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

Good day, and thank you for standing by. Welcome to the uniQure conference call. [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 today, Ms. Maria Cantor, Chief Communications Officer. Ms. Cantor, the floor is yours.

Good morning, and thank you for joining us. This morning, uniQure announced initial observations on the first 4 patients enrolled in the ongoing Phase I/II clinical trial of AMT-130 in Huntington's disease. 2 of these 4 patients received AMT-130, and 2 patients experienced an imitation surgical procedure in this randomized blinded study being conducted in the United States. Early observations shared today relate to safety and tolerability 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 will be making forward-looking statements during this investor call. All statements other than these -- other than those 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 on Form 10-Q filed on October 25, 2021, 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. Nearly 10 years ago, uniQure embarked on a our journey to develop a technology platform that could greatly broaden the applicability of AAV gene therapy to genetic diseases requiring suppression of mediated proteins. From these many years of research from our miQURE platform, a proprietary technology designed to safely and effectively deliver onetime-administered gene-silencing constructs to patients. We're currently applying this powerful, innovative approach to numerous CNS and liver-directed disorders including temporal lobe epilepsy, Alzheimer's disease, Parkinson's disease and other indications. While many genetic disorders can be addressed using our miQURE platform, one of the most prevalent and highest clinical unmet need is Huntington’s disease. Huntington's disease is a monogenic and progressive neurological disorder that leads to devastating movement psychiatric and cognitive decline over the prime time of people's lives. It is caused by a triplet nucleotide expansion within a single gene that leads to a toxic gain of function. There are approximately 80,000 people across the United States and Europe that have been genetically confirmed to have Huntington's disease, and potentially tens of thousands more are at risk who have chosen not to get tested given that there are no approved disease-modifying treatments. The unmet medical need for people living with Huntington’s disease is truly enormous, which drives our commitment and focus to aggressively pursuing a treatment for this devastating disease. There are several reasons why we believe AMT-130 has the potential to be not only first, but a best-in-class approach for the treatment of Huntington’s disease. First, AMT-130 is designed to be administered once with the potential for long-term durability; second, AMT-130 is administered directly to the areas of the brain that are impacted in 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 very important as no matter how effective a drug might be, it simply won't work if it can't reach the disease areas of the brain. At the same time, Huntington's 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 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 nearly 80 patients. Additionally, AMT-130 employs the pol II promoter and it might grow RNA without a passenger strand, which is designed to mitigate off-target effects and other potential toxicity. In June of last year, we initiated a dose-escalating multicenter Phase I/II trial in the United States to evaluate the safety and tolerability of AMT-130 and explore potential efficacy at 2 different doses. Based on the strong recommendation from the FDA, the study is conducted as a double-blinded and randomized trial, including an imitation searchable control. While this is not a traditional first-in-human study design, we believe this approach will produce the most robust data, and has the potential to provide a faster pathway to registration. I've been extremely pleased with the progress we've made in this important trial over the past year. Thus far in the study, we have performed 19 patient procedures, and expect to complete enrollment by the middle of next year. We are also in the process of adding a third cohort to evaluate a more efficient surgical procedure, and we have recently initiated screening for an open-label European study. In total, we expect to enroll 59 patients in our U.S. Phase I/II trials for AMT-130. Today, we are pleased to share additional 12-month observations, focused on safety data from the first 4 patients in the low-dose cohort of the U.S. study, 2 of which were treated with AMT-130. We are very encouraged by these initial safety data, with AMT-130 appearing to be well tolerated in these patients at 1 year of follow-up. Safety is paramount for any first-in-man clinical study, particularly in the context of the historical toxicity challenges observed in previous studies in Huntington's disease and with other CNS-directed gene therapies. As we communicated throughout the year, the variability in exploratory biomarkers from only 2 treated patients does not allow conclusions to be made at this time. We expect to have a much better picture as we gather additional data from a larger number of patients with longer follow-up. In the first half of 2022, all 10 patients in the first cohort will be unblinded, and we anticipate providing a 12-month clinical update largely focused on safety data. In the first half of 2023, we expect to unblind the patients in the higher dose cohort, at which time we expect to present efficacy and safety data across both doses, including 2-year follow-up data on the treated patients in the first dose cohort. In addition to the blinded control data generated from this study, we are also working closely with CHDI to compile a patient matched natural history data set from their HD registry, which will provide an important additional comparison. Let me now turn the call over to Ricardo, who will walk through additional details regarding the Phase I/II study and initial observations from the first 4 enrolled patients.

Thanks, Matt, and good morning, everyone. Our U.S. Phase I/II clinical trial is exploring the safety, tolerability and efficacy of AMT-130 for the treatment of Huntington's disease. It is a double-blinded, placebo-controlled trial that will enroll a total of 26 patients split into a 10-patient low-dose cohort of 6e to the 12 vector genomes, followed by a 16-patient higher dose cohort of 6e of the 13 vector genomes. The patients are in stage 1 and early stage 2 of their disease. This is the earliest symptomatic stage of Huntington's disease. Patients have a total functional capacity score above 10, where 13 is the maximum score on the scale. The patients have more than 40 CAG repeats, and a minimum striatum volume to allow the safe administration of the gene therapy. As Matt said, AMT-130 is administered surgically using MRI-guided convection-enhanced stereotactic neurosurgical delivery directly into the striatum. The multicenter trial consists of a blinded 12-month core study period followed by unblinded long-term follow-up for 5 years. Because this is a first-in-human experience with AMT-130, our Data Safety Monitoring Board has been following the trial closely. We've had 5 DSMB meetings over the course of the study. And after each meeting, the committee has given us permission to continue dosing. AMT-130 has been well tolerated to date, and we're very pleased with the progress we're making. We have enrolled a total of 19 patients, 10 in the low dose and 9 in the high dose cohort. We're encouraged with this progress, and on track to finish enrollment in the study in the first half of next year. A total of 4 patients, 2 doses with a low dose of AMT-130 and 2 controlled patients with imitation surgery have reached the end of the first year of monitoring. These patients had 41 to 44 CAG repeats, a total baseline functional capacity score between 10 and 13, and total motor scores between 7 and 23. Here are our initial observations from these first 4 patients. First, the patients recovered well from the 1-day surgical procedure and were discharged from the hospital and returned home to day after surgery. No serious adverse events associated with AMT-130 were reported in these patients. Overall, the dose patients and the control patients are doing well clinically, and there are no clinical indications of toxicity. Second, neurofilament light chain, a marker of neuronal injury, was measured in the CSF of these patients at baseline and at 3-month intervals. NfL increased immediately following the surgery and declined back to baseline levels of 1 year in both treated patients. NfL is known to increase following surgery, and we're very encouraged to observe that NfL trended downward and returned to baseline levels in the treated patients. NfL-controlled patients remained constant throughout the 12 months. Third, both wild-type Huntington and mutant Huntington were measured in the CSF of these 4 patients. Because of technical issues with the [indiscernible] at our CRO and the small number of patients, there was an unusually high variability in these measurements. And we're, therefore, unable to draw firm conclusions at this time. Upon further investigation, we found that the patients have controlled test samples, did not pass the quality control criteria. We are working with the CRO to optimize these assays for measuring mutant Huntington and wild-type Huntington and expect to reanalyze these samples once the issues are resolved. Fourth, we used MRI to help assess the safety profile of AMT-130. The structural MRI findings are generally consistent with our expectations at this stage and did not reveal any clean clinically meaningful safety finding in either the treated or the control patients, 1 year of follow-up. As expected, T2/FLAIR signals were observed on the MRI in the areas of infusion. These commonly observed MRI findings have been widely reported following intraparencle administration of gene therapies, and the placement of electrolyte deep brain simulation. They do not appear to have clinical consequences, and appear to be decreasing over time. We did not see any additional MRI formalities. Lastly, on the recommendation from the study steering committee and the DSMB, we will be disclosing efficacy data, including polymetric MRI data when the first 2 cohorts have been unblinded, which is expected in the first half of 2023. The disclosure of such data has the potential to introduce bias in this ongoing blinded placebo-controlled study, which could impact our ability to interpret the data and use it for regulatory submissions. We're also expanding the clinical development of AMT-130 beyond these 2 dose cohorts. As announced in our press release this morning, we have initiated patient screening in an open-label study in the EU. This Phase Ib/II study of AMT-130 will enroll 15 patients with early manifest Huntington's disease across the same 2 doses being explored in the U.S. trial. The first procedures in the low-dose cohort are expected to be complete in early 2022, and we expect patients to enroll in the EU study to be complete early in 2023. We have also added a third cohort in the ongoing U.S. study that will explore the use of alternative stereotactic navigation systems to simplify the placement of catheters for infusion of AMT-130. This will help us simplify and shorten the surgical procedure. This third cohort will begin enrollment in the second half of 2022, and will include up to 18 additional randomized patients. In conclusion, we are very pleased with the clinical enrollment in this program, and encouraged by the data related to the safety and tolerability of the AMT-130 in these patients. While it's too early to make statements about exploratory markers and efficacy, we're excited about the prospects of AMT-130 for patients with Huntington's disease. We will provide another clinical update largely focused on safety in the first half of 2022 when the low-dose cohort of patients complete the 1-year follow-up. We also expect to have efficacy and safety data where both cohorts are unblinded in the first half of 2022. Now back to you, Matt.

Thanks, Ricardo. And operator, please open the line for analyst questions.

[Operator Instructions] Our first question comes from Paul Matteis of Stifel.

I wanted to ask a couple of biomarker questions based on at least what you know or what you don't know right now. As it relates to the Huntington assay, can you just explain more what happened and how solvable this is? And I guess bottom line right now, how confident are you that you're potently engaging the target in the deep brain in the cortex? And then as it relates to neurofilament, can you speak more to the magnitude of increase and how long it took to get back to baseline levels?

Sure. Let me start with the Huntington assay. So we can't really say anything about the levels of mutant and wild-type Huntington and CSF because the assays failed the QC as the CRO. We are troubleshooting it. Essentially, what we observed was that it was a great deal more variable than we expected and that there was some correlation between the patients that were treated and the controls, which was unexpected. So unfortunately, I can't tell you much about target engagement. However, what I can tell you is that we are working very hard with the CRO to actually solve the issue. We believe it is very soluble, and we will have information per soon. That's what I can say. Now with regards to NfL. NfL rose immediately after the surgery as expected and then declined over the course of the year, and now it's back to baseline levels. It is trending downward. So we're cautiously -- well, we're optimistic that this indicates that the surgery was safe and that there is no lasting damage.

Just -- I just want to clarify your first comment, Ricardo. Did you say that you think the Huntington -- the samples are salvageable and that you'll actually have some of that assay data at some point soon. Is that right?

Yes. No. So we didn't use all those samples. I -- the assay itself failed. It's -- the samples we can reanalyze the samples.

Okay. So you might disclose that at some point?

We will disclose it at some point, yes.

Our next question comes from Joseph Schwartz of SVB Leerink.

I was wondering if you can give us any insight into your decision to hold back on reporting any volumetric MRI data until both cohorts or unblinded. And does injecting the gene therapy volume itself in the fleet baseline volume to a detectable degree? And do anything to correct for this potential artifact when analyzing volumetric MRI data?

Yes, I can take -- I can answer both questions. So the first question is why not disclose all the volumetric MRI data right now. And in discussions with our steering committee and with the DSMB, it was felt that the volumetric MRI is very closely related to efficacy. And that if we disclosed efficacy now, this would impair our ability to conduct this blinded study and to use it for regulatory purposes. So we've made the decision to only reveal that data once the 2 cohorts have been unblinded. You can imagine that there's this potential for biasing the study if we were to say something about the study, the -- working or not working. So that's one. The second question is, does injection of the gene therapy itself change the volume of different structures, and the answer to that is yes. So if you inject anything really into the brain, initially, you see changes in the MRI. And so we're developing algorithms to sort of compensate for that. We'll talk more about that when we actually disclose the data.

And next, we have Robyn Karnauskas of Truist Securities

I have a couple ones. Earlier you guys have set the bar pretty low, given the small cohorts and only 12 months follow-up time. Given that you will only have low-dose patients that you expect to report in the second quarter, can you help set the expectations for what we should -- we would be seeing from these 10 patients HTT, CSF lowering? Hopefully, you've figured it out with the CRO, and you're going to not show any volumetric imaging, but NfL, what are the metrics that we should that you think are the most meaningful to focus on? And then also given that you haven't seen much of a difference at 12 months, yet do you think you need to see these patients out a little longer in order to start seeing the separation? Is there any reason we should expect you to push out the second quarter data release?

Yes. I'll take that question. So the data release in the middle of next year is going to be comparable to the release today. So it's going to largely focus on the safety and tolerability of the procedure. That data release will include 6 treated patients and 4 sham-controlled patients, right? So we got effectively 40% of the data that's been covered here within this particular release today. What I would say is it depends, right? Your question about how long you have to follow these patients in order to begin to see a treatment effect, it does depend. We do know that Huntington is a relatively slow repressive disease, right? That's been well documented, and that there is variability associated from patient to patient based on many different factors. And that includes age, the aggressiveness of their disease, the number of CAG repeats, et cetera. So to the extent that we have faster progressing disease in the control patients, there might be the potential to demonstrate something in 12 months. Having said that, we are following patients that are treated for 5 years. And we're also compiling, as best we can, the patient matched natural history set of data, right, working closely to CHDI that can provide another comparison. So it obviously depends on the clinical effect side, it depends on the rate of progression of the control. But in the end, we're going to be following these patients for multiple years. And so this study is designed in a way, I think, to really demonstrate efficacy in a fairly robust way given its design.

Up next, we have Joseph Thome of Cowen & Company.

I know you mentioned that you're kind of having this randomized data could provide a faster path to registration potentially if this is positive. Can you share any, I guess, interactions with the FDA, what do you think they would expect for a regulatory package? Have they given you an idea of how many patients would need to be followed, and maybe what the key endpoints would be that they would want to look at?

Yes. I mean we've had interactions with the agency periodically with respect to, of course, the IND. And then as we were beginning to enroll patients, there was a number of discussions with respect to crossover inclusion exclusion criteria as well as the length of the blinding period. What I would say is that I think they made it pretty explicitly clear that they strongly recommended performing, even first in human, a randomized and blinded study. And I think quite frankly, even went so far as to say that it very well has the potential to expedite our goal of registering the product. Now in the end, it depends on the data, right? So there's no promises there. But I do think there's an expectation that they do want to see randomized blinding control data. We have not discussed their requirements for a registration study with a number of patients or those things. I think that is a conversation we'll have with them when we have a little bit more data. But our expectation is that, I think getting approval solely on biomarker data alone in this particular indication will likely be difficult.

Great. And then one follow-up on the earlier question, if I can. Just on the NfL levels in the CSF. I think previously, you indicated the high dose, we might be able to see some changes in CSF, Huntington levels at low dose, given the concentration of the low dose and the localization, we might not. Is that -- has that changed? Do you think once this assay gets figured out, we would be able to see some changes in the line CSF or no?

Yes. We -- based on the preclinical studies in mini pigs, we expect that at the high dose, we might be able to see some signal. We don't know exactly how much of a decrease we will see. In the mini pigs, we saw a 30% decrease. Of course humans have a much larger brain. And so we're not completely certain on what that will actually translate to in CSF measurements of Huntington. Now at the low dose, again, we're uncertain as to what we will see, I guess, what I would say is, of course, we expect to see a smaller signal there. That's -- yes, that's about what I can tell you.

Our next question comes from Danielle Brill of Raymond James.

I guess just looking at the totality of the evidence. I'm just curious, like, are you confident that you're getting target engagement? And do you still think that this low dose is therapeutic? And then I'm curious what info led you to add a new cohort and adjust the catheterization procedure?

Yes. I think that we -- look, we remain optimistic about gene therapy. We -- based on, of course, our preclinical studies where we know that we can deliver the gene therapy straight into the brain and that we get infection of those cells. We think that, that's very likely to be happening in humans as well. We, at the moment, have no evidence for that. But other than that...

I mean what I would say is I -- we have a high degree of confidence that this microRNA construct engages the targeted. I mean in whatever experiment we did, whether it was rats or mice or transgenic pigs, we saw target engagement. And really -- if we can get the construct or the drug into an area of the brain, we saw micro RNA presence. We saw vector DNA, we saw suppression of messenger RNA, we saw suppression of protein. It was highly correlated, and I think we have a high degree of confidence. Now whether or not we'll be able to detect it actually through the spinal fluid given the secretion profile, that might be a different question, but we have a high degree of confidence that we are lowering mutant protein in the brain.

Okay. That's helpful. And then I guess, if you guys could just expand a bit on the new surgical procedure, and the reasoning behind that.

Sure. I can talk a bit about the new surgical procedure. So as we learn more about the surgeries and how to conduct them, the surgical team has come up with what I think are really innovative ideas for how to shorten it and how to, for example, reduce the number of cohorts and how to incorporate robotic placement of anchors, and that's what we will be exploring. We think we can shorten the procedure, which will make it both safer as well as more attractive for the medical system.

And next, we have Salveen Richter of Goldman Sachs.

This is Elizabeth on for Salveen. Just wondering on the data that's coming in the first half of 2023 from the high-dose cohort at 1 year of follow-up. And what would success look like for you on this data? And what kind of separation from control could be expected at that time?

So the question was on the high dose cohort specifically?

Yes, high dose -- I mean, also low dose, but I think more of a focus on the high dose.

Yes. I mean it's hard to -- look, it does depend on the clinical effect size, but I would expect that our view is that with 2 years of follow-up from the low-dose cohort treated patients with comparison to natural history and with 12 months of follow-up from the higher dose, our hope is that, that is sufficient totality and data that we will be able to elucidate efficacy signals. Again, it will -- it does depend on -- the control patients don't progress, right? It's going to be hard to demonstrate separation. But the expectation is with 26 patients of data that, that will be sufficient. Keep in mind, we'll also have 15 patients of data that we'll probably begin to start reading out in 2023 as well. And I mentioned that in totality, we've got 59 patients across 3 different cohorts in the U.S. and the open-label study in Europe with the potential of crossover patients. So I do think that this study is going to produce meaningful data. And I have, I think, reasonable confidence that in the first half of 2023, we'll be in that position.

Yes. There are 2 key comparisons that we're focused on. First is a comparison between the treated patients and the placebo controls, and there we're very much subject to how rapidly do the specific placebos that we selected progress. We will also be comparing to the natural history data where we're actually matching the patients in this kind of synthetic cohort to the characteristics of the patients that we've enrolled in our study. And of course, because there are many more there, we have, I think, a better chance of being able to show a difference. So that's -- I think as Matt said, we have reasonable expectations that we will be able to draw some conclusions and will then give us some indication for how to proceed with the program.

And next, we have Patrick Trucchio of H.C. Wainwright.

Just a follow-up on the third cohort that's being initiated with the alternative stereotactic navigation system. Just wondering if -- for this third cohort, if you'll also need a year of follow-up data or if you would have some data in that first half of 2023 as well that could tell us if this new procedure is having the impact that you're looking for? And how the data from the start cohort could contribute to potentially an accelerated approval pathway?

Yes. I think our expectation is that we'll be able to make a dose decision to inform a registrational strategy in the first 2 dose cohorts of the U.S. study in conjunction with the European study. The third cohort is largely to evaluate the safety of this procedure. It's going to be at the high dose, so we're not evaluating a third dose. And it's really blinded for the purposes of properly evaluating safety. So I think we can utilize the totality of the data, but I don't expect that the unblinding of the third cohort would necessarily be a prerequisite for an aging and registration strategy.

Up next, we have Samantha Corwin of William Blair.

I guess I was curious if we will be seeing any data from cohort 2 in 2022 even any safety data. I'm just considering if a higher dose, it got to be nice to see some of those metrics. And then I have a follow-up question after that.

Yes. The second cohort will not be unblinded until the first half of 2023. And so we will not be discussing any aspects related to the second dose score. Now having said that, our Data Safety Monitoring Board is evaluating constantly all data from the study from all patients in an unblinded manner. And so any statements that they have with respect to safety, we will certainly communicate.

Great. And then were there any other markers, inflammation aside, from NfL that were being measured? And I know that the CHDI Foundation has been working on a Huntington pet ligand. Have you had any conversations with them about potentially using that to look at localized reduction in Huntington? Or is that kind of in your plan later down the line what is partially available?

Yes. So first, on other markers of inflammation, yes, we have other exploratory markers of inflammation that we have been measuring. So far, those are unremarkable, they're essentially safety markers. And -- so that's one, things like YKL-40 and GFAP have -- are being measured. The second part of the question is could we use the pet ligand. We're very enthusiastic about the pet ligand and we have talked and are talking with CHDI about how we could use the pet ligand in some of our patients. And as you know, it's being developed in Belgium, and we're enthusiastic about incorporating that into some of our trials. But we -- it's still it early. So we're not really ready to disclose when those experiments will be done. And -- but yes, your point is a great one. We would very much like to show that we can reduce Huntington in that region of the brain.

Our next question comes from Yun Zhong of Wells Fargo Securities.

So first, I'm wondering about the CSF HTT assay's variability and the QC. Are these 2 issues -- are these related to each other? Or are they -- the high variability and the QC issue independent events?

Well, there are 2 things that play here. One is just a small number of patients and controls, which probably would make any data variable, and humans are just variable. But superimposed on that, there is the fact that the assay itself didn't work. That, of course, leads to extra variability and unexpected values where there should be no values and things like that.

I see. So currently, you don't have a good sense of the extent -- the true extent of variability. Is that fair to say that?

Well, we -- I don't know [ in fact ] to answer that. I would say, we certainly know how variable the numbers we got were. We assumed that that's a combination of the assay not being great, and the -- and it being just a small number of patients and a small number of controls. We really need to figure it out before we make any public statements about this data.

Got it. And then on the NfL. I'm wondering about -- could you comment on the amplitude of the NfL changes compared with what we have seen with the antisense oligonucleotide approach. Is it comparable? Or is the NfL increase that you see -- the trend increase that you saw, was that higher ASOs given that your surgical procedure is more invasive. So I guess it's not unexpected, and it's higher. And also, the kinetics, did it come down to the baseline level at 12 months? Or did it come down -- had it reached the baseline level earlier, for example, at 9 months?

Yes. So when it comes to ASOs, my understanding of that data is that NfL increased and then continued increasing and stayed elevated over time. What we found was that right after surgery, there was an increase. I can't tell you offhand whether that increase was much higher than the increase that was observed with ASOs. What I can tell you is that because we're measuring it approximately every 3 months, there was an initial spike, and then there was a gradual decline to baseline over the course of the year, and which effectively suggests that whenever damage was caused during the surgery was reduced. And in fact, we're very enthusiastic about this because this really does suggest that the surgery is well tolerated, and it also suggests that the treatment is also well tolerated, and isn't leading to additional damage.

And next, we have Kristen Kluska of Cantor Fitzgerald.

So based on the baseline demographics that you laid out for these patients, when generally would you expect to see some of the neuronal damage most apparent from NfL? And then I believe in the past, you've guided that patients could lose roughly 3% to 5% of the putaminal volume on an annual basis. So just wondering if you think that metric is fair based off of these patient demographics.

So we haven't disclosed any data on volumetric MRI. These are early-stage patients. And so generally speaking, they progress slowly. And the literature does suggest that there's a loss of around 2% of putaminal volume over the course of the year.

Okay. And then in regards to some comments you made around durability, could you remind us of the key findings, both from your preclinical models and other clinical experience that gives you confidence in this? And for some of the guided readout that you've provided, do you have any plans to report on anti-AAV5 antibody levels?

I'll take the first question, and then I can hand it over to Ricardo. What I can tell you is that in the transgenic mini pigs, we think we sacrificed animals at 2 years of follow-up, and showed sustained durable suppression of mutant protein in the striatum in the somatic motor cortex, so that we know. And we continue to have transgenic mini pigs that are being followed up longer, but those animals have not been sacrificed. So there's not much more we can say about that in particular. But we do think that this has the potential to be highly durable, and sustained -- have sustained clinical efficacy and in particular, because of the very slow turnover cells inside the brain as well.

Yes. I mean the fact that neurons don't divide, means that the transient is not going to be diluted. And so far, we have not seen any silencing of the transgene or any silencing of the promoters. So we expect that this will lead to a long-term suppression. Of course, we -- in the liver, we have great evidence in humans that there is durability, at least up to 5 years. So that provides a data point in vivo. Now when it comes to AAV -- anti-AAV5 antibodies what was your specific question?

Just if you had any plans to report on any of this data in your upcoming guided readout?

Well, do we plan to report on anti-AAV5 antibodies? We certainly measure AAV5 antibodies. We know that a vast majority of the population have antibody levels that are -- that allows to dose. We know this from our hemophilia study. We think that this is an even lower risk for the Huntington study because we're administering the gene therapy directly into the brain, which is relatively immune privileged. And we also know that following administration of the AAV5 is a big increase in the antibodies. I think we would report on the data as we felt that it was informative.

Yes. And the only thing what I would just add to that is I think from our HOPE-B pivotal study, right? We've demonstrated that we believe we could have a meaningful clinical benefit in 92-plus percent of patients, right? And what we do know -- we have explored this preclinically is that whatever the levels of anti-AAV5 antibodies are systemically, they are meaningfully lower within the CNS compartment, if you will, for the reasons that Ricardo mentioned. So I would expect in extrapolating that whatever -- it would be much more than 92%, it's not 100% that we could potentially be therapeutic in Huntington's.

I guess I can add that, thus far, anti-AAV5 antibodies also not been an issue for us at all.

And next, we have Luca Issi of RBC.

This is Lisa on for Luca. Just wondering, given the DSMB has given the go-ahead in the high-dose cohort and the safety profile were presented today and first cohort patients looks benign. Will you be able to enroll the third cohort without staggering the DSMB review between surgical procedures? And as well, when should we expect any data from the EU trial?

Yes. So I'll take the first part of this question. So the new procedure actually has -- the new cohort actually has 2 parts to it. The first part of it will be exploring these robotic replaced anchors and the second half of it will be exploring a new stereotactic path. So in that sense, we will stage patients. We expect that will be faster because there isn't a concern about the gene therapy itself. It's really post-surgical concerns that we're worried about. But of course, we will start with them to some extent as we learn more about the procedures.

Yes. I think it will -- I think the plan is a shorter stagger, a much shorter...

[indiscernible]

Maybe perhaps a 30-day stagger. So I -- and that's -- so I think it will be -- I don't think that will be an issue. In terms of the data from the European open-label study, what I would expect is that in 2023, we expect to have initial data from that -- from the low-dose cohort.

Our next question comes from Eliana Merle of UBS.

Just could you elaborate a bit just in terms of how you're thinking about [indiscernible] sort of your confidence in the dose [indiscernible] I guess, what -- the target engagement that you're getting. So it looks like if you perhaps needed a higher dose, how you would think about that and if [indiscernible] there.

Yes. You were going in and out there, but I think you were asking a question about dose. I think ultimately, our expectation would be that in 2023, we'll be able to elucidate, get an understanding about efficacy signals related to both doses. And I do ultimately believe that safety of each dose is going to play in very significantly. I would expect that if we're confident about efficacy signals that we would select the highest well-tolerated dose to move into a registrational study.

And next, we have Yun Zhong of BTIG.

So on the NfL changes, you saw that from active treated patients, but not on -- from sham-treated patients. Does that suggest that the NfL change was not due to the surgical procedure itself, but rather due to the injection of AMT-130 into the brain? And also, did you measure microRNA expression? Sorry if I missed it.

Yes. So I can answer both of those questions. We think that the increase in NfL was due to the surgical procedure. We -- and the fact that we returned to baseline despite the fact that the gene therapy is still suggests that it is not due to AMT-130.

Yes. And this is -- just to be clear, this was evidenced in our transgenic pig model. I believe that even in the control animals that we're [indiscernible]. We saw a spike of NfL immediately after the procedure itself. That peaked at around 2 to 3 months, and that's very consistent here. So we don't believe that, that's related to AMT-130, but instead, the actual intervention procedure itself.

And did you measure -- sorry, microRNA question, please?

Yes. So we are -- that is another assay that we're working on. Generally speaking, it's very difficult to measure microRNA in CSF. And so we're not ready to disclose that data.

Okay. And a follow-up question on the third cohort with the new procedure. And do you expect the procedure to affect, for example, distribution recovery within the brain? And the reason why you decided, in the middle of the study, to add this cohort, was that based on any specific feedback that you got from a physician or a patient that participated in the study?

No. We would basically like to simplify the procedure and make it faster. And the initial procedure that was devised was really very -- it was devised to be very safe and to be very conservative. And so now that we have much more experience with the safety of this, we feel that we can just improve it and make it shorter and more efficient. Yes. Also, there have been technology improvements since we initially designed the study that I think will also let us do some things better.

Yes. I mean these patients are under anesthesia, right? They're under general anesthesia. So I think what we want to do -- I mean this is really thinking out about being commercially minded, and trying to make this procedure as efficient as possible and trying to reduce the amount of time patients are under anesthesia.

Yes. That we'd like to be able to meet the best use of surgical suites, which means the faster we make, the better. And we'd like to reduce the amount of time that patients are under anesthesia.

The next question comes from Judah Frommer of Credit Suisse.

The first is just a follow-up on one of the NfL comments made earlier. I thought Ricardo said that NfL kind of backed towards baseline and then continue to trend down. Is that a comment on where it's gone beyond 12 months? Or is that just saying that it's back to baseline for [indiscernible]

Well, yes. No, we're only disclosing 12-month data. The comment was that if you look -- the NfL peak at around 3 months. And it really trended down in every measurement since then and returned to baseline at 12 months. But the measurement between 9 and 12 months, it was continuing to decline.

Okay. That's helpful. And then just on kind of the natural history matched control. How should we think about placebo versus using natural history? Has the agency given you any guidance on what is potentially more meaningful?

Well, I think in general, the FDA prefers a placebo cohort. The issue for us is that our trial is comparatively small. And so we don't really know how much our placebo cohort will progress. So we want to -- if we want to make the best possible case, then we would also like to be able to compare to the natural history, and we don't want just a -- all-comers natural history on to a natural industry that is really matched to the characteristics of our patients.

Our next question comes from Suji Jeong of Jefferies.

I have one question about the third cohort that you're going to add to the ongoing Phase I/II study. So earlier, you said that you're going to release data from the low dose and high dose cohort at the same time in first half of 2023 to avoid any bias to the study. So I was just wondering if you had efficacy data from the 2 cohorts from the earlier study, wouldn't that also imply is that -- bias the results from the third cohort from the study. And I have a follow-up question.

Yes. What I would just say to that, really, the primary objective of this third cohort is to evaluate the safety of the procedure. So the view is that we'll be able to make a dose decision based on the first 2 cohorts that will inform a registrational strategy. Technically, will there be perhaps some bias as it relates to efficacy data? There's a risk of that. But as I said, the primary objective there given that we're evaluating the same dose as the high dose cohort, which is going to have 16 patients in it to begin with, is really to evaluate the safety of that modified, more efficient procedure.

Okay. That's fair. And from this ongoing study, are you measuring plasma and NfL level? And my second question is, what is the minimum level of knockdown [indiscernible] proteins that you need to in the striatum in order to see reduction in CSF?

Yes. So plasma NfL, we're really focusing on TSF NfL because we think that, that's going to be more meaningful for the safety and efficacy of this trial. What is the amount of knockdown? I think the short answer to that is we're not completely sure. We know in pigs, if you knock Huntington down by 7%, you see approximately a 30% decrease in CSF Huntington. And -- so -- but we do also know, of course, that the human brain is much larger. And therefore, the striatum is a much smaller fraction of the human brain than it is of the pig brain. So we're not completely sure what to expect. Nobody has actually -- has done this before. We are aiming for a 70% knockdown in the striatum and 50% knockdown in cortex in our patients. And that was calculated based on what it takes to reverse the phenotype in the preclinical models.

And sir, I see no further questions in the queue. I'll return the conference to you for closing comments.

All right. Thank you, operator. In summary, we are extremely pleased with the progress we are making across our clinical program to investigate this potentially groundbreaking gene therapy treatment for Huntington's disease. The interest in our clinical study and the pace of enrollment has exceeded our expectations. And we are delighted that the first clinical data supports the tolerability of AMT-130 and in particular, the NfL in treated patients has trended downward and returned to baseline. We remain laser-focused on completing enrollment of the higher dose cohort in our U.S. trial as well as expanding our pool of patients through our open-label EU study in a third U.S. cohort to evaluate a more streamlined surgical procedure. I'd like to thank the uniQure program team, our trial sites and study investigators who have worked tirelessly over the last year to drive this program forward. Most of all, I want to express my sincere gratitude to our study participants and their families who truly motivate and inspire of each and every day. Thank you for attending the call, and we look forward to providing further updates in the new year. Have a safe and happy holiday.

This concludes today's conference call. Thank you all for participating. You may now disconnect, and have a pleasant day.