Good day, and thank you for standing by. Welcome to uniQure's AMT-130 Huntington's Disease Program Update. All participants are in a listen-only mode. After the speaker's presentation, there will be a question-and-answer session. To ask a question during the session, you will need to press star one on your telephone. Please be advised that today's conference is being recorded. If you require any further assistance, please press star zero. I would now like to hand the conference over to your speaker today, Maria Cantor, Chief Corporate Affairs Officer. Please go ahead.
Good morning, and thank you for joining us. This morning, uniQure announced safety and biomarker data on 10 patients enrolled in a low-dose cohort of the ongoing phase I/II clinical trial of AMT-130 in Huntington's disease. Six of these 10 patients received AMT-130, and four patients experienced a sham surgical procedure in this randomized blinded study being conducted in the United States.
Observations shared today pertain to safety, tolerability, and biomarker data at 12- months following AMT-130 administration. Joining me for this investor event and webcast are Matt Kapusta, our Chief Executive Officer, and Dr. Ricardo Dolmetsch, our President of Research and Development. Please note that we'll be making forward-looking statements during this investor call. All statements other than the statements of historical 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 filed on May 2, 2022, and other securities filings. Given these risks, uncertainties, and other factors, you should not place undue reliance on these forward-looking statements. We assume no obligation to update these statements even if new information becomes available in the future. Now, let me introduce Matt Kapusta, uniQure's CEO.
Thank you, Maria, and good morning, everyone. We're delighted to share with you today encouraging 12-month data from the low dose cohort in our U.S. phase I/II study of AMT-130 for Huntington's disease. This new data builds on the clinical observations shared last year, further underscoring the tolerability of AMT-130 and, for the first time, providing early indications of target engagement. AMT-130 is our first gene therapy candidate leveraging our miQURE platform, a proprietary technology to deliver one-time administered gene silencing constructs to patients.
We're currently applying this innovative approach to numerous other genetic disorders, including temporal lobe epilepsy, ALS, Alzheimer's, and other indications. As many of you know, Huntington's disease is a progressive neurological disorder that represents one of the most devastating and prevalent monogenic diseases.
It is caused by a triplet nucleotide repeat within a single mutated gene called huntingtin that leads to a toxic gain of function. There are an estimated 72,000 diagnosed patients with manifest Huntington's disease in the United States and EU five. In the U.S., more than 200,000 are at risk of inheriting the disease.
The belief that Huntington's disease is untreatable is one of the factors preventing people at risk who may be symptomatic from discussing a possible diagnosis with healthcare practitioners, families, friends, and loved ones. I'd like to revisit the reasons why we believe AMT-130 has the potential to be not only a first, but best-in-class approach for the treatment of Huntington's disease. First, AMT-130 is designed to be administered once with potential for long-term therapeutic effect.
This is facilitated by our AAV constructs, which deliver genetic material capable of long-term expression of proprietary microRNAs, specially designed to suppress the expression of huntingtin protein. Secondly, AMT-130 is administered directly to the areas of the brain that are implicated 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 absolutely crucial as no matter how effective a drug might be, it simply won't be therapeutic if it can't reach the diseased areas of the brain. Yet at the same time, Huntington'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 one 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 more than 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 March of this year, we completed enrollment of two dose-escalating cohorts of 26 patients in a multicenter phase I/II trial to evaluate the safety and tolerability of AMT-130 and explore potential efficacy at two different doses. Based on the recommendation from the FDA, the study is conducted as a double-blinded and randomized trial, including an imitation surgical control. We believe this approach will produce the most robust data and has the potential to provide a faster pathway to registration.
In enrolling the study, we specifically screened for early manifest Huntington's patients with a defined minimum striatal volume. We believe these patients have greater potential to demonstrate a therapeutic effect on meaningful clinical outcome measures. Moreover, because AMT-130 is a one-time administered therapy and we have a requirement to follow patients for five years, we have a unique ability to evaluate long-term clinical outcomes that distinguishes our clinical program from chronically administered approaches where long-term follow-up and compliance are more challenging.
In addition to the U.S. phase I/II study, we are also in the process of enrolling a 15-patient open label European study evaluating the same two doses. Enrollment in the six patient low-dose cohort has been completed, and the first four patients in the high-dose cohort were recently treated with AMT-130. To date, 36 patients have been enrolled across our two phase I/II studies. Let me now turn the call over to Ricardo, who will walk through the details of the encouraging 12-month data set from the 10-patient low-dose cohort of our U.S. phase I/II study.
Thanks, Matt, and good morning, everyone. I'm very pleased to provide an update on the progress we've made in our U.S. phase I/II clinical trial exploring the safety, tolerability, and efficacy of AMT-130 for the treatment of Huntington's disease. Huntington's disease is a devastating neurodegenerative disease caused by the expansion of a triplet of nucleotides, cytosine, adenine, guanine, that encode the amino acid glutamine in the first exon of the Huntington gene.
CAG expansions that are larger than 39 lead to the formation of protein aggregates, neuronal toxicity, and ultimately to neurodegeneration that is the hallmark of Huntington's disease. Neurodegeneration usually starts in the striatum, a deep brain structure that is composed of the globus pallidus and the caudate nucleus. It then spreads to adjacent somatosensory cortex before reaching other cortical regions.
The symptoms of Huntington's disease parallel the neurodegeneration, starting with psychiatric and motor symptoms and progressing to cognitive symptoms. AMT-130 is a recombinant AAV5 that contains a microRNA that suppresses the production of the huntingtin mRNA and protein. MicroRNAs act by recruiting the RNA interference machinery to trigger the degradation of a target mRNA.
The microRNA in AMT-130 binds specifically to exon one of the huntingtin gene, eliminating both the full-length toxic RNA and protein, as well as the exon one containing mRNA transcripts that produce protein fragments that are thought to be particularly toxic. AMT-130 has been optimized to be non-toxic by being highly target specific. Furthermore, it contains our proprietary miQURE microRNA scaffold, which minimizes the production of microRNA passenger strands that can have toxic side effects.
Studies in mice, pigs, and non-human primates have shown that AMT-130 is both safe and effective in preclinical models. Administration of AMT-130 into the striatum of HD transgenic pigs triggers a transient increase in neurofilament light chain in the cerebrospinal fluid and a sustained decrease in the expression of mutant huntingtin in the striatum and cortex. AMT-130 is delivered one time by convection-enhanced stereotactic injection directly into the striatum of patients.
This route of delivery ensures that neurons in the striatum and in the cortex receive enough of the gene therapy to reduce the amount of the toxic protein. The injection is performed using a catheter that is smaller than a cocktail straw, which is introduced through a millimeter-scale burr hole in the skull. The infusion is performed with contrast enhancements using real-time MRI guidance to ensure appropriate targeting.
The surgery occurs over the course of a day, and the patient typically returns home on the next day. We are currently running two simultaneous trials to test the safety and efficacy of AMT-130. HD-GeneTRX-1 is conducted in the U.S. and is a double-blinded, randomized, placebo-controlled trial. HD-GeneTRX-2 is an open-label trial conducted in the European Union and the U.K. We are testing two doses of AMT-130, 6 × 10^12 vector genomes and 6 × 10^13 vector genomes, to determine the dose that is safest, best tolerated, and most efficacious. Today, I will focus on the U.S. trial, which consists of three cohorts, a low-dose cohort of 10 patients, a high-dose cohort of 16 patients, and a surgical adaptive cohort of 18 patients at the high dose.
We are enrolling patients that are at the earliest symptomatic stages of their disease. They are 25-65 years of age, have a Total Functional Capacity of nine to 13, and have early motor, behavioral, cognitive, or other clinical symptoms consistent with a diagnostic classification level of three or four. The patients must also have a minimal striatal volume to participate in the trial so that we can administer the drug safely and so that they have neurons that can be preserved by the drug.
We believe this patient population has the best chance of getting benefit from AMT-130. This also distinguishes our trial from other studies that have enrolled patients that are at a more advanced stage in their disease. Patients are initially screened to ensure that they meet the enrollment criteria. Baseline measurements are collected immediately before the surgery.
The patients are then evaluated at 14 days, at one month, and then at three month intervals for two years and every six months for up to five years. The liquid biomarkers being measured include neurofilament light chain levels in the blood and the cerebrospinal fluid, and mutant huntingtin protein levels in the cerebrospinal fluid. Anatomical measurements include structural and volumetric MRI.
The clinical endpoints include the Total Motor Score, the Total Functional Capacity, the Symbol Digit Modalities Test, the Stroop Word Test, and HD-CAB for behavioral and psychiatric symptoms. Not all the biomarkers and not all the evaluations are done at every visit to reduce the burden on patients and caregivers. Now let's look at the 12-month data from the U.S. low-dose cohort. The demographics and baseline characteristics of the low-dose and control patients in cohort 1 are relatively well-matched.
They are approximately the same age, have a similar range of CAG repeat, and have similar clinical characteristics as determined by their TFC, TMS, and DCL scores. In the data we have seen so far, AMT-130 has been well tolerated. In the low-dose cohort, we observed no adverse drug reactions related to the drug and no serious unexpected suspected adverse reactions. We did observe two serious events unrelated to the drug, a deep vein thrombosis that resolved with anticoagulants and a postoperative delirium that resolved with supportive care.
95 treatment emergent adverse events unrelated to the drug were also observed. The most commonly reported were non-serious procedural pain, procedural headache, post-lumbar puncture syndrome, and other complications like low body temperature, fatigue, and leg spasms. Neurofilament light chain is a measure of neuronal injury.
As expected, neurofilament light chain increased transiently at one month following surgery in the dosed patients and then declined progressively over the course of the year, returning close to baseline. The dosed patients are represented by the solid lines. You will note that most are very close to the baseline at 12 months.
Two of the six treated patients were at or below the baseline at 12 months, and an additional patient was below the baseline at both 15 and 18 months. The sham control patients did not receive any infusion in the brain and therefore did not show a postoperative increase in neurofilament light chain. Their neurofilament light chain levels seem to be stable or slightly declining over the course of the year.
The graph of the average and the standard deviations also suggests that neurofilament light chain in CSF declined quite dramatically in treated patients by month six and has largely returned to baseline by about a year. Mutant huntingtin accumulates in the striatum of patients with early-stage disease and is released into the cerebrospinal fluid from that region.
The exact way in which huntingtin is released and under what circumstances this happens is not clear. The levels of huntingtin in the CSF are extremely low, and we were only able to get reliable baseline and time point measurements from seven of the 10 patients, four dosed and three control patients. Because AMT-130 is infused in the striatum, our initial expectation of seeing an effect on the levels of mutant huntingtin in CSF was low.
We were therefore encouraged by the initial data from the four treated patients, showing decreases in mean CSF mutant huntingtin at every time point and a 54% reduction at 12 months. In contrast, the mean CSF mutant huntingtin in the three control patients declined 17% at 12 months. To get a better sense of the underlying data, we looked at the individual patients.
The treated patients represented on this graph by the solid lines show a consistent decline in mutant huntingtin over the course of the year, reaching a reduction of 54% at 12 months. The declining trend continues in the two patients with data at 15 and 18 months. The data on the control patients is more variable, as you can see from the dashed brown, purple, and green lines.
While the data is variable, as you would expect from a small sample size, we believe it is consistent with the conclusion that AMT-130 engages its target in the striatum, leading to a decrease in mutant huntingtin in CSF. To summarize, the low dose of AMT-130 is well tolerated thus far. We haven't seen any drug-related adverse events. The adverse events that were observed were related to the surgery, not to AMT-130.
NfL levels increased as expected in dosed patients immediately after the surgery but then declined towards baseline. Three of the six patients were at or below baseline in 12 months, suggesting that the inflammation associated with the surgery has resolved. Trends in cerebrospinal fluid mutant huntingtin in the evaluable dosed patients support the potential for target engagement, generally decreasing over time and achieving a reduction of 54% at 12 months compared to baseline.
Levels of CSF mutant huntingtin in the control patients were more variable but generally trended higher than in treated patients. We're very pleased with the progress that we've made in our ongoing clinical development of AMT-130. We have enrolled all 26 patients in the first two cohorts of the U.S. study. In the European trial, we have achieved full enrollment in the low-dose cohort of 6 patients and have now enrolled four of nine patients in the high-dose cohort.
We expect to complete patient enrollment in the European Union by the end of this year and begin enrolling the third cohort in the U.S. study shortly thereafter. We will disclose biomarker and clinical efficacy data in two years of the low-dose cohort and one year of the high-dose cohort in the second quarter of 2023. Thereafter, we will disclose data on the EU patients and the surgical adaptive patients. Now let me turn the call back over to Matt.
Thank you, Ricardo. Operator, please open the line for analyst questions. Thank you.
Thank you. As a reminder, to ask a question, you will need to press star one on your telephone. To withdraw your question, press the pound key. Standby while we compile the Q&A roster. Our first question is from Joseph Schwartz with SVB Securities. Your line is open.
Hi, this is Beth on for Joseph Schwartz. Thank you for taking our question this morning. We were just wondering what you think the range of CSF mutant huntingtin protein lowering implies about the potential range of lowering that's happening in the brain based on the animal studies you guys have completed.
Yeah. Thank you so much for the question. It's as you know, in the pig studies when we suppressed mutant huntingtin by 80% in the striatum, we saw a 30% decrease in CSF. The anatomy of the human brain is really quite different, so it's difficult for us to know exactly how much we're suppressing mutant huntingtin in the striatum of patients. We're generally very encouraged to see something at all. We didn't expect to see anything. Yeah, I can't really tell you those. That relationship isn't really well understood.
Thank you. Our next question from Paul Matteis with Stifel. Your line is open.
Hey, thanks for taking our question. This is Alex on for Paul. Just a couple, if you don't mind. I wonder if you mentioned in the press release that MRI imaging from a safety perspective didn't show any findings, but I wonder if you could comment on whether you saw any differences versus the sham patients and whether you could, you know, comment on whether there's any efficacy signals there. Then second, on the mHTT assay, I wonder if you could comment on the fact that you didn't see signals in three patients and whether you're confident in the sensitivity of the assay. And maybe if you could also comment on why the, you know, the sham population was so much more variable. Thanks.
Yeah. Okay. Let me just start with the MRI question. We have communicated that we will discuss the MRI findings in the middle of next year. I think that's really all I can say about the MRI beyond the fact that our MRI so far suggests that it's safe and well-tolerated. Of course, our DSMB continues to look at the MRI data as a safety signal. When it comes to the mutant huntingtin assay, I think what we've learned is that the levels of mutant huntingtin in CSF are really low, and the assay is working at the very edge of its limits. In these patients, we didn't get a baseline value at all. It was below the limit of resolution.
That, of course, made it difficult to determine whether there was any lowering. Beyond that, in many of the patients we also missed some of the specific time points, again, because it was either below the limit of resolution or the variability in the technical repeats was too large. That meant that it didn't meet the quality criteria for the assay.
Unfortunately, I can't tell you more than that. As I understand it, this is a common problem, not just for us, but for everybody measuring mutant huntingtin. Now, in terms of the variability in the control patients, you know, it's a small number of patients, and I think you might expect some variability. We're on the side of transparency, so you can see the data that we've seen. Generally speaking, it's encouraging, I would say.
Okay, thanks so much.
Thank you. Our next question comes from Eliana Merle with UBS. Your line is open.
Hey, guys. Thanks so much for taking the question. Just one on the next steps after we get the data next year and how you're thinking about the potential pathway from a future trial design perspective from any early feedback from the regulators. I guess, what would a positive scenario look like when we think about volumetric MRI and how should we think about potential sizing of future trial designs?
If we do see a trend on something like volumetric MRI, what's your comfort level that this could be something that would be supportive of a faster pathway with a phase III? I guess, what did we learn in terms of today's data and how you're thinking about what this means for what we'll learn next year?
Okay. Thanks for that. Let me just unpack the question and just answer bits first. First of all, what are some of the scenarios for next year? Of course, the best possible scenario is if the clinical efficacy data looks really good, as well as the safety data and of course if we have target engagement. That would, by itself, you know, allow us to go to regulators and discuss whether, you know, that data set by itself might be enough for registration. That, of course, is the best possible scenario. Another possible scenario might be that we show that there is some clinical improvement, there is target engagement, and there is safety.
I think that would allow us to then proceed to a phase III registration study. We think that a phase III registration study that has a reasonable chance of showing an effect, given what we've seen so far, is on the order of, you know, 150 patients or so. Of course, that really has to be discussed carefully with both the statisticians and the regulators. That's kind of the right order of magnitude. I hope that helps.
Yeah. Thanks.
Our next question comes from Robyn Karnauskas with Truist Securities. Your line is open.
Hi, this is Alex on for Robyn. One question about the CSF NfL. It seems to be some variability, and we see a 35% decrease in the control group. How in line with sort of historical is that from your perspective and with the variability of the dataset, how does that change your confidence on ability to file on potential earlier time points?
Yeah. We look at the NfL and the control patients as being essentially flat. I mean, that small amount of variability or reduction that you see is unlikely to be real. We don't think that the patients are improving on their own, just because they're in the trial. These have, of course, not been dosed. For that reason, we also think that the dose patients are sort of statistically similar to the control patients.
Now from a natural history point of view, we do know that as people progress with their disease, their NfL creeps upward. I think one thing we've learned from our trial, as well as from an analysis of the natural history of patients that look like ours, is that this happens at a pretty slow rate at this stage. An NfL increase doesn't seem to be the most sensitive way of determining whether somebody's progressing.
Okay. Actually, if I could get one more on the mutant HTT from baseline. I know there's a lot of variability in the data, but there seems to be potentially a significant difference between month nine and 12. Are you looking at the data that way, and do you see a big difference between those two time points for the-
In the controls?
Yeah.
I think the way I look at it is as follows: I think the data on the dose patients actually looks relatively consistent with comparatively small error bars given the small number of patients. If you look, of course, at the control data, it's a lot more variable. You saw the individual ones. You know, it's basically that return to a decrease is driven by this one patient. It's a little difficult to know why that is. You know, when you have a small number of patients, one patient has a big effect.
Definitely. Thanks.
Our next question comes from Salveen Richter with Goldman Sachs. Your line is open.
Hey, good morning, and thank you for taking our question. This is Elizabeth on for Salveen. On the high dose data expected in the first half of next year, could you frame expectations around the clinical data and functional outcomes that you expect to measure at one year, and what would be meaningful there? One question on the mutant HTT assays that you discussed earlier, is there ongoing work to optimize that and improve those assays so that the baseline is able to be measured more consistently? Thank you.
Yeah. Okay. Let me start with the mutant huntingtin assays. The mutant huntingtin assays have been developed and qualified by the whole Huntington field. Of course, we continue to work with multiple CROs to try and improve the assays, but I think the assays are what they are. We understand that this kind of failure rate is something that, unfortunately, we have to live with. I still think, however, that we're likely to get valuable data on most of our patients as in fact we have even in these first 10. Now, in terms of what to expect next year, I think the data that we see today is pretty encouraging.
It suggests that at least we're doing the right experiment, which is to say that we can reduce the amount of the mutant protein in CSF, which is a prerequisite for determining whether doing that will slow the progression of the disease. Of course, I don't know exactly what we're going to find from a functional point of view, either in these patients or the next patients.
What I do know, however, is that it's reasonably likely that we will be able to say something about the clinical improvement because I think the patients are in fact declining or at least the control patients. I think we'll have to wait and see exactly what it looks like. I think beyond that, I guess it would all be speculation. Let me just stop there.
Thank you.
Our next question comes from Joseph Thome with Cowen. Your line is open.
Hi there. Good morning, and thank you for taking our questions. Maybe on the first one, I think going into the study based on the preclinical data, you were targeting a 50% reduction in CSF mHTT and going to 25 in the putamen. I guess with the data that you have right now, how is there an updated thought on how much lowering you think would be safe, especially as you've dosed the higher dose cohort? I know you were shooting for kind of a 75% knockdown. You're already seeing high levels here. How are you thinking about safety and kind of titrating that dose? And then I'll follow up.
Yeah. Look, I think that the best answer to the safety question is simply that so far the therapy is very well tolerated and our DSMB, which of course you know, is completely independent from the company, continues to be enthusiastic about us continuing the study. I don't know exactly what is happening in the patients, but I can tell you that the general sense is that this is, you know, well tolerated. I don't know exactly how much we're lowering huntingtin in the striatum, though I do know based on our preclinical experiments that there is a limit to how much we can reduce the expression of huntingtin even at the high dose.
I think what we found in preclinical studies actually is that the high dose doesn't result in more decrease. What it does is it results in covering more brain real estate. It allows us to both reduce huntingtin in the striatum, but it also gets more coverage of the cortex. I think that's what we'll see, and that is probably what's happening in the higher dose patients. Of course, we'll have to wait to see until we have the data.
All right. Maybe just one on the surgeries themselves. I guess, have you been pleased with kind of the reproducibility of the surgical procedures? Maybe I know you're doing that surgical adaptive cohort. What's sort of the goal there? Do you think you'll be able to reduce some of the initial NfL spikes that you're seeing? Or is this just to make it easier for physicians to administer the drug? That would be helpful. Thanks.
Oh, by the way, I should mention, just in case, people are wondering, of course, we have already dosed quite a large number of patients with a high dose, and we have already evaluated them. We know thus far that appears to be well tolerated. Now, as for the surgical adaptive cohort, what is the idea? What we like to do is we just want to make the surgery more convenient and a little faster because we know that, if we want this to be adopted by the community, we need to have surgeries that are just a little bit shorter. At the moment, the surgery takes most of the day.
To do this, we're experimenting with other ways of putting on stereotactic frames and other ways of introducing the catheters, not because the approach we're using now has any problem. In fact, it's amazingly consistent because as you've seen, we can actually monitor in real time how we fill the specific structures.
That has been, it's actually kind of remarkable. We will continue to do that, but we just like to do it faster. We know that that's gonna be important if we're gonna dose thousands of patients, and we know it's gonna be important for our phase III. That's basically what we're trying to do in the surgical adaptive cohort. It doesn't have anything to do with efficacy or safety. It's more about convenience.
Perfect. Thank you very much.
Our question comes from Danielle Brill with Raymond James. Your line is open.
Hi, guys. This is [inaudible] on for Danielle Brill. Thanks for taking our question, and congrats on the update. So I got another question on the QC for the mutant huntingtin assay. I know in the initial N=4 patients, we were talking about potentially rerunning some of those samples. Were any of those samples successfully rerun? And following up, you know, how confident are you that we're going to have accurate, you know, validated baseline CSF samples for the high-dose cohort? Have you already analyzed that data? Do you have that in hand?
No, we of course don't have a year's worth of data on the high-dose cohort yet because we only finished dosing them relatively recently. You know, now when it comes to the baseline, I can't tell you because I'm blinded to that data as well. I don't actually know how successful we've been in the baseline. One thing I can tell you is this. We did reanalyze all the samples we had from the first four patients where we had trouble with the assay. And some of those actually worked and others didn't work. As I said, our general sense, and now we've done this at two different CROs, is that the assay is really variable.
I mean, it's an assay that depends on the binding of two antibodies next to each other, and we're using the most sensitive technology that's out there. This is the most validated approach to single molecule counting. The fact remains that some fraction of the time, the levels of mutant huntingtin in the CSF are just really, really low. In order to get really reliable data, you need enough of it again, and it has to be really reproducible across the technical repeats, and that just doesn't always happen. As I said before, I am pretty confident that we will have enough data to be able to make a decision, even if one or two of the patients actually fail.
Great. Thanks so much. If I could squeeze one more in. If you just say only, most of the patients in the high-dose cohort have been dosed, how many patients have been dosed in the high-dose cohort?
No, it-
The entire high-dose cohort has been enrolled, and of the 16 patients, 10 have been treated, and there's six control patients.
Right.
Got it.
I think what I meant is evaluated. We haven't finished evaluating the high-dose cohort yet, of course, I mean, we haven't had the data for a year.
Got it. Thanks for the clarification.
Our next question comes from Kristen Kluska with Cantor Fitzgerald. Your line is open.
Hi. Good morning, everybody. Thanks for taking the questions. I know this is still a small patient number, but it seems that one of the control patients was an outlier that seemed to skew a lot of the mean levels reported across these measurements. On an individual patient basis, are you looking at or considering any different trends that have been observed?
Yeah, I mean, even what I would say, Kristen, is that even if you look at the ranges, there does seem to be. I mean, the data, of course, is variable, but if you look even at the ranges of the treated patients compared to the ranges of the control patients, there does appear to be differentiation, even irrespective of that one patient where there was more variability.
Of course, it's hard to determine, you know, if there was really one measurement at 12- months where that patient came down and through the nine months of follow-up, that patient experienced elevated mutant huntingtin. We'll have to follow this patient up longer to get a better sense of what's going on. Of course, as we collect more data on more patients, I think some of this will come into greater focus.
Thank you.
Our next comes from Yanan Zhu with Wells Fargo Securities. Your line is open.
Hi. Thanks for taking my question. Just wondering about the kinetics of HTT reduction in the treated patients. Seems like the level at month nine further declined after month nine. Is there any rationale for that? You know, what would your expectation be for the kinetics of the HTT reduction? Thanks.
Yeah, that's an excellent question. We know that it takes a while for the AAV episomes to actually form and for the amount of microRNA to stabilize, and that, based on our previous studies, takes several months. In addition to this, you're right, we're seeing you know, like, just further declines. Without much data, we think that that's basically because what you're doing is you're changing the equilibrium, so you're producing less mutant huntingtin, and therefore you're allowing the neurons and the astrocytes and the microglia to remove the mutant huntingtin that is there, that has accumulated.
What you're seeing really is less and less of it being released because there is more and more of it that is being reduced by the existing clearance machinery. Even though the microRNA works much. It's likely to work much faster than this, the rate of decline of the protein in CSF has slower kinetics because it reflects the rate of clearance from the brain, and these aggregates clear relatively slowly.
Got it. If I can squeeze a quick follow-up, that is, with the alternative administration route, would you expect any different difference in the impact to the either the level of reduction or the kinetics of the reduction? Thanks.
No. We're aiming to fill the exact same structures in the exact same way. We just want to do it faster and more conveniently.
Great. Thanks.
Our next question comes from Luca Issi with RBC Capital Markets. Your line is open.
Well, great. Thanks so much for taking my question. Maybe two quick ones. Maybe one high level, Matt. You know, how are you thinking about the strategic value of the asset now that you have clinical proof of concept? Would this be a good time to partner the asset? Do you want to wait for the MRI data or maybe the funding of data? Do you wanna keep this in-house even longer? Like, any thought there would be much appreciated. Maybe, Ricardo, on the control arm, what is the increase in huntingtin at 12- months that you would have expected based on natural history?
Sure. I'm happy to answer the first question. I mean, look, in the end, we're very encouraged by the data. I think when we looked at this small number of patients, particularly given the animal data, I think this is up there with, you know, what we consider, you know, reasonably, favorable scenarios. Having said that, we really are interested in seeing more data from this program.
As we mentioned, we've got, 36 patients that have been enrolled, and more patients that will be enrolled as part of completing the European study and the surgical adaptive cohort. You know, this is a program, and an unmet need that, right now we're excited this is a proprietary program, and we currently have no plans on considering a partnership. The second question.
Yep.
Oh, yeah. Sorry.
That natural history.
What would we expect on the mutant huntingtin based on the natural history? Generally speaking, the levels of mutant huntingtin increase slightly over the course of the disease. However, there is a bit of a caveat when it comes to natural history, specifically when it comes to mutant huntingtin, which is simply that we're enrolling a population of patients that is at a very early stage of the disease and has a lot of preserved striatum.
We were able to create a natural history cohort based on sort of a much larger natural history data set that was collected by CHDI. We have information about the clinical progression of these patients, but we don't have information about the amount of mutant huntingtin in the CSF of these patients. I can't tell you exactly from a completely matched patient pool, so to speak. I don't have the exact answer. What I can tell you, though, is generally, you do expect mutant huntingtin to increase as in fact it appears to be doing in our sham patients. You don't expect it to decline on its own.
Got it. Super helpful. Maybe a super quick one. Were you surprised not to see a spike in NfL in the control arm, given that the procedure is obviously fairly invasive here? Or how should we think about that part?
No, not at all. It turns out that the mutant patients aren't actually getting brain surgery. We're not introducing a catheter into the brain. We're not breaking the blood-brain barrier. We're not doing anything like that. They're getting anesthesia, and they're getting a little burr hole so that they can, you know, so that they won't know whether they got it or not, but they are not. We're not going into the brain, so we do not expect an NfL spike.
Thanks so much.
Our next question comes from Sami Corwin with William Blair. Your line is open.
Hi there. Thanks for taking my question. Could you remind us if you were also measuring wild type huntingtin, and if you saw any reductions in that wild type huntingtin? Just based on the results today, do you expect to see any functional benefit with the low dose now?
There is no assay for just wild type huntingtin, but there is an assay for total huntingtin that is the mix of wild type and mutant. We did in fact do that. The results of that are generally consistent with what we've shown you. It's much more variable because the assay is about 2x less sensitive than the mutant assay, and so you just lose more points. Yes, we did that. Yeah, that's about what I can tell you. The first question.
Functional data for low.
Yeah, I'm sorry. Yes. What do we expect to see a functional effect in the low dose? I mean, I think we're generally encouraged. We are seeing what appears to be target engagement at the low dose, and so I guess I'm cautiously optimistic that that means that we're doing something good. I hope that we will see functional effect now.
Great. Thanks.
Our next question comes from Patrick Trucchio with H.C. Wainwright. Your line is open.
Good morning, team. This is Jason on for Patrick. Our first question is just to kind of understand the decline or how significant is this 53.8% decline for the CSF mHTT. Kind of, can you also kind of provide some color on the patient-by-patient rates of decline? Is this kind of driven by a super responder or is it just from a few responders or like they're relatively even in terms of decline in mutant HTT? Thank you.
Yeah. We're very encouraged by this. This is kind of at the upper level of where we thought we might see an effect in mutant huntingtin in CSF. I think this provides at least the first evidence that we are engaging the target. In that sense, I think it's very significant, at least for us, because it means that the drug is doing something in the brain and is doing what we expect it to do, and we can now do the right experiment. That's-- Now in terms of whether it's driven by any super responder. No, actually in the patients it's remarkably uniform. All the patients have a decrease. The error bars are actually pretty small in the patients. The noise comes in the placebos where there is just a lot of variability.
Yeah. Just to be clear, the range. We did present the data in the slides, which will be on the website. The range in treated patients of decline was 44%-71% decrease.
Thank you. Our next question comes from Judah Frommer with Credit Suisse. Your line is open.
Yeah. Thanks for taking the question. Just to follow up on an earlier question, is there a concern and has there been in the preclinical data that you may be depressing huntingtin production too much? I guess based on what you're seeing in the low dose, is there any concern that the high dose may be depressing huntingtin further than you'd like to? Then second, can you just remind us from a biomarker perspective, how are you thinking about mutant huntingtin versus NfL versus a volumetric MRI and support of a potentially accelerated approval path there?
Yeah. Okay. Let me take your second question first. I think we think that in order to get approval, we need to show some clinical benefit, even accelerated approval. I think it'll of course be important to show that you're also reducing mutant huntingtin. It'll also be important, of course, critical to show that it's safe. That's kind of how we see it.
You know, a volumetric MRI data would be supportive as well. Really, I think the key thing that regulators care about, the patients care about, the physicians care about, and that we care about is whether it actually makes people's lives better. That has to be what we focus on, and that is, in fact, why we have so many clinical endpoints in our studies. That's the first question.
The first question was concern about the magnitude of lowering.
Oh, yes. The next question is, are we worried about the high-dose cohort? I think the answer so far is no. I mean, we have now enrolled all the patients in the high-dose cohort some time ago. It seems to be safe and relatively well-tolerated. We don't think that we reduce huntingtin too much. That certainly was not the case in any of the preclinical studies. It doesn't seem to be the case here.
As I said before, our general observation is that when we increase the dose, it doesn't actually reduce the amount of lowering that you get in the striatum. What it does is it reduces the number of cells that take up the virus. The virus spreads further and therefore you suppress huntingtin in more cells, but you don't actually suppress huntingtin more. There seems to be a kind of threshold effect for microRNAs, at least ours.
Okay. A really quick follow-up just on the functional data. Any sense from the natural history or your general expectation on when you can demonstrate that functional benefit in this patient population?
Yeah. You know, I think that, of course, with time, we will have a better chance of seeing some separation between the patients and the controls. Our natural history data does suggest that over the course of one to two years, people get significantly worse, at least on their motor scores. This is largely because, of course, the part of the brain that is degenerating most quickly is the striatum, and the thing that you can measure the most efficiently is motor function. Without knowing what the data looks like, you know, I would say that we are focused on whether we can see an effect on motor function.
Great.
We think there's a reasonable chance that we will be able to see it in the course of this study over the next, you know, year or two.
Great. Thanks again.
Thank you. As a reminder to ask a question at the time, please press star then one. Our next question comes from Yun Zhong with BTIG. Your line is open.
Hi. Thank you very much for taking the question. Based on today's data and also, data from other studies in neurodegenerative diseases, do you still think neurofilament light chain could still be a good biomarker for clinical intervention? Also, what if the two-year data from the low-dose cohort still is flat and, if you know, the volumetric MRI data and based on literature, there seems to be already a 70% reduction in the striatum volume when patients are diagnosed. If there's no meaningful separation in the volumetric MRI either, what do you think the possibility of eventually being able to see any improvement in clinical endpoints?
Well keep in mind that we specifically screened in patients that at baseline had minimum striatal volume. We do know that at the time they entered this study and received AMT-130, they do have viable striatal cells that can be transduced and potentially preserved. But you're right. I think that in the end, you know, when you start looking at two-year follow-up data, the biomarkers become supportive, and what becomes more important is really looking at the functional data. We believe, given the fact that these are early manifestations with preserved striatal volume, that there is a great potential to have a therapeutic effect.
Yeah. NfL as a marker for the progression of individual patient is not great. It is clear that NfL does increase over the course of the disease. At this stage of the disease, it does so very slowly, and at an individual patient level, it doesn't seem to be that informative. I would say, we tend to treat NfL more as a marker of resolved inflammation after the surgery than we do as a marker for disease progression. I'm more enthusiastic about other ways of doing that.
Okay. Did you say that you will have functional data when you report the unblinded data in 2023?
Yes. We will definitely have functional data.
Okay, great. Thank you.
Our next question comes from [inaudible] with Mizuho. Your line is open.
Hey, guys. Thanks for taking my questions. I have a couple. I guess the first question I was hoping you guys can help me clarify. So the three patients that did not have measurable mHTT, is that a function of the assay, or is it just, you know, it could be because they just didn't have I guess the biomarker and maybe they they're not Huntington's patients or they haven't I guess progressed to that kind of level.
Secondly, could you also you know if you take out the in the control arm if you take out the one patient that was very variable does that reduces the level of increase significantly? I'm just asking largely because I think in the Roche study, I don't know, also how similar the patients are and what the assays used are the same. In the Roche studies, pretty much the control arm were relatively flat, so in terms of changes in mHTT. Just wanted to see your thoughts on that. Thanks.
Let's just start with the assay. We really do think. First of all the patients, of course, have Huntington's disease. They have been diagnosed genetically, so we know that they have greater than 40 CAGs. As sadly in Huntington's, genetics is destiny. Once you have a certain number of repeats, you will get the disease. All of them, of course, have symptoms. We're quite certain that they have Huntington's. Now, the question is why did the assay fail? We really think it's assay failure, not actually any issue with the patients. We have been doing a lot of work to try and make sure that we have as few failed assays as possible.
In the end, it seems as if we're operating at the, you know, low end of the assay, and therefore some fraction of the time we will not be able to get data. Of course, without baseline data, it's very difficult to interpret things. When it comes to what we see, I think we're relatively confident that we're seeing a decrease in the dosed patients.
You saw the data, so you've seen that there's a lot of variability in the control patients. We don't really understand why that's the case. You can do the experiments removing any single patient from that set, and it would change the average. I don't know how you would do this. We have shown you the data we have, and as we accumulate more patients, we'll have more reliable data both on the controls and on the dosed patients.
Okay. Thanks.
Thank you. I'm currently showing no further questions at this time. I'd like to turn the call back over to Matt Kapusta for closing remarks.
Thank you, operator. We are very pleased with the progress we are making across our clinical programs to investigate this potentially groundbreaking gene therapy for the treatment of Huntington's disease. To summarize our findings thus far, AMT-130 continues to be generally well tolerated for up to one year in the six treated patients from the low-dose cohort. Thus far, there have been no significant adverse events associated with AMT-130, and mean NfL levels are near baseline at 12- months. We are also encouraged by the lowering of mutant huntingtin protein observed in the treated patients. While this is a small number of patients, we believe these trends are early indications of target engagement.
As we look forward, we expect to complete enrollment of our 15-patient open label European study by the end of this year and to initiate thereafter a third U.S. cohort to evaluate a more streamlined surgical procedure. We expect to have one to two years of safety and efficacy data, including clinical outcomes on all 26 patients in the U.S. study in the second quarter of 2023.
I'd like to thank the HD-GeneTRX program team, our trial sites and study investigators who have worked tirelessly over the past year to drive this program forward. Most of all, I wanted to sincerely thank our study participants and their families who motivate and inspire us each and every day. Thanks for attending the call. We look forward to providing further updates on this very important study.
This concludes today's conference call. Thank you for participating. You may now disconnect.