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

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

Good morning, and thank you for joining us. This morning, uniQure announced updated interim data on AMT-130 in patients with Huntington's disease from our ongoing Phase I/II clinical trials in the United States and Europe. This update includes data on safety and tolerability, exploratory efficacy, biomarkers and volumetric imaging, including up to 30 months of follow-up on patients treated with AMT-130 in a low-dose cohort and up to 24 months of follow-up [ patients ] treated with AMT-130 in a high-dose cohort. Joining me for this investor event and webcast are Matt Kapusta, our Chief Executive Officer; Dr. Walid Abi-Saab, our Chief Medical Officer; and Dr. Ed Wild Professor of Neurology at University College London, Queen Square Institute of Neurology, a consultant neurologist at National Hospital for Neurology and Neurosurgery and Associate Director of UCL Huntington's Disease Center. The slides that will be included in this morning's webcast will be available on the Investor page of uniQure's website shortly after the conclusion of this event. Please note that we'll be making forward-looking statements during this call. All statements other than 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 on Form 10-Q filed on November 7, 2023, and the other securities filings. Given these risks, you should not place undue reliance on these forward-looking statements, and we assume no obligation to update these statements even if new information becomes available in the future. Now let me introduce Matt Kapusta, uniQure's CEO.

Thanks, Maria, and good morning, everyone. I'd like to start by briefly discussing Huntington's disease, a truly devastating genetic disorder that has afflicted an estimated 80,000 individuals in North America and Europe with tens of thousands more at risk of developing this inheritable disease. These figures underscore the global magnitude of Huntington's as 1 of the most prevalent monogenic diseases. Huntington's typically manifests during the prime years of individuals' lives. A period typically dedicated to family, raising children and advancing careers. The symptoms are debilitating. Impairing one's ability to move, think and behave normally, essential aspects of our identity. As functional capabilities gradually decline, lives are stripped of what's most cherished leading to heartbreaking consequences. While the genetic cause of Huntington's has been known for decades, there is still no available disease-modifying therapies. At uniQure, we have been tirelessly working to instill much needed hope within the Huntington's community. And today, we are delighted to share more encouraging interim data from our ongoing Phase I/II clinical trials of AMT-130, which includes up to 2.5 years of follow-up on 29 treated patients. The key takeaways from the interim analysis are as follows: first, patients receiving a onetime treatment of AMT-130 continue to show evidence of preserved neurological function with potential dose-dependent clinical benefits compared to an inclusion criteria natural history cohort. Second, treated patients continue to show favorable trends in neurofilament light chain across both dose cohorts. Specifically, the mean NfL for patients in the low-dose cohort remains below baseline at 30 months and has further declined in the high-dose cohort nearing baseline to 18 months. Third, changes in volumetric imaging and mutant Huntington protein were inconclusive and appeared not to be clinically meaningful. Most notably, we believe these data are confounded by the direct surgical administration of AMT-130 deep within the brain. And lastly, but importantly, the surgical administration of AMT-130 continues to be generally well tolerated at both doses with a manageable safety profile. In summary, we believe these promising interim data support ongoing clinical development of AMT-130 and we're very much looking forward to engaging with regulators next year to discuss our path forward. We also expect next year to complete dosing of a third cohort to further evaluate the impact of immunosuppression on the near-term safety profile. Dosing of this third cohort was initiated earlier this quarter. Now let me turn the call over to Dr. Abi-Saab, uniQure's Chief Medical Officer, who will go through the data presentation.

Thank you, Matt. Good morning, good afternoon, everyone. I'm very pleased to provide this interim update on our ongoing Phase I/II studies of AMT-130. First, let me start by profoundly thanking the patients, their family and caregivers, and the larger Huntington's disease community for their selfless dedication and helping to develop a potentially disease-modifying treatment for this devastating disease. Huntington's disease is an autosomal dominant disease, which typically manifests between the ages of 30 and 50. Over a period of 10 to 15 years, it progresses steadily for a pre-manifest stage to an advanced stage characterized by motor, psychiatric and cognitive symptoms. The patients in our studies are at the early stage of the disease, experiencing some symptoms of characteristic patient. This is referred to as early manifest disease. Huntington's disease is caused by an expansion of the CAG trinucleotide repeat in the Huntington gene. The expanded repeat also appears in Huntington's messenger RNA and results in toxicity of the mutant Huntington protein leading to the degeneration of neurons. The striatum, A region of the brain that controls movement as well as reward and motivation is affected by the early stages of the disease, which then generally spreads to the rest of the brain, as depicted on the slide. AMT-130 is an investigational onetime delivered AAV5 gene therapy designed to silence apparent mRNA and resulting mutant Huntington protein. By reducing levels of mutated protein, AMT-130 has the potential to stabilize the disease and hold for the progression. AMT-130 includes a microRNA that target exon 1 of the Huntington gene. It reduces both the full h the full-length Huntington protein and the toxic exon 1 slice isoform. AMT-130 is introduced directly into the striatum of patients so that it reaches the intended target cells implicated in the disease. It is delivered via 6 injections through a stereotactically placed cannula using convection enhancement. The direct delivery of AMT-130 is monitored using real-time MRI and gadolinium contrast agent to ensure [indiscernible]. We are conducting 2 clinical studies of AMT-130, 1 in the U.S. and 1 in Europe. The studies consist of an initial screening visit followed by surgery. Patients are followed for a total of 5 years with visits at regular intervals as shown on the slide. During each visit, we collect cerebrospinal fluid or CSF, by lumbar puncture to measure neurofilament light chain, a biomarker for neuronal injury and disease progression and to measure mutant Huntington levels. We perform MRIs for safety and to measure whole brain volumes. Most importantly, in each visit, we perform a series of clinical assessments, including the total function capacity, which measures the ability of patients to perform activities of daily life, the total motor score, which measures motor symptoms and 2 cognitive tests, the Stroop Word Test and the Symbol Digit Modality Test. These 4 measures are combined to calculate the composite unified Huntington's disease rating scale or cUHDRS, which was designed to detect disease progression with a high degree of sensitivity, particularly in the early stages of the disease. It is increasingly being used in clinical research and its ability to detect progression has been demonstrated in a few recent trials. The U.S. study of AMT-130 known as HD-GeneTRX1 included a double-blind, randomized and [ sham ] control sequential design, whereby in cohort 1, 6 patients received a low dose of 6e to the 12 vector genomes and 4 patients underwent a sham surgery that included anesthesia and a surface incision only with no administration of AMT-130. After Cohort 1 was fully enrolled, Cohort 2 then included 10 patients who received a high dose of 6e to the 13 vector genomes while 6 patients received a sham surgery. After 1 year, the sham for controlled patients were eligible to cross over to the achievement on. 4 patients have crossed over to receive AMT-130 for a total of 20 patients dosed in the U.S. study. We're also conducting HD Gene TRX2, a European study that is an open-label study. The first Cohort enrolled 6 patients were received a low dose, followed by a cohort of 7 patients who received the high dose. We recently also initiated dosing of a third cohort of up to 12 patients to further explore the effects of perioperative immunosuppression. Today, I'll present the combined internal safety and efficacy results from Cohorts 1 and 2 of the U.S. and the European studies, with the data cutoff of September 30, 2023. The 4 crossover patients mentioned earlier are included in the safety data, but not the efficacy analysis of this updated interim analysis. Development of disease-modifying therapies and Huntington's disease require selection of patients early in their disease force in order to increase the likelihood of therapeutic effect and preserve as much function as possible. Due to the slow progressing nature of the disease, in order to demonstrate a potential therapeutic effect, it is necessary to observe patients for several years. This mix, including placebo or sham control is very challenging and potentially unethical as untreated control patients would likely progress beyond the point of being eligible to receive active therapy at the end of the control period. As such, using an external control derived for natural history studies would be very useful in serious and rare diseases, such as Huntington's disease. In our study, the control arm extends only 1 year. Given that we're following treated patients for 5 years, we have partnered with CHDI, to cure Huntington disease [indiscernible] to use their TRACK-HD natural history study to create 2 natural history cohorts that serve as longer-term comparisons for our streams. One data set shown here in gray consist of 105 patients that meet the per protocol clinical inclusion criteria for our study. Because our patients were also selected on the basis of striatal volume, we narrow the sample to the 31 patients that met both a clinical and striatal volume inclusion criteria. You will notice that the clinical progression of the second group shown in the orange bars is slower than the first group. Since it is a closer match to our population, we will be using big data from this smaller sample in subsequent slides as a reference to help us better evaluate and interpret our results. Overall, the patients in the study were generally balanced across the treatment groups in terms of age, sex, time from diagnosis, CAG repeats and disease stage. They had an average TFC of 12 out of 13, which means that they were reasonably functional and relatively early in their disease. AMT-130 was generally well tolerated, particularly when considering the intra-parenteral administration and the complex surgery involved. The surgical, procedural and drug-related adverse events were manageable. In particular, CNS inflammation seen in several SAEs improved with glucocorticoid medications. As a result, the short course of perioperative steroid prophylaxis has been added to the treatment regimen for Cohort 3. In addition, investigators may use steroids for longer periods and potentially other immunosuppressive therapy at their discretion after discussion with UniQure's medical team. There were no clinically relevant differences between treatment groups and vital signs, ECG or clinical chemistry and hematology laboratory [ values ]. Here we report the safety on all patients in our studies. Note that 4 of the 10 sham patients crossed over and their safety results are included both in the sham group for their first year of follow-up and in the respective treatment arm once they receive active treatment. The procedure-related adverse events appear to be similar across all 3 groups. There were no drug-related or treatment emergent serious adverse events or SAEs in the control or low-dose group. In the high-dose group, there were a total of 6 treatment emergent adverse events, 4 of which were serious and related to CNS inflammation. Moving on to efficacy. Here, we show the data on the cUHDRS, a composite clinical measurement that combines the [ TFC ], the Total Motor Score and the throughput test and the Symbol Digit Modality Test. It is the most sensitive measure of disease progression because it measures multiple functional endpoints. The number of patients' data at the various endpoints can be found in the table below the chart and are included in subsequent slides. The cUHDRS was generally preserved in both cohorts of treated patients. Both doses showed a favorable difference when compared to the nonconcurrent criteria match natural cohort depicted in the orange dash line. The high dose, depicted in blue appears to show standardization of systems at month 18 compared to baseline. While the mean cUHDRS for the low dose cohort dropped between month 24 and 30, which remains above the natural history. It's important to point out that this decline in cUHDRS was mostly driven by a drop in 1 of the cognitive measures and was not observed in the Total Motor Score and Total Functional Capacity, which have been generally preserved. We will show this further on the following slides. Overall, we believe that these data are very encouraging, as they appear to indicate a stabilization of symptoms after treatment, which is our therapeutic objective with AMT-130. I'm further encouraged as we are starting to see early evidence of a potential dose dependence suggesting biological activity of AMT-130. The Total Functional Capacity is a measure of the ability of patients to carry out activities of daily living, such as doing their finances and caring for themselves. This is an important endpoint, which like the cUHDRS might be considered as a regulatory endpoint in HD. In this measure, patients treated both -- with both the low and high doses had largely preserved function over the course of the study, particularly after the first 12 months. When contrasted with the natural history cohort, these effects become all the more evident the longer patients are followed. The Total Motor Score is a measure of motor dysfunction in HD. Higher numbers on this score correspond to worse impairment. Both doses show preserved function compared to their baseline starting the second year after treatment for the low dose, and consistently throughout for the high dose. When compared to the natural history, both doses show favorable differences. These 2 word test measures cognitive capacity and particularly the ability to disentangle 2 conflicting stimuli. In this test, the treated patients across both doses have largely preserved function relative to baseline. For the low dose, there was a decline between months 24 and 30, the significance of which is unclear. However, this reduction in the 2 score contributed to most of the previously noted decline in the cUHDRS for the low-dose cohort in month 3. It is important to note that there is significant intravariability -- intrapatient variability observed in the 2 cohort scores, particularly in visits at month 24 and 30. The Symbol Digit Modality Test is a test in which patients are asked to use a key to decode a message of those of symbols. It measures processing speed and cognitive capacity. In this test, patients on the high dose showed favorable trends starting from 12 compared to both the baseline and the history. Patients at the low dose appear to be consistently at or below the natural history line. The differences we observed between the high- and low-dose patients are more accentuated in the cognitive measures such as SDMT and the Stroop test. One possible explanation is that the high dose is achieving greater h immunosuppression in the cortical regions of the brain, which are critical for these cognitive tests. This is consistent with our preclinical studies where higher doses of AMT-130 had greater activity in the cortex. We will continue to follow these trends as longer-term clinical data become available. In summary, we are very encouraged by these interim clinical results. There is continued confirmation of a strong potential positive clinical effect as evidenced by stabilization of symptoms when compared to baseline and potentially a favorable difference when compared to the natural history. Furthermore, there are early signs suggestive of a dose dependence in the observed clinical effects. Patients treated with the low dose have generally preserved motor function and functional capacity at 30 months relative to baseline and relative to the natural history. Patients treated with the high dose preserved diverse functions relative to baseline and are trending favorably to the natural history across all 4 functional measures at 18 months. In the next few slides, I will go over the biomarker and volumetric imaging data. To better understand the expected changes in CSF NfL over time, we work with Professor Ed Wild, who is with us on this call. We have conducted a study called HD-CSF whereby he measures NfL CSF levels at baseline and then again at 24 months in 71 patients. We use clinical volumetric criteria to match 19 subjects from that study with our studies. As you can see on the chart, depicted in the value in orange at month 24 and also labeled, these patients showed a 26% increase in CSF NfL levels from baseline, which is consistent with expected increase of regeneration as the disease progresses. As we have previously described, in our studies, we observed a decrease in CSF NfL immediately after surgery. This increase is not dose dependent and is in line with what has been observed in patients undergoing other brain surgeries like the implantation of deep brain stimulation electrodes. In the dose patients, neurofilament light chain starts to decline soon after the surgery and continues declining in a consistent manner over time, returning to baseline at month 12 for the low dose and generally staying below baseline at most endpoints thereafter. For the high dose, CSF NfL levels steadily declined in our now near baseline study among 15. In this update, we continue to see an encouraging decline from the 1-year data we reported last June. And as evidenced by the size of the error bars at month 12 at the high dose group, these results are largely influenced by 1 patient experienced a serious adverse invent of CNS inflammation and whose CSF NFL levels were approximately two to threefold higher relative to baseline until their last measurement at month 18. On the next slide, we show the CSF NfL results when we exclude this patient. As you can see, the error bars become tighter in the high-dose group, excluding the outlier patient and dropped below baseline at month 18. The values at month 24 are not affected as the station has not yet reached this follow-up milestone. Note that at month 24, there are only 2 subjects, so these results should be viewed with caution. In totality, the trend in NfL with both doses in the context of expected increases in untreated patients are consistent with the observed clinical and functional data suggesting preservation of function and disease stabilization. This is what we were hoping to see in this interim analysis. Mean change on baseline of MACT and CSF levels over time are shown here. And trends are generally consistent with what we presented in the June interim update of the U.S. study. While these data are being presented in the interest of transparency, neither we nor our expert advisers believe CSF MACT is materially representative of MACT pharmacodynamics in the brain AMT-130 [indiscernible]. AMT-130 is surgically infused directly into the [indiscernible], which represents only 2% of the brain total volume. Moreover, MACT from the brain typically leads into the CSF from cells lining the ventricles, which are not directly transduced by AMT-130. These limitations are distinctly different from other experimental therapies that are either administered orally with systemic bioavailability or infused intrathecally into the CSF where MACT measurements are taken. These measurement challenges are also exacerbated by very small quantities of MACT protein normally present in CSF. In our study, many baseline MACT measurements were near or below the assays lower limit of complification, which is approximately 25% lower. In these cases, decreases from baseline are difficult to measure and very small increases disproportionately inflate the percentage change from baseline. To reduce the variability in MACT measurements, samples were batched and analyzed only when a full year of samples were available for a given patient. As a result, going forward, MACT data will only be presented on an annual basis. Here, we show the total brain volume over time as measured by MRI. We observe that both doses appear to trend below the nature history. However, the volumetric changes do not appear to be clinically meaningful nor are they associated with protracted increases in NfL, which would be expected if no redegenerate -- no degeneration was accelerating. In summary, through up to 2.5 years of follow-up, we continue to be very encouraged by the data. And as a whole, these data represents what we hope to see at this interim update. We strongly believe that functional and NfL measures are the most important data to assess potential efficacy in Huntington's disease, and these data are tracking in a direction that we believe will provide opportunity for the specialist with regulators beginning next year. We continue to see generally preserved function across multiple measures over the longer-term follow-up that is favorable to the natural history with potential dose-dependent effects. These data are corroborated by downward trending NfL, that is near or below baseline across both those cohorts. Moreover, with 33 procedures completed as of September 30, we believe the surgical administration at both doses is generally well tolerated with a manageable safety profile. Here are the planned next steps for this program over the following 6 months. We have initiated Cohort 3 in the U.S. We plan to enroll approximately 12 patients in a double-blind randomized manner to the low and high dose in a 1:1 ratio. The intent of this third cohort is to investigate the effects of immunosuppression and CNS inflammation following surgery. In the first quarter of 2024, we plan to request an FDA interaction to discuss the totality of the data observed to date and potential regulatory strategies for ongoing development. Lastly, in the middle of next year, we plan to provide an additional update on the ongoing studies, which will include up to 3 years of follow-up on the 33 patients treated in cohorts 1 and 2. At this time, we estimate that more than 20 patients will have at least 2 years of following. Now it is my pleasure to introduce Dr. Ed Wild, who has graciously agreed to provide his thoughts on these interim data. Ed?

Thank you, Walid. Hello, everyone. By way of disclosure, I should start by saying that I'm a clinical investigator on the AMT-130 program at UCL. And I'm a consultant to the sponsor uniQure. I'm also an investigator and adviser on multiple other therapeutic programs in Huntington's disease, in Huntington lowering as well as other modalities. And my academic background is largely in bio fluid, biomarkers and volumetric imaging in HD. And I think that the main message that I would like to convey on the basis of these data, from my perspective as an HD clinician and therapeutics researcher is that the big picture is that this is the first ever gene therapy in Huntington's disease, which happens to have a 3-year head start over any other gene therapies in this condition. And we enter the gene therapy modality, accepting upfront that there's going to be an inevitable short-term cost of the surgical mode of delivery and perhaps the viral vector as well. But that upfront cost and risk needs to be balanced against the potential for lifelong relief from a mutant Huntington pathology if the therapeutic is effective. And so I think, the main thing I would urge the audience to bear in mind is that this modality can't and shouldn't be judged as we would judge a presentation about a small molecule or an ASO or any of the therapeutics that we're a bit more used to hearing about in HD, where there's a lot of focus on Huntington and biomarkers. Essentially, this is a program, which unveils novel biology, and we have to pave the road ahead while we are walking it. We have to discover the biology of how this therapeutic interacts with the vulnerable HD brain and do what we can to optimize dosing, delivery and the response to therapeutics to allow potential benefits to emerge as clearly and as early as possible. But we mustn't forget that this is a safety trial first and foremost. And so far, we've seen some AEs and some evidence of inflammation. But these have all been generally manageable with interventions that we, as neurologists, are well used to dealing with. Overall, the safety outcomes, I think, have been extremely encouraging given the invasiveness and novelty of what's being attempted here. It's also worth noting that the high-dose patients who have been followed the longest are also the ones who didn't receive perioperative steroid treatment at the start of that dosing cohort. So, potential benefits of immunosuppression in the high-dose cohort may take longer to emerge. What I would say overall, though, is that with an asset that was unsafe or poorly tolerated, I think at this stage, things will be looking very different, particularly in terms of the clinical outcomes. In respect of which I think clinical is -- it needs to be given priority over everything else that's been presented. The purpose of biomarkers is to predict clinical effect or to contextualize clinical effect in terms of biology. But really, if the clinical outcomes are heading in the direction that we would like, the biofluid and other biomarkers automatically become less important. If things were the other way around, there'd be no point having a favorable biomarker signal if it didn't predict clinical improvement. The cUHDRS was specifically developed to be very sensitive to clinical decline in HD and in other programs has already shown itself to be very sensitive to unfavorable clinical trends if those are what a drug is going to produce. So that's not what we're seeing here. We're not seeing any dose-related decline in cUHDRS. We're seeing those signals on the favorable side of where we -- of the natural history comparison and we're starting to see what appears to be a dose-dependent response if that continues. This is not proof of efficacy, and I think that the sponsor has been responsible in making that clear. But I think this is what we would like to be seeing at this stage in terms of clinical if we are going to subsequently observe an efficacy signal. Of the components of the cUHDRS, I think that the TMS and TFC are probably the ones that are most germane to this program, in terms of being more objective and less acceptable to practice effect. I think that the observation of the differential cognitive change in the 2 dosing cohorts is interesting. And I think the hypothesis that's been advanced about greater cortical penetration makes sense, but it remains to be seen whether that trend persists and what the basis of it might be. So what about mutant Huntington, I think it's complex. I'm obviously very personally fond of the assay, having been involved in its development, but it is far from perfect and everyone in the field is aware of that. I'm also on record and you can check my YouTube videos from many years ago saying that it is entirely possible for a striatal delivered gene therapy agent to produce meaningful clinical benefit in Huntington's disease without ever altering mutant Huntington in CSF simply because of the percentage of brain that's actually being treated. There are also more -- perhaps advanced biological reasons for the signal to be more difficult to interpret. I think the main 1 of which hasn't really been discussed much is the potential effect of surgery. We know that brain injury will release mutant Huntington in CSF and [indiscernible] group has shown that. And so when we see a neurofilament increase in the operated patients, we can expect some release of mutant Huntington from brain. There are also potential effects of inflammation on mutant Huntington secretion or release or altered CSF flow [ and inflammation ]. So it's a very complex signal. And I think it's 1 where if it falls, that's meaningful. If it doesn't fall, we're really not -- that's a message that doesn't tell us much of use, certainly not when compared with clinical outcomes. So what about volumetric MRI. Again, I think this is a very complex signal. MRI volumes can increase or decrease for many reasons. The signal is the final common pathway of many biological processes, including atrophy, CSF flow and inflammation. And I think crucially, none of the algorithm is used to measuring brain volumes were trend on operated brain that also have some postoperative edema. So I think the meaning of these changes is unclear. They would worry me if we were seeing a corresponding sustained unexplained increase in NFL. I think what we're seeing is an explained short-term increase in NfL that appears to be settling in the way that we would like it to. NfL is much more sensitive to neuronal damage as opposed to being contributed to by other cells. And in this early HD population, we would expect it to be gradually increasing with the natural history. And as we've seen, that isn't what's happening. The numbers are still very small, particularly at the furthest out time points. So it's 1 that we have to keep an eye on. But as long as the clinical continues heading in the right direction, everything else really is something that gives us biological information, but the clinical is really the be all and all of any program, particularly at such an early stage. So in summary, we've never been in this situation before. This is novel biology, and it's difficult to predict the future. We need to keep thinking imaginatively about patient populations and surgical techniques. And crucially, I think the prospects offered by imaginative management of inflammation to really optimize the postoperative period and enable potential benefits to emerge early and as clearly as possible. Biomarkers will tell us to some extent, what's happening or why the clinical picture is changing in the direction that it is, but can't tell us more than the clinical picture. To my eye, though, this is a gene therapy program at this stage that is on track, that is where it needs to be at this point, and it would be wise, in my opinion, to allow more patients to be treated and for the monitoring of the existing patients to continue.

Thank you, Dr. Wild. We are now available to answer questions from our research analysts. Operator, please open the line.

[Operator Instructions]. The first question comes from Paul Matteis with Stifel.

Congratulations. On your regulatory discussions, can you just kind of walk us through what questions are you going to be posing. And then in the U.S. with the FDA, there's been a lot of discussion recently from [ Saber ] about the use of natural history. How are you thinking about proposing to the agency using TRACK-HD. And then just 1 other thing I kind of wanted to kind of clarify here is when we talk about the possibility for accelerated approval with 130, is there a path for that if we can't ultimately use biomarkers and not relying on clinical comparisons?

Thanks, Paul. It's Walid, I'll take the question. Yes, absolutely. I think we believe that the accelerated approval pathway is possible, particularly in light of the messages from senior leadership of [ Saber ] as you indicated. Huntington's disease is particularly the right disease for it to chronic debilitating disease, a rare disease and our program particularly in gene therapy lends itself to this. So we're very encouraged by the data that we have today. We have stabilization of symptoms on the clinical and functional endpoints. We have NfL data that are very encouraging with a low dose going below baseline with a high dose actually getting near baseline and if we exclude 1 outlier, which we believe is an important distinction to be able to show clearly goes below baseline at month 18. We believe that all of these data give us a great foundation to start discussion with the regulators early next year. So I think initially, we're going to have a Type C meeting with them to start discussing the data themselves because it would be the first time that they've seen this and also discuss with them the possibility of using external controls and natural history. I think we're fortunate in the space of Huntington's disease, where there's a richness of the natural history data that are collected to what I would like to call "regulatory-grade data" because they're really collected very similarly to what we do in trials and also the way they are safe and databases and access to these databases. So I think we have a lot of elements here that would help us have these constructive discussions with the regulators. We're eager to have them early next year. This will be 1 of many to follow. And we were hoping with that, we will be able to move in a direction, as you indicated. Of course, we will be communicating on the outcomes of this as we have more information. Thank you.

The next question comes from [indiscernible] with Guggenheim.

This is Roy from Debjit's team. We were hoping you could frame the importance of the whole brain volume data for the discussion with the FDA. Is there a specific change from baseline or a threshold that the agency or neurologists would like to see?

Yes. Obviously, we haven't had interactions with the FDA so we can't really comment on that. But given that this is specialization of Dr. Wild. Maybe, Ed, you can comment on that, if you don't mind.

Sure. I mean I think the answer to the question is no, there isn't a threshold for brain volume change in either direction that would be intrinsically clinically meaningful in the context of therapeutics in Huntington's disease. We have a good idea of what the expected annual rate of atrophy is globally and regionally. But when those changes are reflected in the context of a therapeutic, context becomes much more important than the value of atrophy. So I think if every biomarker is pointing in the same direction as the direction of clinical change, then it becomes easier to interpret. And then the biomarker, in this case, volumetric imaging is something that can tell you something -- it can give you a sort of information towards a biological explanation of what you're witnessing in the other measures. But brain atrophy, I think, is unfortunately the sort of a prime example of a final common pathway for many biological processes. For instance, in the [indiscernible] program, we saw increases in ventricular volume, but no corresponding decrease in brain atrophy. And the meaning of that is still [indiscernible]. I would -- so I wouldn't want to place thresholds on any of these research relevant biomarkers in the absence of contemplating the broader picture. And again, I would say, in terms of the hierarchy, clinical is first and foremost. If the patients are getting better or stabilizing, that's much more important than what's happening to any biomarker. If they're getting worse equally, that's much more important. But it's several -- and the next in my hierarchy would be neurofilament, because it's a much more direct report of what is happening inside the relevant tissue type, and it's a much, much more dynamic market than brain volume change. But I think, I would urge everyone, including the regulators to contemplate the broader picture and not to focus on duly on any 1 particular measure.

The next question comes from Joseph Thome with TD Cowen.

Maybe for Dr. Wild, you indicated this was a good update for a gene therapy program at this stage. Maybe what would you be looking for in further data sets in order to get comfortable using this therapy in the commercial setting, more patients, longer follow-up, kind of what would you be looking for? And when you think about the clinical meaningfulness of the SDMT and SWT measures versus the UHDRS and some of the others. How do you view those in clinical practice?

So what I'd be looking for next is exactly, as you said, more patients, more data, longer-term follow-up. I think that the clinical trends that have been seen, particularly on the composite UHDRS, which is sensitive in both directions, improvement and deterioration, I think, it looks good, and it looks like a dose-dependent signal may emerge or rather this is what we would expect at this stage if we are about to see the emergence of a dose-dependent signal, but the numbers are small. And as time has gone on, the approach to things like inflammation has altered, and we would expect that, that might start to produce more rapid emergence of efficacy in the subsequently treated patients if such a signal is to be seen. The truth -- the NfL patterns that we've been seeing below baseline in the low-dose cohort and the point estimate sitting somewhere between baseline and natural history expectation, high-dose cohort with smaller numbers. Again, it looks tantalizing. It's what we would expect to be seeing now NfL if reductions are about to be firmly seen. And if we see critical NfL heading in the same direction, then I think then that's when it really starts to be a pretty compelling package. In terms of SDMT and Stroop, in all honesty, these aren't really tools that we use in isolation in the clinical assessment and management of HD patients. They are sensitive to early change in HD. And they are, as with all cognitive measures probably more cortically dependent than more motor tasks like the UHDRS Total Motor Score. But in isolation, 1 of these scores or a couple of them wouldn't tell me much. If I'm a clinically assessing the cognitive state of a patient, they'll undergo a much more comprehensive battery and my clinical judgment will be influenced by that plus everything else I'm seeing. But the bottom line when assessing the impact of any cognitive change in a patient always comes down to what's the impact on your everyday functioning. And that's what the TFC is. It's less sensitive because it's a rather more crude scale as 13, but it's the bottom line for function in Huntington's disease. And if small fluctuations in a single cognitive score are not having an adverse impact on day-to-day functioning, they're less important than something which does have such an impact. And probably more commonly used in the clinic is the Total Motor Score, for the kind of year-to-year monitoring of how much someone's HD has progressed. So I think, again, I think it comes down to the -- looking at the holistic assessment of the participants, and that's what the cUHDRS is for and then looking at the broader picture, which does include biomarkers and most notably NfL.

The next question comes from Joseph Schwartz with Leerink Partners.

I wanted to follow up on the statement in the press release and Dr. Wild's commentary that the pharmacodynamics of mutant Huntington and the CSF may not be materially representative of mutant Huntington in the targeted brain regions for the patients treated with AMT-130. And since animal models, I thought showed declines that were somewhat correlated between mutant Huntington and CSF and brain tissue. I was wondering why it might be different in humans?

Ed why don't you start that off and then we can chime in as well.

Yes, yes. It's a really fascinating question. I think that the main expectation in the field that we might see mutant Huntington decreases comes from studies in the mini pig model of Huntington's disease, which is a large animal with a brain that's a bit like a human brain. But conspicuously, those animals don't show much in the way of clinical phenotype at the point where they're still able to go into an MRI scanner and have lumber punctures. So there was, I think, a surprising degree of a mutant Huntington lowering in lumbar CSF in those animals. But I think the fact remains that the human Huntington's disease brain is a vastly different thing from the brain of healthy-looking pig that has mutant Huntington expression. It's possible that the dynamics of release in terms of passive release from damaged cells versus active secretion is different in those animals, the flow of CSF may be different, the performance of the [indiscernible] structure may be different or it may come down to anatomical differences in the spinal cord versus lumbar intrathecal space of those animals. The bottom line for me is that although I found those pig data extremely encouraging, I have always said that we may not see a similar difference in humans. It may be that the -- it may come down to the relative volumes of brain that are injected or it may be to do with the postoperative inflammation that's been seen causing some release of neurofilament -- sorry, of mutant Huntington potentially from non-neuronal tissues, which might offset any potentially detectable recent Huntington decrease in CSF that would be there to be seen from relevant i.e. neuronal tissues. That's how I see things. And again, on the very simple level, for me, it comes down to mutant Huntington decreases would be nice to see if we see them because that could be seen as a firming target engagement. But if we don't see them, it doesn't mean we don't have target engagement. What we really need -- and cUHDRS is working extremely hard on this is a clinically viable Pet ligand for Huntington that, I think, is 1 biomarker for which you would hope to see evidence of regional target engagement in the human HD break, but we're not there yet.

I think you covered the points that we were going to make, so we can move to the next question.

The next question comes from Ellie Merle with UBS.

This is Jasmine on Ellie. We had 1 on AMT-260 for temporal lobe epilepsy. Just how are preparations going for getting the first patient next year? And kind of how should we think about time line for when we could see initial clinical data from here?

Yes. Jasmine, this is Matt. Things are going really well in terms of the Phase I/II preparation for temporal lobe epilepsy. We will provide further commentary in terms of timing of data and expectations once we begin enrolling patients.

The next question comes from Sammy Corwin with William Blair.

A couple for Dr. Wild. Given the small end, what degree of slowing in disease progression do you think is clinically meaningful, and how much follow-up would you want to see to comfortably say that AMT-130 has slowed or stopped disease progression. And then just looking at the variable cognitive changes and decrease in brain volume, do you think either of those could be a safety signal related to inflammation, and would you expect steroids to aid in the efficacy profile or just the safety profile of AMT-130?

Sammy, great questions. Clinically meaningful change, I think, is very difficult to quantify in HD. Simply because all we've ever seen is people getting worse. And obviously, we can look at the natural history. And again, cUHDRS led by Kristina [indiscernible] has done a -- have done a really nice sort of the enroll HD cohort, which was published earlier this year in movement disorders, which does give nominal figures for minimally clinically significant change. I wouldn't want to personally put a figure on what would be seen as clinically significant, simply because everyone with HD has always got worse and anything that we can do to deflect that would be a huge breakthrough, particularly if it's sustained. And the results from a small trial in early manifest HD could potentially translate in the fullness of time, into hugely significant differences in the life trajectory of everyone who's at risk of Huntington's disease. Ultimately, we want to be treating to prevent the onset of HD. And so what we really need is a foot in the door to show that we can alter the trajectory of the disease. -- in someone in 1 person with Huntington's disease with the hope that we can then generalize that approach to produce the maximum benefit for everyone who's at risk. I'm sorry if that's a vague answer, but I don't have -- I don't have any numeric answers to give you except I would direct you to that movement in sort of paper if you do want numeric point estimates. The other question I think was about safety of volumetric MRI or rather, could volumetric MRI be seen as a safety marker. I think that it is 1 of the things that we need to contemplate when we are considering the balance of safety and efficacy. A change in brain volume that we understand is a potentially helpful signal, a change in brain volume that we don't understand needs to be filed under things we don't understand and therefore, shouldn't try and interpret the signals complex edema and postoperative or post-transduction inflammation absolutely can lead to changes in volumetric measures as can many things, including, for instance, the removal of aggregated proteins from parenchymal tissues. And I think it would be premature to advance explanations for measures that we don't understand in this very complex novel biological context. Once we have a much better understanding and once we have enough -- I mean, the end for reliable quantification of brain volume and brain atrophy is pretty high and certainly much higher than you would need for establishing a reliable trend in neurofilament, say. So again, I would just advise caution in interpreting those values, and they need to be interpreted in the context of everything else we're measuring. But I think -- the combination of NfL and brain volume could be potentially useful if they start behaving in a concordant way. So for instance, if we've seen big decreases in brain volume and a sustained unexplained increase in NfL, that, I think, starts to be worry, but that's not what we're seeing. What we're seeing is an expected NfL spike, which declines in the expected way and a brain volume change that we don't understand. And incidentally, is a brain volume change of the kind that's been seen in a number of other programs, and as broadly speaking, remained unexplained in those other programs. Your final question was about immunosuppression -- and I can't remember what the question was. Would you mind repeating?

If you think immunosuppression could aid in the efficacy as well or the adjustment can be beneficial to the safety profile?

I see Yes. No, I think it's both. I think that the -- what we're looking at is basically a tug of war that is different from 1 person to the next and different between 1 dose and the other, between the brand's tendency to produce inflammation when unknown previously unencountered substances are introduced to it versus what we expect to be the beneficial effects of lowering exon 1 containing Huntington protein. And -- so the idea with the steroid treatment is that we now know that there is a tendency to produce inflammation to occur and by suppressing it early and potentially thinking about suppressing it in the longer term, if that turns out to be something that wants to be attempted. You could tip the balance in favor of whatever efficacy signal is there being visible earlier. So yes, to some extent, it's a safety thing because if you allow inflammation to proceed unabated in some patients that will start to produce symptoms and those symptoms could be undesirable in themselves or could increase the stress on what we already know are vulnerable neurons in HD. So that's the safety aspect. The efficacy aspect is that if you can suppress the information as well as that being a good thing to do in itself, are you may be able to reveal earlier and more visibly the efficacy signal in terms of things like clinical progress and indeed, neurofilament.

The next question comes from Salveen Richter with Goldman Sachs.

This is Lydia, on for Salveen. Congrats on the update. So just 1 on the regulatory side, how do you intend to message to street post your discussion with the FDA? And what can we expect from a disclosure standpoint here?

Walid?

Yes. So I think we -- as I discussed previously, we intend to have a discussion with the FDA as early as -- in the year next year. based on these data. And I think after we come out of the meeting, depending on how clear the message is for us, we will guide as to where we are and what are the next steps. I think it's a bit premature right now to figure this out, but we will be transparent about where we stand and tell you about next steps we have to take. .

At this time, I would like to turn the call back to Matt for closing remarks.

Okay. Thank you, everybody, for joining the call today and a special thanks to Dr. Walid, to Dr. Wild for his participation. We are very pleased with these encouraging interim data and look forward to advancing clinical development of AMT-130, including reporting additional data initiating regulatory discussions next year. Have a great day and a happy holiday.

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