Enrollment in the 6 patient low-dose cohort has been completed and the first 4 patients in the high-dose cohort were recently treated with AMT-130. To date, 36 patients have been enrolled across our 2 Phase I/II studies. Let me now turn the call over to Ricardo, who will walk through the details of the encouraging 12-month data set from the 10-patient low-dose cohort of our U.S. Phase I/II study.

Thanks, Matt, and good morning, everyone. I'm very pleased to provide an update on the progress we've made in our U.S. Phase I/II clinical trial, exploring the safety, tolerability and efficacy of AMT-130 for the treatment of Huntington's disease. Huntington's disease is a devastating neurodegenerative disease caused by the expansion of triplet nucleotide, cytosine, adenine, guanine that encode the amino acid glutamine from the first exon of the Huntington gene. CAG expansions that are larger than 39 the [indiscernible] formation of protein aggregates [indiscernible] toxicity and ultimately to neurodegeneration that is a hallmark of Huntington's disease. Neurodegeneration usually starts in the striatum, a deeper in structure that is composed of the globus pallidus and the caudate nucleus and then spreads to adjacent somatosensory cortex, before reaching other cortical regions. The symptoms of Huntington's disease, parallel to neurodegeneration starting with psychiatric in motor symptoms and progressing to cognitive symptoms. AMT-130 is a recombinant AAV5 that contain the MicroRNA that suppresses the production of the Huntington mRNA in protein. MicroRNAs act by recruiting the RNA interference machinery to turbo the degradation of the target mRNA. The MicroRNA and AMT-130 binds specifically to hunting -- to exon-1 of Huntington gene, eliminating both the full-length toxic RNA and protein as well as the exon-1 containing mRNA transcripts that produce protein fragments that are to possibly particularly toxic. AMT-130 has been optimized to be non-toxic by being highly target-specific. Furthermore, contains our proprietary miQURE MicroRNA scaffold, which minimizes the production of MicroRNA passenger trends that can have toxic side effects. Studies in mice, pigs and non-human primates have shown that AMT-130 is both safe and effective in preclinical models. Administration of AMT-130 in to the striatum of HD transgenic pig triggers a transient increase in neurofilament light chain in the cerebrospinal fluid and a sustained decrease in the expression of mutant Huntington in the striatum and cortex. AMT-130 has delivered 1 time by convection-enhanced stereotactic injection directly into the striatum of patients. This route of delivery ensures that neurons of the striatum and in the cortex received enough of the gene therapy to reduce the amount of the toxic protein. The injection is performed using a catheter that is smaller than a cocktail straw, which is introduced with millimeter scale burr hole into skull. The infusion is performed with contract enhancements using real-time MRI guidance to ensure appropriate targeting. The surgery occurs over the course of the day and the patient typically returns home on the next day. We are currently running 2 simultaneous trials to test the safety and efficacy of AMT-130. HD GeneTRX1 is conducted in the U.S. and is a double-blinded, randomized, placebo-controlled trial. HD TRX2 is an open-label trial conducted in the European Union and the U.K. We are testing 2 doses in AMT-130, 6e in to the 12 factor genomes and 6e to the 13 factor genomes to determine the dose that the safest, best tolerated and most efficacious. Today, I will focus on the U.S. trial, consists of 3 cohorts: a low-dose cohort of 10 patients, a high dose cohort of 16 patients and a surgical adaptive cohort of 18 patients at the high dose. We are enrolling patients that are at the earliest symptomatic stages of their disease. They are 25 through 65 years of age have a total functional capacity of 9 to 13 and have early motor behavioral cognitive for other clinical symptoms consistent with the diagnostic classification levels of 3 or 4. The patients must also have a minimal [ cerebral ] volume to participate in the trial so that we can administer the drug safely and so that the neuron can be preserved by the drug. We believe this patient population has the best chance of getting benefit from AMT-130. This also distinguishes our trial from other studies that have enrolled patients that are more advanced stage in their disease. Patients are initially screened to ensure that they meet the enrollment criteria. Baseline measurements are collected immediately before the surgery. The patients are then evaluated at 14 days and 1 month and then the 3 months intervals for 2 years and every 6 months for up to 5 years. The liquid biomarker being measured include neurofilament light chain levels in the blood and the cerebrospinal fluid and mutant Huntington protein levels in the cerebrospinal fluid. Anatomical measurements include structural and volumetric MRI. The clinical endpoints include the Total Motor Score, the Total Functional Capacity, the Symbol Digit Modality Test. The Stroop Word Test and HD-CAB for behavioral and psychiatric symptoms. Not all the biomarkers and not all the evaluations are done in every visit to reduce the burden on patients and caregivers. Now let's look at the 12-month data from the U.S. low-dose cohort. The demographics and baseline characteristics of the low dose and control patients in Cohort 1 are relatively well matched. They are approximately the same age, have a similar range of CAG repeat and have similar clinical characteristics as is driven by their TFC, TMS and DCL scores. And the data we have seen so far, AMT-130 has been well tolerated. In the low-dose cohort, we observed no adverse drug reactions related to the drug and no serious unexpected suspected adverse reactions. We did observe 2 serious events unrelated to the drug, a deep vein thrombosis and resolved with anticoagulants and a post-operative delirium that resolved with support of care. 95 treatment-emergent adverse events unrelated to the drug were also observed. The most commonly reported were non-serious procedural pain, procedural headache, post-lumber puncture syndrome and other complications like low body temperature, fatigue, hand and leg spasms. Neurofilament light chain is a measure of neuronal injury. As expected, neurofilament light chain increased [indiscernible] and 1-month fall in surgery in the dose patients and then declined progressively over the course of the year returning close to baseline. The dosed patients are represented by the solid lines. You will note that most are very close to the baseline at 12 months. 2 of the 6 treated patients were at or below the baseline in 12 months, and an additional patient was below the baseline at both 15 and 18 months. The sham controlled patients did not receive any infusion in the brain and therefore did not show a post-operative increase in neurofilament light chain. Their neurofilament light chain levels seem to be stable or slightly declining over the course of the year. The graph of the average and the standard deviations also suggest that neurofilament light chain in CSF declined quite dramatically in treated patients by month 6 and has largely returned to baseline by about 1 year. [indiscernible] Huntington accumulates to the striatum of patients with early-stage disease and is released into the cerebrospinal fluid from that region. The exact way in which Huntington's released and under what circumstances that happens is not clear. The levels of Huntington in the CSF are extremely low, and we were only able to get reliable baseline and time point measurements from 7 of the 10 patients, 4 dosed and 3 control patients. Because AMT-130 is infused in the striatum, our initial expectation is seeing an effect on the levels of mutant Huntington in CSF was low. We were, therefore, encouraged by the initial data from the 4 treated patients showing decreases in mean CSF mutant Huntington at every time point and a 54% reduction at 12 months. In contrast, the mean CSF mutant Huntington in the 3 control patients declined 17% at 12 months. To get a better sense of the underlying data, we look at the individual patients. The treated patients represented on this graph by the solid lines show a consistent decline in mutant Huntington over the course of the year, reaching a reduction of 54% at 12 months. The declining trend continues in the 2 patients with data 15 and 18 months. The data on the control patients is more variable, as you can see from the dash, brown, purple and green lines. While the data is variable, as you would expect from a small sample size, we believe it is consistent with the conclusion that AMT-130 engages is targeted striatum, leading to a decrease in mutant Huntington in CSF. So to summarize. The low dose of the AMT-130 is well tolerated thus far. We haven't seen any drug-related adverse events. The adverse events that were observed were related to the surgery, not to AMT-130. NFL levels increased as expected in those patients immediately after the surgery, but then declined towards baseline. 3 of the 6 patients were at or below baseline in 12 months, suggesting that the inflammation associated with the surgery has resolved. Trends in cerebrospinal fluid mutant Huntington in the evaluable dose patients support the potential for target engagement, generally decreasing over time and achieving a reduction of 54% at 12 months compared to baseline. Levels of CSF mutant Huntington in the control patients were more variable but generally trended higher than in treated patients. We're very pleased with the progress that we've made in our ongoing clinical development of AMT-130. We have enrolled all 26 patients in the first 2 cohorts of the U.S. study. In the European trial, we have achieved full enrollment in the loose cohort of 6 patients and have now of those 4 of 9 patients in the high dose cohort. We expect to complete patient enrollment in the European Union by the end of this year and begin enrolling the third cohort in the U.S. study shortly thereafter. We will disclose biomarker and clinical efficacy data in 2 years of the low-dose cohort and 1 year high-dose cohort in the second quarter of 2023. Thereafter, we will disclose data on the EU patients and the surgical adaptive patients. Now let me turn the call back over to Matt.

Thank you, Ricardo. Operator, please open the line for analyst questions. Thank you.

[Operator Instructions] Our first question is from Jon Schwartz with SVB Securities.

This is Dae Gon for Joe Schwartz. We were just wondering what you think the range of CSF mutant Huntington protein lowering applies about the potential range of lowering that's happening in the brain based on the animal studies you guys have completed?

Yes. Thank you so much for the question. It's -- as you know, in the pig studies when we suppressed mutant Huntington by 80% in the striatum, and we saw a 30% decrease in CSF. But the anatomy of the human brain is really quite different. So it's difficult for us to know exactly how much we're suppressing in Huntington in this striatum of patients. We're generally very encouraged to see something at all. We didn't expect to see anything. So -- so yes, I can't really tell you those -- that relationship isn't really well understood.

Our next question is Paul Matteis with Stifel.

This is Alex on for Paul. Just a couple if you don't mind. I wonder if -- you mentioned in the press release that MRI imaging from a safety perspective didn't show any findings. But I wonder if you could comment on whether you saw any differences versus the sham patients and whether you could comment on whether there's any efficacy signals there? And then second, on the MACT assay, I wonder if you could comment on the fact that you didn't see signals in 3 patients and whether you're confident in the sensitivity of the assay and maybe if you could also comment on why the sham population was so much more variable.

Yes. Okay. Let me just start with the MRI question. So we have communicated that we will discuss the MRI findings in the middle of next year. I think that's really all I can say about the MRI and beyond the fact that our MRI so far suggests that it's safe and well tolerated. And of course, our DSMB continues to look at the MRI data as a safety signal. When it comes to the mutant Huntington assay I think what we've learned is that the levels of mutant Huntington and CSF are really low and the assay is working at the very edge of its limits. And so in these patients, we didn't get reliable -- we didn't get a baseline value at all. It was below the limit of resolution. And so that, of course, means it's difficult to determine whether there was any lowering. Beyond that, in many of the patients, we also missed some of the specific time points. Again, because it was either below the limit of resolution or the variability in the technical repeats was too large. And so that meant that it didn't meet the quality criteria for the assay. So unfortunately, I can't tell you more than that. I think we will -- as I understand that this is a common problem not just for us before everybody measuring in Huntington. Now in terms of the variability in the control patients, it's a small number of patients, and I think you might expect some variability. We have first -- we're trying to -- we're on the side of transparency, so you can see the data that we've seen. But generally speaking, it's encouraging, I would say.

Our next question comes from Ellie Merle with UBS.

Just 1 on the next steps after we get the data next year and how you're thinking about the potential pathway from a future trial design perspective from any early feedback from the regulators? I guess what would a positive scenario look like when we think about volumetric MRI. And how should we think about potential sizing of future trial design. If we do see a trend on something like volumetric MRI, what's your comfort level that could be something that would be supportive of a faster pathway with the Phase III? And I guess what did we learn in terms of today's data and how you're thinking about what this means for what we'll learn next year.

Okay. Let me just unpack the question and just answer this first. First of all, what it takes for us to -- so what are some of the scenarios for next year? So of course, the best possible scenario is if the clinical efficacy data looks really good, as well as the safety data. And of course, [indiscernible] engagement. That's what it by itself would allow us to go to regulators and discuss whether that data set by itself might be enough for registration. That, of course, is the best possible scenario. Another possible scenario might be that we show that there are -- that there is some clinical improvement, there's target engagement and their safety. And I think that would allow us to then proceed to a Phase III registration study. We think that a Phase III registration study that has a reasonable chance of showing and effective on what we've seen so far is on the order of 150 patients or so. But of course, that really has to be discussed carefully with both the [indiscernible] patients and the regulators. But that's kind of the right order of magnitude. I hope that helps.

Our next question comes from Rob Karnauskas with Truist Securities.

This is Alex on for Robyn. One question about the CSF NfL, since speaks in variability, and we see a 35% decrease in the control group. How in line with the sort of historical is that from your perspective? And with the variability of the data set, how does that change your confidence on ability to file on potential earlier time points.

Yes. I -- we look at the NFL and the control patients as being centrally flat. I mean that small amount of variability or reduction that you see is unlikely to be real. We don't think that the patients are improving on their own, just because they're in the trial these of course, not been dosed. And for that reason, we also think that the dose patients are sort of statistically similar to the control patients. Now from natural history point of view, we do know that as people progress with their disease, their NfL creeps upward. But I think 1 thing we've learned from our trial as well as from an analysis of the natural history of patients and look like ours is that this happens at a pretty slow rate at this stage. So an NfL increase doesn't seem to be the most sensitive way of determining whether somebody is progressing.

Okay. And actually, if I could get 1 more on the an HTT from baseline. I know there's a lot of variability in the data, but there seems to be potentially a significant difference between month 9 and 12. I just know if -- are you looking at the data that way? And do you see a big difference between the 2 time points or...

In the controls?

Yes.

Sorry, yes, yes. So I think the way I look at it is as follows: I think the data on the dose patients actually looks relatively consistent with comparatively small error bars given the small number of patients. If you look, of course, at the control data, it's a lot more variable. You sell the individual ones. And it's basically that return to a decrease is driven by this 1 patient. So it's a little difficult to know why that is. It's -- when you have a small number of patients, 1 patient has a big effect.

Our next question comes from Salveen Richter with Goldman Sachs.

This is Elizabeth on for Salveen. On the high-dose expected in the first half of next year, could you frame expectations around the clinical data and functional outcomes that you expect to measure at 1 year? And what would be meaningful there? And then 1 question on the mutant HTT assays that you discussed earlier their ongoing work to optimize that and improve those assays so that the baseline is able to be measured more consistently?

Yes. Okay. Let me start with the mutant Huntington assays. The mutant Huntington assays have been developed and qualified by the whole Huntington field. And of course, we continue to work with multiple CROs to try and improve the assays, but I think the assays are what they are. We understand that this kind of failure rate is something that unfortunately we have to live with. I still think, however, that we're likely to get valuable data on most of our patients as in fact, we have even in these first 10. Now in terms of what to expect next year, I think the data that we see today is pretty encouraging. It suggests that at least we're doing the right experiment, which is to say that we can reduce the amount of the mutant protein in CSF, which is a prerequisite for determining whether doing that will slow the progression of the disease. Of course, I don't know exactly what we're going to find from a functional point of view, either of these patients or the next patient. What I do know, however, is that it's reasonably likely that we will be able to say something about the clinical improvement because I think the patients are, in fact, declining, at least control patients. So I think we'll have to wait and see exactly what it looks like. I think beyond that, I guess it would all be speculation. So let me just stop there.

Our next question comes from Joseph Thome with Cowen.

Maybe on the first one, I think going into the study based on preclinical data, you were targeting a 50% reduction in the rate and going to 25% in the outer brain. I guess with the data that you have right now, is there an updated thought on how much lowering you think would be safe especially as you've dosed the higher dose cohort, I know you were shooting for kind of a 75% knockdown. You're already seeing high levels here. How are you thinking about safety and kind of [indiscernible] follow-up.

Yes. Look, I think that the best answer to the safety question is simply that, so far, the therapy is very well tolerated. And our DSMB, which as you know, is completely independent from the company continues to be enthusiastic about us continuing the study. So I don't know exactly what is happening in the patients, but I can tell you that the general sense is that this is well tolerated. I don't know exactly how much we're lowering Huntington in the stride. I do know, based on our preclinical experiments that there is a limit to that. But there is a limit to how much we can reduce the expression of Huntington even at the high dose. So I think what we found in preclinical studies actually is that the high dose doesn't result in more decrease. What it does is it results in covering more brain real estate. So it allows us to both reduce Huntington in striatum, but also gets more coverage of the cortex. So I think that's what we'll see and that is probably what's happening in the higher dose patients. But of course, we'll have to wait to see until we have the data.

All right. And then maybe just 1 on the surgeries themselves. I guess have you been pleased with kind of the reproducibility of the surgical procedures? And maybe I know you're doing that surgical adaptive cohort, what's sort of the goal there? Do you think you'll be able to reduce some of the initial NfL spikes that you're seeing? Or is this just to make it easier for physicians to administer the drug, that would be helpful.

By the way, I should mention, just in case people are wondering, of course, we have already dosed quite a large number of patients with a high dose, and we have already evaluated them. And so thus far, that appears to be well tolerated. Now as for the surgical adaptive cohort, what is the idea? So what we'd like to do is we just want to make the surgery more convenient and a little faster. Because we know that if we want this to be -- if we wants us to be adopted by the community, we need to have surgeries that are just a little bit shorter at the moment, the surgery, it takes most of the day. And so -- to do this, we are experimenting with other ways of putting on [indiscernible] frames and other ways of introducing the catheters not because the approach we're using now has an problem. In fact, it's amazingly consistent because as you've seen, we can actually monitor in real time how we fill the specific structures and that has been actually kind of remarkable. So we will continue to do that. But we just like to do it faster, and we know that that's going to be important for into dose thousands of patients, and we know it's going to be important for our Phase III. So that's basically what we're trying to do in the surgical adaptive cohort. It doesn't have anything to do with efficacy or safety. It's more about convenience.

Our question comes from Danielle Brill with Raymond James.

This is Alex on for Danielle. Congrats on the update. So I got another question on the QC Huntington assay I know in the initial n = 4 patients, we were talking about potentially rerunning some of those samples. Were any of those samples successfully rerun? And following up how confident are you that we're going to have accurate validated baseline CSF samples for the high-dose cohort. Have you already analyzed that data you have that in hand?

So no, we, of course, don't have a year's worth of data on the high-dose cohort yet because they were only really finished dosing them relatively recently. So we -- now when it comes to the baseline, I can't tell you because that unfortunately is I'm blinded to that data as well. So I don't actually know how successful we've been in the baseline. One thing I can tell you is this, we did reanalyze all the samples we had from the first 4 patients where we had trouble with the assay. And some of those actually work and others didn't work. As I said, our general sense, and now we've done this in 2 different CROs is that the assay is really variable. I mean it's an all that depends on the binding of 2 antibodies next to each other. And we are using the most sensitive technology that's out there. This is the most validated approach to a single molecule accounting. But the factor means that some fraction of the time, the levels of mutant Huntington in the CSF are just really, really low. And so in order to get really reliable data you need enough of it and it has to be really reproducible across the technical repeats and that just doesn't always happen. As I said before, I am pretty confident that we will have enough data to be able to make a decision even if 1 or 2 of the patients actually fail.

Great. And if I could squeeze 1 more in. Can you just say only most of the patients in the high-dose cohort have been dosed, how many patients have been dosed in the high-dose cohort?

No. The entire high-dose cohort has been enrolled and of the 16 patients, 10 have been treated, and there are 6 controlled patients right now. What I meant is evaluated. So we haven't finished evaluating the high-dose cohort yes, of course because they haven't been dosed for -- I mean we haven't had the data for a year.

Our next question comes from Kris Kluska with Cantor Fitzgerald.

So I know this is still a small patient number but it seems that 1 of the control patients was an outlier that seemed to skew a lot of the mean levels reported across these measurements. So on an individual patient basis, are you looking at or considering any different trends that have been observed?

Yes. I mean even -- what I would say, Kristen, is that even if you look at the ranges, there does seem to be -- I mean the data, of course, is variable. But if you look even at the ranges of the treated patients compared to the ranges of the control patients, there does appear to be differentiation even irrespective of that 1 patient where there was more variability. And of course, it's hard to determine if there is really 1 measurement at 12 months where that patient came down. And through the 9 months of follow-up, that patient experienced elevated mutant Huntington. So it's -- we'll have to follow this patient up longer to get a better sense of what's going on. And of course, as we collect more data on more patients. I think some of this will come into greater focus.

Our next one comes from Yanan Zhu with Wells Fargo Securities.

Just wondering about the kinetics of HTT reduction in the treated patients seems like the level at month-9 further declined after month-9. Is there any rationale for that? And what was your -- what would your expectation be for the kinetics of HTT reduction?

Yes, that's an excellent question. So -- we know that it takes a while for the AV episomes to actually form and for the amount of [indiscernible] to stabilize. And that's based on our previous studies take several months. But in addition to this, you're right, we are seeing just further declines. I -- without much data, we think that, that's basically because what you're doing is you're changing the equilibrium. So you're producing less mutant Huntington, and therefore, you're allowing the neurons and the astrocyte and microglia to remove mutant Huntington that is there that is accumulated. So what you're seeing really is less and less of it being released because there is more and more of it that is being reduced by existing clearance machinery. So even though the miQURE imports much is likely to work much faster than this. The rate of decline of the protein in CSF has slower kinetics because it reflects the rate of clearance from the brain and these aggregates clear relatively slowly.

Got it. If I can squeeze a quick follow-up that is, with the alternative administration route, would you expect any different -- difference in the impact to the -- either the level of reduction or the kinetics of the reduction.

No. No. We're aiming to fill the exact same structures in the exact same way. We just want to do it faster and more conveniently.

Our next question comes from Luca Issi with RBC Capital.

Well, great. Maybe 2 quick ones. Maybe 1 high level, Matt. how are you thinking about the strategic value of the asset now that you have clinical proof of concept? Would this be a good time to partner the asset? Do you want to wait for the MRI data or maybe the function of data? Do you want to keep this in-house, even longer, like any thoughts there would be much appreciated. And then maybe, Ricardo, on the control arm, what is the increase in mutant Huntington at 12 months that you would have expected based on natural history?

Sure. I'm happy to answer the first question. I mean look, in the end, we're very encouraged by the data. I think when we looked at the small number of patients, particularly given the animal data, I think this is up there with what we considered reasonably favorable scenarios. Having said that, we really are interested in seeing more data from this program. As we mentioned, we've got 36 patients that have been enrolled and more patients that will be enrolled as part of completing the European study and the surgical adaptive cohorts. And this is a program and an unmet need. Right now, we're excited. This is a proprietary program, and we currently have no plans on considering a partnership. And then the second question.

Yes. Yes. Sorry. Natural history -- absolutely. So what would we expect -- I'm sorry, what would we expect on the mutant Huntington based on that natural history? So generally speaking, the levels of mutant Huntington increased slightly over the course of this disease. However, there is a bit of a caveat when it comes to the natural history, specific when it comes to mutant Huntington, which is simply that we're enrolling a population of patients that is at a very early stage of the disease and has a lot of preserved striatum. We were able to create a natural history cohort based on sort of a much larger natural history data set that was collected by CHDI. And so we have information about the clinical progression of these patients, but we don't have information about the amount of mutant Huntington in the CSF of these patients. So I can't tell you exactly from a completely matched patient pool, so to speak. So I don't have the exact answer. What I can tell you though is, generally, we do expect mutant Huntington to increase as in fact, it appears to be doing in our sham patients. So you don't expect it to decline on some.

Got it. Super helpful. And maybe a super quick one. Were you surprised not to see a spike in NfL in the control arm, given that the procedure is obviously fairly invasive here? Or how should we think about that part?

No. So no, not at all. So it turns out that mutant patients aren't actually getting brain surgery. So we're not introducing a catheter into the brain. We're not breaking the blood brain barrier. We're not doing anything like that. We did there -- They're getting anesthesia and they're getting a little burr hole so that they can -- so that they won't know whether they got it or not, but they are not -- we're not going into the brain. So we do not expect an NfL spike.

Our next question comes from [ Sam Corwin ] from William Blair.

Could you remind us if you were also measuring the wild-type mutant -- sorry, wild-type Huntington. And if you saw any reduction in that wild-type Huntington. And then just based on the results today, do you expect to see any functional benefit with the low dose now?

Okay. So first, so there is no assay for just wild-type Huntington, but there is an assay for total Huntington that is the mix of wild-type and mutant and we did, in fact, do that. And it -- that was -- the results of that are generally consistent with what we've shown you. It's much more variable because the assay is about 2x less sensitive than the mutant assay. And so you just lose more points. But yes, we did that. And it's -- yes, that's about what I can tell you. Now -- the -- okay, so the first question. Oh yes, I'm sorry. Yes. And then do we expect to see a functional effect on the low dose. And the -- I think -- I mean, I think we're generally encouraged. We are seeing what appears to be target engagement at the lower dose. And so I guess I'm cautiously optimistic that, that means that we're doing something good. And so I hope that we will see functional effect now.

Our next question comes from Pat Trucchio with H.C. Wainwright.

This is Jason on for Patrick. And our first question is just to kind of understand the decline or how significant is this a 53.8% decline for the CSF mHTT. And just kind of can you just kind of provide some color on patient-by-patient rates have declined. And is this kind of driven by super responder or is it just from a few responders or like they're relatively even in terms of decline in mutant HTT?

Yes. So we're very encouraged by this. This is kind of at the upper level of where we thought we might see an effect in mutant Huntington and CSF. So I think this provides at least the first evidence that we are engaging to target. So in that sense, I think it's very significant at least for us, because it means that we're doing -- that the drug is doing something in the brain and it's doing what we expect it to do, and we can now do the right experiment. So that's -- now in terms of whether it's served by any super responder. Now actually, in the patients, it's [indiscernible]. All the patients have a decrease. The are [ air pockets ] are actually pretty small in the patients. The noise comes in the placebos where there is just a lot of variability.

And just to be clear, the range we did present the data in the slides, which will be on the website, the range in treating patients of decline with a 44% decrease to a 71% decrease.

Our next question comes from Judah Frommer with Credit Suisse.

Just to follow up on an earlier question. Is there a concern and has there been in the preclinical data that you may be the suppressing Huntington production too much, I guess, based on what you're seeing in the low-dose, is there any concern that the high-dose maybe suppressing Huntington further than you'd like to? And then second, can you just remind us from a biomarker perspective, how are you thinking about Huntington versus NfL versus the volumetric MRI in support of a potentially accelerated approval path there?

Yes. Okay. So let me take your second question first. I think -- we think that in order to get approval, we need to show some clinical benefit, even accelerated approval. So -- we -- I think it will, of course, be important to show that you're also reducing mutant Huntington. And it will also be important, of course, critical to show that it's safe. So that's kind of how we see it. And then volumetric MRI data would be supportive as well. But really, I think the key thing that regulators care about the patients care about, the physicians care about and that we care about whether it actually makes people's lives better. And so that has to be what we focus on, and that is, in fact, why we have so many clinical endpoints in our studies. So that's the first question.

The first question was concerned about the magnitude of lower.

Yes. So the next question is do we -- are you worried about the high-dose cohort. And I think the answer so far is no. I mean we have now enrolled the patients in the high-dose cohort some time ago, it seems to be safe and relatively well tolerated. We don't think that we reduce Huntington too much. That certainly was not the case in any of the preclinical studies. And it -- it doesn't seem to be the case here. As I said before, our general observation is that when we increase the dose it doesn't actually reduce the amount of lowering that you get in this striatum, what it does is it reduces the number of cells to take up the virus. The virus spreads further and therefore, you have -- you suppress Huntington in more cells, but you don't actually suppress Huntington more. There seems to be a kind of threshold effect for MicroRNAs of these [indiscernible].

Okay. And a really quick follow-up just on the functional data. Any sense from the natural history or your general expectation on when you can demonstrate that functional benefit in this patient population?

Yes. I think that, of course, with time, we will have a better chance of seeing some separation between the patients and the controls. Our natural history data does suggest that over the course of 1 to 2 years, people get significantly worse on their [indiscernible] motor scores. And this is largely because of course, the part of the brain that is generating most quickly with striatum and the thing that you can measure the most efficiently is motor function. So without knowing what the data looks like, I would say that we are focused on whether we can see an effect on motor function. And we think there is a reasonable chance that we will be able to see it in the course of the study over the next year or 2.

[Operator Instructions] Our next question comes from Yun Zhong with BTIG.

Based on today's data and also data from other studies in neurodegenerative diseases, do you still think neurofilament light chain could still be a good biomarker for clinical intervention? Also, if -- what is the 2-year data from the low-dose cohort still is flat? And if the volumetric MRI data and based on literatures, there seems to be already a 70% reduction in the striatum volume when patients are diagnosed. So if there's no meaningful separation in volumetric MRI either what do you think the possibility of eventually being able to see any improvement in clinical endpoint?

Well, keep in mind that we specifically streamed in patients that at baseline had minimum striatum volume. So we do know that at the time they entered the study and received AMT-130, they do have viable striatum cells that can be transfused and potentially preserved. But you're right, I think that in the end, when you start looking at 2-year follow-up data, the biomarkers become supportive and what becomes more important is really looking at functional data. And we believe given the fact that these are early manifest patients with preserved striatum volume that there is a great potential to have therapeutic effect.

Yes. And NfL, has a marker for the progression of individual patient is not great. It is clear that NfL does increase over the course of the disease. But at this stage of the disease, it does so very slowly. And at an individual patient level, it doesn't seem to be that informative. So I would say we tend to treat NfL more as a marker of resolved inflammation after the surgery than we do as a marker for disease progression. I'm more enthusiastic about other ways of doing that.

Okay. So did you say that you will have functional data when you report the unblinded data in 2023.

Yes, we will definitely have functional data.

Our next question comes from Uy Ear with Mizuho.

I have a couple. I guess the first question, I was hoping you guys can help me clarify. So the 3 patients that did not have measurable mHTT. Is that a function of the assay? Or is it just -- it could be because they just didn't have, I guess, the biomarker and maybe they're not Huntington's patients. Well, they haven't, I guess, progressed at that kind of level? And secondly, could you also -- if you take out the -- in the control arm, if you take out the 1 patient that was very variable, does that reduces the level of increase significantly? I'm just asking largely because I think in the Roche study, I don't know also how similar the patients are and what the assays use are the same. But in the Roche studies, pretty much the control arm were relatively flat. So in terms of changes in mHTT, I just wanted to see your thoughts on that?

Yes. So let's just start with the assay. We really do -- first of all, all the patients, of course, have Huntington's disease, they have been diagnosed genetically. So we know that they have greater than 40 CAGs. And as sadly in Huntington's genetics is destiny. So once you have a certain number of repeats, you will get the disease. And all of them of course had symptoms. So quite certainly that they have Huntington. Now the question is why did they -- why did the assay fail? We really think it's assay failure, not actually any issue with the patients. And -- we have been doing a lot of work to try and make sure that we have as few failed assays as possible. But in the end, it seems as if we're operating at the low end of the assay and therefore, some fraction of the time, we will not be able to get data. And of course, without baseline data, it's very difficult to interpret things. Now when it comes to what we see, I think we're relatively confident that the dosed patients that we're seeing a decrease in dosed patients. You saw the data. So you've seen that there's a lot of variability in the control patients. We don't really understand why that's the case. You can do the impairment of removing any single patient from that set, and it will change average. But I don't know how you would do this. We have shown you the data we have. And as we accumulate more patients, we'll have more reliable data both on the controls and on the dosed patients.

And I'm currently showing no further questions at this time. I'd like to turn the call back over to Matt Kapusta for closing remarks.

Thank you, operator. We are very pleased with the progress we're making across our clinical program to investigate this potentially groundbreaking gene therapy for the treatment of Huntington's disease. To summarize our findings thus far, AMT-130 continues to be generally well tolerated for up to 1 year in 6 treated patients from the low-dose cohort. Thus far, there have been no significant adverse events associated with AMT-130 and mean NfL levels are near baseline at 12 months. We are also encouraged by the lowering of mutant Huntington protein observed in the treated patients. And while this is a small number of patients, we believe these trends are early indications and target engagement. As we look forward, we expect to complete enrollment of our 15-patient open-label European study by the end of this year, and to initiate thereafter a third U.S. cohort to evaluate a more streamlined surgical procedure. We expect to have 1 to 2 years of safety and efficacy data, including clinical outcomes on all 26 patients in the U.S. study in the second quarter of 2023. I'd like to thank the uniQure program team, our trial sites and study investigators who have worked tirelessly over the past year to drive this program forward. And most of all [indiscernible] to sincerely thank their study participants and their families to motivate and inspire us each and every day. Thanks for attending the call. We look forward to providing further updates on this very important study.

This concludes today's conference call. Thank you for participating. You may now disconnect.