Good day, and thank you for standing by. Welcome to the uniQure conference call. At this time, all participants are on a listen-only mode. After the speaker's presentations, there'll be a question-and-answer session. To ask a question during that session, you will need to press star one on your telephone. Please be advised today's conference is being recorded, and if you require any assistance during the call, please press star zero. 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 four patients enrolled in the ongoing phase I/II clinical trial of AMT-130 in Huntington's disease. Two of these four patients received AMT-130, and two patients experienced an imitation surgical procedure in this randomized blinded study being conducted in the U.S. 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 those of historical fact 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 25th, 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 as 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 journey to develop a technology platform that would greatly broaden the applicability of AAV gene therapy to genetic diseases requiring suppression of mutated proteins. From these many years of research sprung our miQURE platform, a proprietary technology designed to safely and effectively deliver one-time 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 needs 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 a 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 diseased 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. Lastly, AMT-130 leverages our AAV5 capsid, which we have shown to be well-tolerated in six different clinical studies in nearly 80 patients.
Additionally, AMT-130 employs a Pol II promoter and a microRNA 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, multi-center, phase I/II trial in the United States to evaluate the safety and tolerability of AMT-130 and explore potential efficacy at two different doses based on the strong recommendation from the FDA. The study is conducted as a double-blinded and randomized trial, including an imitation surgical 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. and EU phase I/II trials for AMT-130. Today, we are pleased to share initial 12-month observations focused on safety data from the first four patients in the low-dose cohort of the U.S. study, two 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 one 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 two 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 two-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 four 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 6 × 10^{12} vector genomes, followed by a 16-patient higher-dose cohort of 6 × 10^{13} vector genomes. The patients are in stage one and early stage two of their disease. This is the earliest symptomatic stage of Huntington's disease. Patients have a total functional capacity score above 10, where a 13 is the maximum score on this scale. The patients have more than 40 CAG repeats and a minimum striatal 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 five 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 five 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 nine 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 four patients, two dosed with a low dose of AMT-130 and two control patients who had sham surgery, have reached the end of the first year of monitoring. These patients had 41-44 CAG repeats, a total baseline Total Functional Capacity score between 10 and 13, and total motor Total Motor Scores between seven and 23. Here are our initial observations from these first four patients. First, the patients recovered well from the one-day surgical procedure and were discharged from the hospital and returned home the day after surgery. No serious adverse events associated with AMT-130 were reported in these patients. Overall, the dosed patients and the control patients are doing well clinically, and there are no clinical indications of toxicity. Second, neurofilament light change, a marker of neuronal injury, was measured in the CSF of these patients at baseline and at three-month intervals.
NfL increased immediately following the surgery and declined back to baseline levels at one 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 in the control patients remained constant throughout the 12 months. Third, both wild-type Huntington and mutant Huntington were measured in the CSF of these four patients. Because of technical issues with the assay 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 control test samples did not pass the quality control criteria.
We're 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 new, clinically meaningful safety findings in either the treated or the control patients one 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 intraparenchymal administration of gene therapies and the placement of electrodes for deep brain stimulation. They do not appear to have clinical consequences and appear to be decreasing over time. We did not see any additional MRI abnormalities.
Lastly, based on the recommendation from the study steering committee and the DSMB, we will be disclosing efficacy data, including volumetric MRI data, when the first two 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 two 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 I-B/II study of AMT-130 will enroll 15 patients with early manifest Huntington's disease across the same two 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 enrollment 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're very pleased with the clinical enrollments in this program and encouraged by the data related to the safety and tolerability of 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 completes a one-year follow-up. We also expect to have efficacy and safety data when both cohorts are unblinded in the first half of 2023. Now back to you, Matt.
Thanks, Ricardo. Operator, please open the line for analyst questions.
Thank you. As a reminder, to ask a question you'll need to press star one on your telephone. To withdraw your question, please press the pound key. We ask that you please limit yourself to one question and to one follow-up only. Stand by as we compile the Q&A roster. Our first question comes from Paul Matteis of Stifel. Your line is open.
Hey, thank you so much for the update and taking the questions. Appreciate it. I wanted to ask a couple 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? I guess bottom line right now, how confident are you that you're potently engaging the target in the deep brain in the cortex? 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? Thanks so much.
Sure. Let me start with the Huntington assay. We can't really say anything about the levels of mutant and wild-type Huntington in CSF because the assay failed the QC at the CRO. We're 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. 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 this issue. We believe it is very solvable, and we will have this information for you soon. Sadly, that's what I can say.
Now, with regards to 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. We're cautiously optimistic that this indicates that the surgery was safe, and that there is no lasting damage.
Thanks. I just want to clarify your first comment, Ricardo. Did you say that you think the Huntington samples are salvageable and that you'll actually have some of that assay data at some point soon? Is that right?
Yeah. No, we didn't use all the samples. The assay itself failed. It's the samples we can reanalyze.
Okay. You might disclose that at some point?
We will disclose it at some point, yes.
Okay. Okay.
Thank you.
Thanks very much.
Thank you. Our next question comes from Joseph Schwartz of SVB Leerink. Your line is open.
Hi. Thanks very much. 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 are u nblinded. Does injecting the gene therapy volume itself inflate baseline volume to a detectable degree? Do you do anything to correct for this potential artifact when analyzing volumetric MRI data?
I can take and answer both questions. The first question is why not disclose all the volumetric MRI data right now? In discussions with our steering committee and with the DSMB, it was felt that volumetric MRI is very closely related to efficacy, and that if we disclose efficacy now, this would impair our ability to conduct this blinded study and to use it for regulatory purposes. We've made the decision to only reveal that data once the two cohorts have been unblinded. If you can imagine that there's this potential for biasing the study if we were to say something about the study working or not working. That's one. The second question is, does injection of the gene therapy itself change the volume of different structures? The answer to that is yes.
If you inject anything really into the brain, initially you see changes in the MRI. We're developing algorithms to compensate for that. We'll talk more about that when we actually disclose the data.
Thank you. Next, we have Robyn Karnauskas of Truist Securities. Your line is open.
Hey, guys. Thank you so much for taking my questions. This is. You know, 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 would be seeing from these 10 patients? HTT CSF lowering. Hopefully you figure it out with the CRO. You're going to not show any volumetric imaging, but NfL, what are the metrics that you think are the most meaningful to focus on?
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? Thank you.
Yeah, I'll take that question. The data release in the middle of next year is gonna be comparable to the release today. It is gonna largely focus on the safety and tolerability of the procedure. That data release will include six treated patients and four sham-controlled patients, right? We got effectively 40% of the data that's been covered here within this particular release today. What I would say is, you know, 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's is a relatively slow progressive 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. To the extent that, you know, 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 five years, and we're also compiling, as best we can, a patient-matched natural history set of data, right? Working closely with CHDI, that can provide another comparison. It obviously depends on the clinical effect side. It depends on the rate of progression of the control. But in the end, you know, we're gonna be following these patients for multiple years.
You know, this study is designed in a way, I think, to really demonstrate efficacy in a fairly robust way given its design.
Great. Thank you so much.
Thank you. Up next, we have Joseph Thome of Cowen and Company. Your line is open.
Hi there. Good morning. Thanks for the update, and thanks for taking our question. I know you mentioned that, you know, kind of having a randomized data could provide a, you know, faster path to registration potentially if this is positive. Can you share any, I guess, interactions with the FDA and what 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 endpoint would be that they would want to look at?
Yeah. I mean, we've had interactions with the agency periodically with respect to, of course, the IND. Then, as we were beginning to enroll patients, there was, you know, 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 blinded study. I think, you know, 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?
There's no promises there, but I do think there's an expectation that they do want to see randomized, blinded, controlled data. We have not discussed, you know, their requirements for a registration study or 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. Our expectation is that, I think, you know, getting approval solely on biomarker data alone, you know, in this particular indication will likely be difficult.
Great. Thank you. One follow-up on the earlier question, if I can. Just on the NfL levels and 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 low dose in the CSF, or no?
Yeah. Based on the preclinical studies in mini pigs, we expected 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 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 about what I can tell you.
Perfect. Thank you very much.
Thank you. Our next question comes from Danielle Brill of Raymond James. Your line is open.
Hi, guys. Good morning. Thanks so much for the questions. I guess, you know, 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? I'm curious what info led you to add a new cohort and adjust the catheter, catheterization procedure. Thank you.
I think that we remain optimistic about our gene therapy. 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. At the moment, we have no evidence for that. But other than that.
Yeah. I mean, Danielle, what I would say is we have a high degree of confidence that this microRNA construct engages the target. I mean, whatever experiment we did, whether it was rats or mice or transgenic pigs, we saw target engagement. If we can get the construct or the drug into an area of the brain, we saw microRNA presence, we saw vector DNA, we saw suppression of messenger RNA, and 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 in the cerebrospinal fluid, given the secretion profile, you know, that might be a different question.
We have a high degree of confidence that we are lowering mutant protein in the brain.
Okay. That's helpful. 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. You know, 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 burr holes and how to incorporate robotic placement of anchors. 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.
Okay. That makes sense. Thank you so much.
Thank you. Next, we have Salveen Richter of Goldman Sachs asking a question. Your line is open.
Hey. Good morning, and thank you for taking our question. 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 one 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? Thank you.
The question was on the high-dose cohort specifically?
Yes. High dose. I mean, also low dose, but I think, you know, more of a focus on the high dose.
Yeah. I mean, it's hard, you know. Look, it'll depend on the clinical effect size, but I would expect that our view is that with two 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, that our hope is that that is sufficient totality of data that we will be able to elucidate efficacy signals. You know, again, it does depend on, you know, if the control patients don't progress, right? It's going to be hard to demonstrate separation. The expectation is with 26 patients of data that will be sufficient.
You know, keep in mind, we'll also have 15 patients of data that will probably begin to start reading out in 2023 as well. I mentioned that, you know, in totality, we've got 59 patients across three different cohorts in the U.S., in the open label study in Europe with the potential of crossover patients. I do think that, you know, this study is gonna produce meaningful data. You know, I have, you know, I think reasonable confidence that in the first half of 2023 we'll be in that position.
Yeah. There, there are two key comparisons that we're focused on. First is the comparison between the treated patients and the placebo controls. 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. Of course, because there are many more there, we have, I think, a better chance of being able to show a difference. That's. I think as Matt said, we have reasonable expectations that we will be able to draw some conclusions that will then give us some indication for how to proceed with the program.
Great. Thank you.
Thank you. Next, we have Patrick Trucchio of H.C. Wainwright. Your line is open.
Thanks. Good morning. 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 this third cohort could contribute to potentially an accelerated approval pathway. Thanks.
Yeah. I think our expectation is that we'll be able to make a dose decision to inform a registrational strategy in the first two 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. 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 engaging in a registrational strategy.
Thank you very much.
Thank you. Up next, we have Sami Corwin of William Blair. The line is open.
Hi, there. Thanks for taking my question. Thanks for the update. 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 it's a higher dose. It'd kinda be nice to see some of those metrics. I have a follow-up question after that.
Yeah. The second cohort will not be unblinded until the first half of 2023. We will not be discussing, you know, any aspects related to the second dose cohort. Now, having said that, our data safety monitoring board is evaluating constantly all data from the study from all patients in an unblinded manner. You know, any statements that they have with respect to safety, you know, we will certainly communicate.
Great. Were there any other markers of inflammation aside from NfL that were being measured? I know that the CHDI Foundation has been working on a Huntington's PET ligand. Have you had any conversations with them about potentially using that to look at localized reduction in Huntington's, or is that kind of in your plan later down the line once it's commercially available?
Yeah. 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. That's one. Things like, you know, YKL-40 and GFAP are being measured. The second part of the question is, would 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. As you know, it's being developed in Belgium, and we're, you know, enthusiastic about incorporating that into some of our trials. It's still a little early, so we're not really ready to disclose when those experiments will be done.
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.
Great. Thanks.
Thank you. Our next question comes from Yanan Zhu of Wells Fargo Securities. Your line is open.
Hi. Thanks for taking my questions. First I'm wondering about the CSF-HTT assay's variability and the QC. Are these two issues related to each other or are they, you know, the high variability and the QC issue independent events?
Well, there are two things at play here. One is just the small number of patients and controls, which probably would make any data variable. Humans are just variable. Superimposed on that, there is the fact that the assay itself didn't work. That, of course, leads to extra variability and, you know, unexpected values where there should be no values and things like that.
I see. Currently you don't have a good sense of, the extent, the true extent of variability. Is that fair to say, about?
Well, I don't know exactly how to answer that. I would say, we certainly know how variable the numbers we got were. We assume that that's a combination of the assay not being great 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. On the NfL, I'm wondering. 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 temporary transient increase that you saw, was that higher than an ASO, given that, you know, it's usually your surgical procedure is more invasive, so I guess it's not unexpected it is higher. Also the kinetics.
[Uh].
Did it come down to the baseline level at 12 months, or had it reached the baseline level earlier, for example, at nine months? Thank you.
Yeah. 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 three months, there was an initial spike, and then there was a gradual decline to baseline over the course of the year. Which effectively suggests that whatever damage was caused during the surgery was reduced.
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.
Very helpful. Thank you.
Thank you. Next, we have Kristen Kluska of Cantor Fitzgerald. Your line is open.
Hi. Good morning. Thank you for taking my questions. 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%-5% of the putamen volume on an annual basis. Just wondering if you think that metric is fair based off of these patient demographics.
We haven't disclosed any data on volumetric MRI. These are early-stage patients and so generally speaking, they progress slowly. Yet the literature does suggest that there's a loss of around 2% of putamen volume over the course of a year.
Okay, thanks. 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? For some of the guidance readouts 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 minipigs, we've, I think, sacrificed animals at two years of follow-up and showed a sustained durable suppression of mutant protein in the striatum and the somatomotor cortex. That we know, and we continue to have transgenic minipigs 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. We do think that this has the potential to be highly durable and sustained clinical efficacy. In particular, because of the very slow turnover of cells inside the brain as well.
Yes. I mean, the fact that neurons don't divide.
Means that the transgene is not going to be as muted. So far we have not seen any silencing of the transgene or any silencing of the promoter. We expect that this will lead to long-term suppression. Of course, in the liver, we have great evidence in humans that there is durability at least up to five years. 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 the vast majority of the population have antibody levels that allows the 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. We also know that following administration of the AAV5, there's a big increase in the antibodies. I think we would report on the data if we felt that it was, you know, informative.
Yeah. Maybe what I would just add to that is, you know, I think from our HOPE-B pivotal study, right, we've demonstrated that, you know, we believe we could have a meaningful clinical benefit in 92%+ of patients, right? What we do know, and 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. I would expect, in extrapolating that, you know, it would be much more than 92%, if not 100%, that we could potentially be therapeutic in Huntington's.
I guess I can add that thus far, anti-AAV5 antibody levels have not been an issue for us at all.
Thank you.
Thank you. Next we have Luca Issi of RBC. Your line is open.
Perfect. Thanks for taking our question. This is Lisa in for Luca. Just wondering, given the DSMB has given the go-ahead in the high-dose cohort and the safety profile so presented today and the first four patients looks benign, will you be able to enroll the third cohort without staggering the DSMB review between surgical procedures? As well, when should we expect any data from the EU trial? Thanks.
I'll take the first part of this question. The new cohort actually has two parts to it. The first part of it will be exploring these robotically placed anchors, and the second half of it will be exploring a new stereotactic path. In that sense, we will stagger patients. We expect that the enrollment will be faster because there isn't a concern about the gene therapy itself. It's really postsurgical concerns that we're worried about. Of course, we will stagger them to some extent as we learn more about the procedures.
Yeah. I think the plan is a shorter stagger, a much shorter stagger.
I think it's actually.
Maybe perhaps a 30-day stagger. I don't think that'll be an issue. In terms of the data from the European open label study, what I would expect is that, in 2023, we would expect to have initial data from that, from the low-dose cohort.
Perfect. Thank you.
Thank you. Our next question comes from Eliana Merle of UBS. Your line is open.
Hey, guys. Thanks so much for taking the question. Just could you elaborate a bit just in terms of how you're thinking about all sort of your confidence in the dose? You know, I guess the target engagement that you're getting. Like if you perhaps needed a higher dose, how you would think about that and if potential paths there.
Yeah. You were going in and out there, but I think you were asking a question about dose. I think, you know, ultimately our expectation would be that in 2023, we'll be able to elucidate, get an understanding about efficacy signals related to both doses. 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.
Thanks.
Thank you. Next we have Yun Zhong of BTIG. Line is open.
Hi, thanks very much for taking the question. On the NfL changes, you saw that from active treated patient but not from a sham treated patient. 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.
Yeah, I can answer both of those questions. No, we think that the increase in NfL was due to the surgical procedure and the fact that it returned to baseline despite the fact that the gene therapy is still there suggests that it is not due to AMT-130.
Yeah. This was, you know, just to be clear, this was evidenced in our transgenic pig model. I believe that even in the control animals that received saline, we saw a spike of NfL immediately after the procedure itself, that peaked at around two to three months, and that's very consistent here. We don't believe that that's related to AMT-130, but instead the actual intervention of the procedure itself.
Did you measure microRNA expression, please?
That is another assay that we're working on. Generally speaking, it's very difficult to measure microRNA in CSF. We're not ready to disclose that data.
Okay. A follow-up question on the third cohort with the new procedure. Do you expect the procedure to affect, for example, the distribution, coverage within the brain? 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 patient that participated in the study?
No. We would basically like to simplify the procedure and make it faster. You know, the initial procedure that was devised to be very safe and to be very conservative. 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, you know, more efficient.
Yeah.
There have been technology improvements since we initially designed the study that I think will also let us do some things better.
Yeah. I mean, these patients are under anesthesia, right? They're under general anesthesia. 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.
Yeah. I mean, if at all possible, for example, we'd like to be able to make the best use of surgical suites, which means that the faster we make it, the better. We'd like to reduce the amount of time that patients are under anesthesia.
Okay, great. Thank you very much.
Thank you. The next question comes from Judah Frommer of Credit Suisse. Your line is open.
Hi. Thanks for taking the question. The first is just a follow-up on one of the NfL comments made earlier. I saw Ricardo said that NfL kind of trended back toward baseline and then continued 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-
Well, yeah. No, we're only disclosing 12 months data. The comment was that if you look this, the NfL peaked at around three months, and it really trended down in every measurement since then, and returned to baseline at 12 months. The measurement between nine and 12 months, it was continuing to decline.
Okay. That's helpful. Then just on kind of the natural history matched control, how should we think about, you know, placebo versus using natural history? Is the agency giving you any guidance on, you know, 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. If we want to make the best possible case, then we will also like to be able to compare it with the natural history, and we don't want just an all-comer natural history. We want a natural history that is really matched to the characteristics of our patients.
Okay. Thank you.
Thank you. Our next question comes from Suji Jeong of Jefferies. Your line is open.
Hi. Good morning, and thanks for the question. I have a question about the third cohort that you are going to add to the ongoing phase I/II study. 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 in the study. I was just wondering if you had extracted data from the two cohort from the earlier study, wouldn't that also bias the results from the third cohort from that study? I have a follow-up question.
Yeah. What I would just say to that, really the primary objective of this third cohort is to evaluate the safety of the procedure. You know, the view is that we'll be able to make a dose decision based on the first two cohorts that will inform our registrational strategy. Technically, will there be perhaps some bias as it relates to efficacy data? There's a risk of that. As I said, the primary objective there, given that we're evaluating the same dose as the high-dose cohort, which is gonna have 16 patients in it, to begin with, is really to evaluate the safety of that modified, more efficient procedure.
Okay. That's fair. Thank you. From this ongoing study, are you measuring plasma NfL levels? My second question is, what is the minimum level of knockdown of Huntington protein that you need to achieve in the striatum in order to see a reduction in CSF?
Yeah. Plasma NfL, we're really focusing on CSF 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 70%, you see approximately a 30% decrease in CSF Huntington. We do also know, of course, that the human brain is much larger, and therefore, that the striatum is a much smaller fraction of the human brain than it is of the pig brain. We're not completely sure what to expect. Nobody has actually done this before.
We are aiming for a 70% knockdown in the striatum and a 50% knockdown in cortex, in our patients. That was calculated based on what it takes to reverse the phenotype in the preclinical models.
That helps. Thank you.
Thank you. 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 enrollments of the higher dose cohort in our U.S. trial, as well as expanding our pool of patients through our open- label EU study and 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 us 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.