Ladies and gentlemen, thank you for standing by. Welcome to the Huntington's Disease Program Update, AMT-130. At this time, 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 one on your telephone. You will then hear an automated message advising your hand is raised. To withdraw your question, please press star one one again. 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 Centre.
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 know that we'll be making forward-looking statements during this call. All statements other than statements of historical facts are forward-looking statements. They are based on management's beliefs and assumptions and on information available to management only as of the date of this conference call. Our actual results could differ materially from those anticipated in these forward-looking statements, including, without limitation, the factors described in uniQure's quarterly report on Form 10-Q, filed on November 7, 2023, and 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 as 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 one 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 are 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 one-time treatment of AMT-130 continue to show evidence of preserved neurological function with potential dose-dependent clinical benefits compared to an inclusion criteria match 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 huntingtin 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 nearer-term safety profile. Dosing of this third cohort was initiated earlier this quarter. Now let me turn the call over to Dr. Walid 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 in 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 from 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 HD. This is referred to as early manifest disease. Huntington's disease is caused by an expansion of the CAG trinucleotide repeat in the huntingtin gene.
The expanded repeat also appears in huntingtin messenger RNA and results in toxicity of the mutant huntingtin 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, one-time delivered AAV5 gene therapy designed to silence huntingtin mRNA and resulting mutant huntingtin protein. By reducing levels of mutated protein, AMT-130 has the potential to stabilize the disease and halt further progression. AMT-130 encodes a micro-RNA that targets exon 1 of the huntingtin gene, which reduces both the full-length huntingtin protein and the toxic exon 1 splice 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 six injections through a stereotactically placed cannula using convection enhancement. The direct delivery of AMT-130 is monitored using real-time MRI and a gadolinium contrast agent to ensure coverage of the striatum. We are conducting two clinical studies of AMT-130, one in the U.S. and one in Europe. The studies consist of an initial screening visit, followed by surgery. Patients are followed for a total of five 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 huntingtin levels. We perform MRIs for safety and to measure whole brain volume.
Most importantly, in each visit, we perform a series of clinical assessments, including the Total Functional Capacity, which measures the ability of patients to perform activities of daily life, the Total Motor Score, which measures motor symptoms, and two cognitive tests, the Stroop Word Test and the Symbol Digit Modalities Test. These four 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-GeneTRX-1, included a double-blind, randomized, and sham-controlled sequential design, whereby in cohort one, six patients received a low dose of 6 x 10^12 vector genomes, and four patients underwent a sham surgery that included anesthesia and a surface incision only, with no administration of AMT-130. After cohort one was fully enrolled, cohort two then included 10 patients who received a high dose of 6 x 10^13 vector genomes, while six patients received the sham surgery. After one year, the sham or control patients were eligible to cross over to the treatment arm. Four 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-GeneTRX-2, a European study that is an open-label study. The first cohort enrolled six patients who received a low dose, followed by a cohort of seven patients who received a 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 interim safety and efficacy results from cohorts one and two of the U.S. and the European studies, with a data cutoff of September 30, 2023. The four 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 in Huntington's disease requires selection of patients early in their disease course 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 makes including placebo or sham controls 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 from natural history studies could be very useful in serious and rare diseases, such as Huntington's disease. In our study, the control arm extends only one year. Given that we're following treated patients for five years, we have partnered with CHDI, the Cure Huntington's Disease Initiative, to use their TRACK-HD natural history study to create two natural history cohorts that serve as longer-term comparisons for our study.
One data set, shown here in gray, consists of 105 patients that meet the per-protocol key inclusion criteria for our study. Because our patients were also selected on the basis of striatal volume, we narrowed the sample to the 31 patients that met both the 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 the 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 intraparenchymal 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, a short course of perioperative steroid prophylaxis has been added to the treatment regimen for cohort three. 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 in vital signs, ECG, or clinical chemistry and hematology laboratory values. Here we report the safety on all patients in our studies.
Note that four 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 their respective treatment arm once they received active treatment. The procedure-related adverse events appeared to be similar across all three 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 six treatment-emergent adverse events, four 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 Stroop Word Test, and the Symbol Digit Modalities 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 non-concurrent criteria-matched natural history cohort depicted in the orange dashed line. The high dose, depicted in blue, appears to show stabilization of symptoms at month 18 compared to baseline. While the mean cUHDRS for the low dose cohort dropped between months 24 and 30, it remains above the natural history. It's important to point out that this decline in cUHDRS was mostly driven by a drop in one 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 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.... The Stroop Word Test measures cognitive capacity, and particularly the ability to disentangle two conflicting stimuli. Mm-hmm. 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 Stroop score contributed to most of the previously noted decline in the mean cUHDRS for the low dose cohort in month 3.
It is important to note that there is significant intra variability, intra-patient variability observed in the Stroop Word scores, particularly in visits at months 24 and 30. The Symbol Digit Modalities Test is a test in which patients are asked to use a key to decode a message composed of symbols. It measures processing speed and cognitive capacity. In this test, patients on the high dose showed favorable trends starting from month 12 compared to both the baseline and the natural history. Patients at the low dose appeared 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 Word Test.
One possible explanation is that the high dose is achieving greater mHTT suppression 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 with the natural history. Furthermore, there are early signs suggestive of a dose dependence in the observed clinical effects. Patients treated with a 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 preserve diverse functions relative to baseline and are trending favorably to the natural history across all 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 worked with Professor Ed Wild, who is with us on this call. He has conducted a study called HD-CSF, whereby he measures NfL CSF levels at baseline and then again at 24 months in 71 patients. We used clinical and 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 in neurodegeneration as the disease progresses. As we have previously described, in our studies, we observed an increase in CSF NfL immediately after surgery. This increase is not dose-dependent and is in line with that, with what has been observed in patients undergoing other brain surgeries, like the implantation of deep brain stimulation electrodes. In the dosed 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 time points thereafter.
For the high dose, CSF NfL levels steadily decline and are now near baseline, starting at month 15. In this update, we continue to see an encouraging decline from the 1-year data we reported last June. As evidenced by the size of the error bars at month 12 in the high dose group, these results are largely influenced by one patient who experienced a serious adverse event of CNS inflammation, and whose CSF NfL levels were approximately 2- to 3-fold higher relative to baseline until their last measurement at month 18. On the next slide, we show the CSF level, 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 drop below baseline at month 18.
The values at month 24 are not affected, as this patient has not yet reached this follow-up milestone. Note that at month 24, there are only two subjects, so these results should be viewed with caution. In totality, the trends 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 from baseline of mHTT 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 advisors believe CSF, mHTT is materially representative of mHTT pharmacodynamics in the brain, where AMT-130 is administered.
AMT-130 is surgically infused directly into the striatum, which represents only 2% of the brain's total volume. Moreover, mHTT from the brain typically leaks into the CSF from cells lining the ventricles, which are not directly transfused by AMT-130. These limitations are distinctly different from other experimental therapies that are either administered orally with systemic bioavailability or infused intraspinally into the CSF, where mHTT measurements are taken. These measurement challenges are also exacerbated by very small quantities of mHTT protein normally present in CSF. In our study, many baseline mHTT measurements were near or below the assay's lower limit of quantification, which is approximately 25 picomolar. In these cases, decreases from baseline are difficult to measure, and very small increases disproportionately inflate the % change from baseline.
To reduce the variability in mHTT measurements, samples were batched and analyzed only when a full year of samples were available for a given patient. As a result, going forward, mHTT 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 natural history. However, the volumetric changes do not appear to be clinically meaningful, nor are they associated with correlated increases in NfL, which would be expected if neurodegeneration 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 opportunities for discussions 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 potentially dose-dependent effects. These data are corroborated by downward trending NfL that is near or below baseline across both dose cohorts. Moreover, with 33 procedures completed as of September 30th, 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 six months. We have initiated cohort three 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 was to investigate the effects of immunosuppression on 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, observed to date, and potentially, or 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 three years of follow-up on the 33 patients treated in cohorts one and two. At this time, we estimate that more than 20 patients will have at least two years of follow-up. 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 advisor on multiple other therapeutic programs in Huntington's disease, in huntingtin lowering, as well as other modalities. My academic background is largely in biofluid biomarkers and volumetric imaging in HD. 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 a 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 three-year head start over any other gene therapies in this condition.
We enter the gene therapy modality, accepting upfront that there's gonna 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 huntingtin pathology if the therapeutic is effective. 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 huntingtin 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 that high dose cohort may take longer to emerge. What I would say on the overall, though, is that with an asset that was unsafe or poorly tolerated, I think at this stage, things would be looking very different, particularly in terms of the clinical outcomes. In respect of which I think clinical 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 in 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. And 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's 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 susceptible to practice effects.
I think that the observation of the differential cognitive change in the two 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 huntingtin? 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 striatally delivered gene therapy agent to produce meaningful clinical benefit in Huntington's disease without ever altering mutant huntingtin 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 one of which, which hasn't really been discussed much, is the potential effect of surgery. We know that brain injury will release mutant huntingtin in CSF, and Amber Southwell's group has shown that. And so when we see a neurofilament increase in the operated patients, we can expect some release of mutant huntingtin from brain. There are also potential effects of inflammation on mutant huntingtin secretion or release, or altered CSF flow, or lymphatic current. So it's a very complex signal, and I think it's one where if it falls, that's meaningful.
If it doesn't fall, we really know that's a message that doesn't tell us much 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 algorithms used for measuring brain volumes were trained on operated brains 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, 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, you know, 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 one that we have to keep an eye on, but as long as the clinical continues heading in the right direction, you know, everything else really is something that gives us biological information.
But, you know, the clinical is really the be-all and end-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.
Thank you, Dr. Wild. We are now available to answer questions from our research analysts. Operator, please open the line.
Thank you. As a reminder, to ask a question, please press star one one on your telephone and wait for your name to be announced. To withdraw your question, please press star one one again. Please limit to one question, and feel free to go back into the queue for any additional follow-up. Please stand by while we compile the Q&A roster. The first question comes from Paul Matteis with Stifel. Your line is open.
Hey, thank you for the update and congratulations. On your regulatory discussions, can you just kind of walk us through what questions you are going to be posing? And then, you know, in the U.S., with the FDA, there's been a lot of discussion recently from CBER about the use of natural history. You know, how are you thinking about, you know, proposing to the agency using TRACK-HD? And then just one other thing I kind of wanted to kind of clarify here is, you know, when we talk about the possibility for accelerated approval with one thirty, is there a path for that if we can't ultimately use biomarkers and are relying on clinical comparisons? Thanks so much.
Thanks, Paul. Walid, I'll take the question. Yes, absolutely. I think we believe that, the accelerated approval pathway is possible, particularly in light of the, you know, the messages from senior leadership of CBER, as you indicated. You know, Huntington's disease is particularly, the right disease for it. It's a chronic, debilitating disease, a rare disease, and our program for the gene therapy, it 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 the low dose going below baseline, with the high dose actually getting near baseline, and if we exclude one 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 gonna have a Type C meeting with them to start discussing the data them, you know, themselves, because this 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, quote, unquote, regulatory grade data, because they're really collected very similarly to what we do in trials, and also the way they are saved in 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 one 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.
Please stand by for the next question. The next question comes from Ry Forseth with Guggenheim. Your line is open.
Hi, this is Ry 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?
Yeah. Obviously, we haven't had interactions with the FDA, so we can't really comment on that. But given that this is a 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 deflected in the context of a therapeutic, context becomes much more important than the value of atrophy. So, you know, 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, it can give you a sort of, information towards a biological explanation of what you're witnessing in the other measures. But, you know, brain atrophy, I think, is, is unfortunately the sort of, prime example of a final common pathway for many biological processes. For instance, in the tominersen program, we saw increases in ventricular volume, but no corresponding decrease in brain atrophy. And the meaning of that, you know, is, is still obscure. I would, I would say, I wouldn't want to, I wouldn't want to, place thresholds on any of these, research relevant biomarkers, in the absence of contemplating the broader picture. And I, 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, you know, and the next in my hierarchy would be neurofilament, because that's a much more direct report of what is happening inside the relevant tissue type, and it's a much, much more dynamic marker than brain volume change. But, you know, I think I would urge everyone, including the regulators, to contemplate the broader picture and not to focus solely on any one particular measure.
Thank you.
Operator, next question.
The next question comes from Joseph Thome with TD Cowen. Your line is open.
Hi there. Good morning. Thank you for the update and for taking our question. Maybe for Dr. Wild, you indicated that this is a good update for a gene therapy program at this stage. Maybe, what would you be looking for in further datasets in order to get comfortable using this therapy in the commercial setting? More patients, longer follow-up, kinda, what would you be looking for? And when you think about the clinical meaningfulness of the SDMT and SWT measures versus, you know, the UHDRS and some of the others, how do you view those in clinical practice? Thank you.
So, what I'd be looking for next is exactly, as you said, more patients, more data, longer term follow-up. You know, 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, you know, 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 as such a signal is to be seen.
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 if NfL reductions are about to be firmly seen, and if we see clinical and NfL heading in the same direction, then I think, then, you know, 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, 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, one of these scores or a couple of them wouldn't tell me much. If I'm clinically assessing the, cognitive state of a patient, they'll, they'll undergo a much more comprehensive battery and, well, you know, 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 you know, 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, then they're less important than something which does have such an impact. And you know, 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, you know, again, I think it comes down to looking at the holistic assessment of the participants, and that's what the cUHDRS is for.
you know, then looking at the broader picture, which does include biomarkers and most notably, NfL.
Perfect. Very helpful. Thank you.
Please stand by for the next question. The next question comes from Joseph Schwartz with Leerink Partners. Your line is open.
...Thanks very much. I wanted to follow up on the statement in the press release and Dr. Wild's commentary that the pharmacodynamics of mutant huntingtin and the CSF may not be materially representative of mutant huntingtin in the targeted brain regions for the patients treated with AMT-130. Since animal models I thought showed declines that were somewhat correlated between mutant huntingtin and CSF and brain tissue. I was wondering why it might be different in humans?
I want to start that off, and then we can-
Oh, sure.
We can chime in as well.
Yeah, yeah. It's a really fascinating question. I think that the main expectation in the field that we might see mutant huntingtin 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 lumbar punctures. So there was, I think, a surprising degree of a mutant huntingtin 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 a healthy-looking pig that has Huntington 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 glymphatic 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've always said that we may not see a similar difference in humans. It may be that it may come down to the relative volumes of brain that are injected. Or it may be to do with the post-operative inflammation that's been seen causing some release of neurofilament...
Sorry, of mutant huntingtin, potentially from non-neuronal tissues, which might offset any potentially detectable mutant huntingtin decrease in CSF that would be there to be seen from relevant, i.e., neuronal tissues. I, you know, that's how I, that's how I see things. And again, it, on the very simple level, for me, it comes down to mutant huntingtin decreases would be nice to see if we see them, because that could be seen as affirming target engagement. But if we don't see them, it doesn't mean we don't have target engagement. What we really need, and CHDI is working extremely hard on this, is a clinically viable PET ligand for mutant huntingtin. That, I think, is one biomarker for which you would hope to see evidence of regional target engagement in the human HD brain, but we're not there yet.
Thanks, Ed. I think you covered the points that we were going to make, so we can move to the next question.
Please stand by for the next question. The next question comes m Ellie Merle with UBS. Your line is open.
Hi, this is Jasmine on for Ellie. Thanks so much for taking our question. We had one on AMT-260 for temporal lobe epilepsy. Just how are preparations going for dosing the first patient next year? And kind of how should we think about timelines for when we could see initial clinical data from here?
Yeah. Hey, Jasmine, this is Matt. Things are going really well in terms of the phase one, two preparation for temporal lobe epilepsy. We'll provide further commentary in terms of timing of data and expectations once we begin enrolling patients.
Okay, great. Thank you.
Please stand by for the next question. The next question comes from Sami Corwin with William Blair. Your line is open.
Hi there. Congrats on the update, and thanks for taking my questions. A couple for Dr. Wild. Given the small n, 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, you know, 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? Thank you.
Hi, Sami. 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 you know, obviously, we can look at the natural history and again, CHDI, led by Cristina Sampaio, have done a really nice study 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.
The results from a small trial in early manifest HD could potentially translate in the fullness of time into, you know, hugely significant differences in the life trajectory of everyone who's at risk of Huntington's disease. You know, ultimately, we want to be treating to prevent the onset of HD. 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 one person with Huntington's disease with the hope that we can then generalize that approach to produce the maximal benefit for everyone who's at risk.
I'm sorry if that's a vague answer, but I don't have a numeric answer to give you, except I would direct you to that Movement Disorders 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 one 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 post-operative or post transduction inflammation absolutely can lead to changes in volumetric MRI measures, as can many things, including, for instance, the removal of aggregate aggregated proteins from parenchymal tissues. 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 n, I mean, the n, 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 neurofilaments, say. 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 worrying. 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. Incidentally, it's a brain volume change of the kind that's been seen in a number of other programs and has, 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 if you just think it'd be beneficial to the safety profile?
Oh, I see. Yeah. No, I think it's both. I think that what we're looking at is basically a tug-of-war that is different from one person to the next and different between one dose and the other, between the brain'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 huntingtin protein.
And so the idea with the steroid treatment is that we now know that there is a tendency for 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 inflammation, as well as that being a good thing to do in itself, you may be able to reveal earlier, and more, visibly, the efficacy signal in terms of things like clinical progress and indeed, neurofilament.
Great. Thank you.
Please stand by for the next question. The next question comes from Salveen Richter with Goldman Sachs. Your line is open.
Hi, this is Olivia on for Salveen. Congrats on the update, and thanks so much for taking our question. So just one on the regulatory side. How do you intend to message to the street, post your discussion with the FDA, and what can we expect from a disclosure standpoint here? Thank you.
Walid?
Yeah. So I think we, as I discussed previously, we intend to have a discussion with the FDA as early as early 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, you know, 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 te`l you about next steps we plan to take.
Thanks so much.
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. 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 and 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.