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

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

Good morning, and thank you for joining us. This morning, uniQure announced updated interim data on 29 patients treated with AMT-130 in our ongoing Huntington's disease Phase I/II clinical trials that are taking place in the U.S., Europe, and the U.K. The update consists of data on clinical measures, exploratory biomarkers and safety and tolerability as well as anticipated regulatory next step. . 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. Victor Sung, Professor of Neurology at the University of Alabama at Birmingham, the Director of its Huntington's Disease Clinic and a clinical investigator in the AMT-130 U.S. trial. The slides included in this morning's webcast will be available on the Investor page of uniQure's website shortly after the conclusion of the investor call. Please note that we'll be making forward-looking statements during this call and all statements other than those of historical fact are forward-looking statements. They are based on management's beliefs and assumptions and on information available to management only as of the date of this conference call. Our actual results could differ materially from those anticipated in these forward-looking statements for many reasons, including without limitation, the factors described in uniQure's most recent SEC filings. Given these risks, you should not place undue reliance on those forward-looking statements, and we assume no obligation to update these statements even if new information becomes available in the future. Now let me introduce Matt Kapusta, uniQure's CEO.

Thank you, Maria, and good morning, everyone. We are really delighted to share with you today exciting data from our U.S. and EU Phase I/II studies of AMT-130 in Huntington's disease. For the first time in a clinical setting, we have demonstrated statistically significant dose-dependent slowing of disease progression and reduction of a key marker of neurodegeneration in Huntington's disease patients at 24 months. We and key opinion leaders in the HD field we have recently spoken to believe these long-term data provide very encouraging and compelling evidence of AMT-130s disease-modifying potential. These results also follow our recent announcement of the FDA's first ever RMAT designation in Huntington's disease, and we very much look forward to engaging with the FDA later this year to discuss the potential for expedited clinical development of AMT-130. Huntington's disease is one of the most prevalent monogenic disorders affecting approximately 70,000 people in the U.S. and Europe alone with hundreds of thousands of others at risk of inheriting the disease. While Huntington's was one of the earliest rare diseases to be genetically characterized, there continue to be no disease-modifying treatments available for these patients. In personally talking to many patients living with HD and their loved ones, the heartbreak and devastation are immediately clear. The onset of symptoms generally occurs between 30 to 50 years of age, a time typically dedicated to raising children and building careers. Yet the progression of disease is almost torturously slow with symptoms gradually worsening over the next 10 to 25 years, ultimately robbing people of their jobs, relationships, mobility and the ability to care for themselves. Our vision for AMT-130 is to delay or slow the advancement of this horrible disease, and by doing so, give time back to patients and their families. We at uniQure believe AMT-130 has the potential to be not only a first-in-class treatment for Huntington's disease, but also a best-in-class therapy with several important differentiating features. First, AMT-130 is a onetime-administered therapy with potentially lasting effects. Remember, Huntington is a lifelong disorder with disease burden detectable decades before the onset of symptoms. Therapeutic intervention as early as possible is critical to preserve function. As such, providing patients a one-and-done therapeutic option with durable effect can offer patients meaningful advantages compared to repeated lumbar punctures for the remainder of patient's life. Moreover, in early clinical trials like ours, patients that receive AMT-130 can be followed for years and compared to robust natural history data sets to support clinical benefit. Second, as a onetime therapy, AMT-130 can be delivered directly to the brain, ensuring therapeutic bioavailability in key regions where there is known pathology. Drug delivery to the brain has vexed the industry for decades, yet it's absolutely essential for achieving clinical efficacy in Huntington's disease. Starting the administration of AMT-130, the filling of critical brain structures is observed in real time under contrast-enhanced MRI. Moreover, in multiple animal species, large and small and including disease models, we have demonstrated meaningful cortical spread with a high correlation between levels of vector DNA and the suppression of both messenger RNA and mutant Huntington's protein in the range of 25% to 75%. And lastly, AMT-130 leverages our proprietary miQURE gene silencing technology, and was specifically designed to target the first exon of the Huntington gene. In doing so, AMT-130 has been demonstrated to suppress not only the full-length mutant Huntington protein, but also the highly toxic exon 1 splice isoform. We believe no other current therapeutic candidate specifically targets this highly toxic fragment. With that, let me turn the call over to Dr. Walid Abi-Saab, who will discuss the updated results, including new statistical analyses and next steps for the program in more detail. Walid?

Thank you, Matt. Good morning. Good afternoon, everybody. I'm here, I'm very excited to share with you this important update on our Huntington's disease program. Let me start by thanking the patients, their caregivers and the larger Huntington disease community without whom none of this would have been possible. We have made significant progress since our last update. We now have patients followed up to 3 years, the longest interventional study in Huntington's disease to date. More importantly, perhaps, now that the majority of our patients have reached the 3-year mark, we were able to conduct post hoc analysis, demonstrating a statistically significant dose-dependent slowing of disease progression in patients treated with AMT-130 as well as exploratory biomarker evidence demonstrating a reduction in neurodegeneration. AMT-130 continues to be well-tolerated with a manageable safety profile with no new drug-related serious adverse events reported since the last update. Most importantly, with the recent RMAT designation, we will be discussing with the FDA in the second half of the year, the development path towards a potential accelerated approval. In the next few slides, I will talk you through the clinical measures and the comparison to an external cohort. The key efficacy endpoint in our studies is the composite unified Huntington's disease rating scale or cUHDRS for short. It's a composite score based on measurements of the key affected areas in Huntington's disease, specifically function as measured by the total functional capacity, which assesses impairment and occupation, ability to manage finances, daily chores and the rest, motor function as measured by the total motor score, which assesses abnormal movements and rigidity and cognition, which is very important to patients. Cognition is measured by 2 tests of attention, processing speed and working memory. Recently, an independent study in patients with early Huntington's disease concluded that the cUHDRS is the most sensitive measure of progression of the disease. cUHDRS best characterizes the clinical progression and provides an opportunity to improve efficiency of clinical trials relative to individual measures. Meaning it has a stronger signal to noise ratio compared to individual components. And consequently, the signal could be picked up on this scale before it becomes apparent on individual scales. We are thrilled to have received an RMAT designation for AMT-130 as it is the first Huntington disease compound in development to receive such a distinction. More importantly, RMAT designation will allow for more frequent interactions and discussions with regulators on the requirements for an accelerated approval. The data that supported the RMAT application were those we shared last December with only 8 patients having reached the 2-year mark, which is a much less mature data set than what we will be showing you today. To evaluate the effects of AMT-130 by comparing to a natural history cohort, we use propensity score methodology, a standard approach when comparing clinical trial data to an external cohort. Those analyses provided evidence of potential benefit of AMT-130 and led the FDA to grant us RMAT designation. With this update, we continue to build on what was presented to the agency now that we have 21 patients who have completed 24 months of follow-up. Since our update in December 2023, we have expanded our natural history cohort beyond the initial TRACK-HD/TRACK-HD-ON study to include the PREDICT-HD study as well. Thanks to our ongoing collaboration with CHDI, we have access to these studies and to their databases. We have selected these studies because, first, they prospectively collect data longitudinally. They employ a consistent and regular radar training similar to clinical trial settings and both include clinical as well as imaging endpoints, which are key inclusion criteria in our studies. Starting with approximately 2,000 patients from both natural history studies, we applied the clinical and imaging criteria from our studies and selected those patients for whom we have baseline plus 2 or more years of follow-up data available. Using these criteria, we ended up with a total of 154 patients from both studies. Similar to the RMAT application and the statistical analysis we are sharing with you for the first time today, we use the propensity score methodology to compare outcomes for AMT-130 patients versus natural history external cohort at the 2-year mark. Propensity score weighting is a standard statistical approach commonly used for these analyses as they're designed to reduce selection bias when comparing to an external cohort. This methodology has been used in support of a number of regulatory submissions to date. We used 8 baseline characteristics for the propensity score weighting to generate an external group that is nearly identical to the 21 AMT-130 treated patients who have completed 2 years of follow-up. With the majority of our patients having reached the important 2-year time point, we could now conduct for the first time, robust post-hoc statistical analysis yielding nominal P values to better understand the potential efficacy of AMT-130 in Huntington's disease. Here, we show how well matched the AMT-130 treated patients are to the propensity score weighted external control. As you see on virtually all key baseline characteristics, the 2 groups look virtually identical. As you can see on this graph, AMT-130 shows dose-dependent and statistically significant difference from the external cohort on cUHDRS after 24 months. This is 1 of the 2 most important graphs you will see in this presentation. The external cohort is depicted in gray whereas the low and high dose of AMT-130 are shown in purple and blue or teal, respectively. While the external cohort declined from baseline by 1 point after 2 years, the AMT-130 treated patients declined by 0.7 and 0.2 points for the low and high dose, respectively. These results suggest an 80% reduction in the rate of disease progression by AMT-130 at the high dose as measured by the sensitive composite score relative to a well-matched external cohort. Reaching statistical significance with such a small sample size is impressive and reflects the large observed effect size. If these effects are maintained over time, AMT-130 has the potential to be a groundbreaking treatment for Huntington's disease patients. Here, we show the time course for the cUHDRS over a 2-year period for both dose levels of AMT-130. We also include the external cohort to provide context for the AMT-130 data. As you can see, AMT-130 shows sustained favorable effects over the 2-year period relative to the natural history group, in addition, we can also see consistent dose-dependent effects over the duration. Here, we show the 4 components of the cUHDRS over the 2-year period, across both doses and external control group. Naturally, we see more variability when we look at these individual scales compared to the composite endpoint, confirming the utility of the composite score in reducing the variability and improving the signal-to-noise ratio as has been demonstrated in recent studies. For example, the low dose appears to have significant fluctuation on the TMS score, and we know better than the external control on the SDMT but it does on TFC and the Stroop Test. Nonetheless, when we look at the totality of the data, the high dose, in particular, appears to perform better than the control across most of those measures. Moving on to neurodegeneration. Neurofilament light chain is an important biomarker of neurodegeneration. It is released from damaged neurons and is reliably measured in both CSF and plasma. It is very sensitive in measuring toxicity to neurons, whether from neurodegeneration like in Huntington's disease or ALS from neuroinflammation like in multiple sclerosis, or any type of toxicity like drug-related toxicity as was recently shown in recent trials in Huntington's disease. As such, long-term trends in CSF neurofilament light chain is viewed by Huntington's disease expert as not just a safety measure, but potentially one of the best characterized biomarker of neurodegeneration activity. Importantly, a reduction in NfL levels was used as a circuit biomarker supporting the recent accelerated approval of a treatment of ALS. In this slide, we show the time course of NfL -- sorry, I had to look at the slide. In this slide, we show the time course of CSF, NfL over a 2-year period. The low and high dose are depicted on the graph in the same purple and teal color, respectively. As we have previously reported, we see an immediate spike in CSF, NfL following surgery and probably because of it, and treatment with AMT-130 and then a gradual return to baseline. The increase is believed to be ready to the surgical procedure because it is not dose-dependent. Consistent with the known pharmacokinetics of CSF, NfL levels, the return to baseline takes several months. However, we're very pleased to see that 2 years after treatment, both doses of AMT-130 have CSF levels below baseline, a result that has never been seen before in a clinical trial setting, therapeutic setting in Huntington's disease. As you can see in the graph inset, which zooms in on the data between month 12 and 24, the trends clearly continue downward for both doses. This would be the second most important graph that we're showing you today. The reductions in NfL below baseline and AMT treated patients is very relevant considering the increased one would expect in untreated patients as their Huntington's disease progresses. Recently, an independent study called HD-CSF measures NfL levels in the cerebrospinal fluid longitudinally in 71 patients at the start of the study and then 2 years later. They found that CSF, NfL levels inevitably increase as the disease progresses, and these findings suggest that neuronal damage accelerates as the disease progresses. In fact, when we analyze data from 19 out of those 71 subjects in the HD-CSF trial and select those who met our clinical and MRI inclusion criteria, we found that their NfL levels after 2 years increased by 26% relative to their baseline as shown in the gray bar on the left side of this graph. In contrast, the 21 patients who received the AMT-130 in our studies had a statistically significant reduction of 11% relative to their baseline after 2 years, as shown in the orange on the right-hand side of the graph. These data suggest that consistent with this mechanism of action, AMT-130 reduces neurodegeneration in Huntington's disease. Furthermore, these observations appear to be consistent with the favorable clinical data suggesting disease slowing. Next slide. Safety and tolerability are the primary endpoints in this Phase I/II study. In this update, if you can turn to the next slide, please. Thank you. In the next -- in this update, we have no new AMT-130 related serious adverse events to report and AMT-130 remains generally well-tolerated with a manageable safety profile. I'll pause for a minute so people -- if you can go back to the slides for a second, please. Just to give people a chance to look at this. This is a slide that I've seen before. It hasn't changed, but I want to give people a chance to do that. All right. Let's move on to conclusion, please. I'm extremely pleased with the results of this interim analysis to date. AMT-130 continues to be generally well-tolerated with a manageable safety profile with up to 3 years of clinical observation. This is the longest study evaluating a potentially disease-modifying therapy in Huntington's disease. As Huntington's disease, the slow progressing disease, longitudinal study of 2 or more years are necessary to show treatment effects in patients at early stages of their disease. With the majority of patients in our studies having reached 2 years of treatment, our data are starting to look promising with consistent clinical and biomarker data pointing out to potential beneficial effects of AMT-130 relative to well matched external control groups. Consistent with this mechanism of action, AMT-130 demonstrated a dose-dependent effect on a clinical composite score designed to sensitively measure disease progression in early Huntington's disease. Furthermore, CSF, NfL levels are significantly reduced below baseline, suggesting a reduction in the ongoing neurodegeneration. These are clearly different to what is expected if patients were left untreated. The totality of evidence presented today suggests that onetime treatment with AMT-130 reduces the progression of Huntington's disease over a 2-year period. If this treatment is maintained over time, this therapy has the potential to be groundbreaking in the treatment of this devastating disease. In the second half of this year, we will work closely with the FDA to clarify the regulatory path towards further development of AMT-130 and potential for accelerated approval. We will complete enrollment of Cohort 3, which consists of up to 12 patients and as AMT evaluate the effects of immune suppression on perioperative safety. We aim to provide an initial safety update from Cohort 3 in the first half of 2025. We will also provide a 3-year analysis similar to this current one by mid-2025. And with this, I conclude my part of the presentation, and I now have the pleasure to introduce Dr. Victor Sung, who has graciously agreed to provide his thoughts on the data update and first-time experience with AMT-130. Victor?

Thank you, Walid, and good morning, everyone. First, let me provide some context for my commentary today. I'm a Professor of Neurology at the University of Alabama at Birmingham, the Director of our UAB Huntington's Disease Clinic. I'm also on the Steering Committee for AMT-130. More importantly, for this conversation, I'm also a Site PI for AMT-130 and have 4 high-dose patients who have received AMT-130 under my care. But before I touch on my personal experience with AMT-130, I wanted to highlight several points, which I believe makes this data particularly compelling. So my biggest takeaways are the statistically significant improvement of cUHDRS at 24 months, which is a time interval at which the disease should have clearly worsened clinically. This is clinically important because cUHDRS as Walid mentioned, contains motor functional and cognitive components to them, which are all the key parts of the disease that patients recognize and find impactful. The other thing -- the next thing is the high dose being 0.2 from baseline at the 24-month mark on cUHDRS means that this group is essentially unchanged from a motor and cognitive standpoint from baseline, which is both impressive and unprecedented. For the CSF, NfL data, while this has traditionally been a safety of biomarker, I'm really, really excited about this data. It's significant and noteworthy that it's the first ever treatment in HD to show CSF, NfL falling below baseline at any point during a treatment trial. So that's pretty significant. The natural history cohort had a 26% increase in CSF, NfL in the 2-year time frame, which is in line with about 10% to 15% inexorable increases that we generally quote to our patients that NfL will worsen over time year by year. But the AMT-130 patients had an 11% decrease over 2 years time point, which really shouldn't happen and can only be attributed to AMT-130. To me, this is even more impressive considering the 400% increase seen initially due to the instrumentation. And from that big increase initially falling to 11% below baseline at the 2-year standpoint is really incredibly exciting. And this is the first study to show both statistically significant improvement in a functional outcome and lowering of NfL to below baseline levels in HD, and that combination really incredibly exciting. Mutant Huntington levels in gene therapy are hard to interpret because of the way that projections to cortex and the changes are delayed when you have a therapy that's injected into the basal ganglia. Similarly, volumetric MRI data is hard to interpret in the therapy where we instrument the basal ganglia and the resulting neuroinflammation there will make volumetric data hard to interpret and even more emphasizes the significance of the NfL and the functional data presented today. My experience with AMT-130 is really colored by my 4 treated patients who I followed for years now and who have done generally well. In particular, I have one patient who had gathered his family at the time of diagnosis to tell them all the grave news about his diagnosis and that he would ultimately follow the path of the parentally inherited HD from, and he told me the story and that there were lots of tears at that gathering, but then this patient had the opportunity to participate in the AMT-130 trial and now roughly 3 years after study entry, they're still working full time at an age that their parent who inherited the HD from had already died. And that patient's family member said, "Wait, I thought you said that you were going to follow the path of your parent and they're kind of all waiting for that other shoe to drop. And they really attribute his -- the subjects continued stability to AMT-130. So that's just a positive success story that I've experienced personally. And with that, I'll pass it back to Matt, and I believe we will take some questions.

Thanks, Victor. Operator, you can open the line up now for Q&A. Thank you.

[Operator Instructions] Our first question which will come from [ Rye Forsyth ] of Guggenheim Securities, LLC.

This is [ Rye ] from Debjit's team at Guggenheim. Congratulations on the data. Looking forward, what data or operational factors drove your decision to target a mid-2025 month 36 update relative to maybe a month 30 update.

This is Walid. Well, we believe the most useful way to compare our data right now as the study is progressing and patients are at this stage coming maybe twice a year for the evaluation is to compare them to the external control. And since the external control natural history, the visits are annual next meaningful update after the second year will be the third year data. And so we believe that by this time next year, we hope that we can build and expand on the data that we've shown you today with looking at a further progression of the disease or essentially slowing of the progression of the disease with AMT-130. That's truly what's driving that decision.

Our next question will be coming from Paul Matteis of Stifel.

Thanks so much for taking the questions and for the update this morning. A couple, so one is, I guess, what is your level of confidence right now that you can conduct a natural history control study. Two, do you think that this study is well suited to be expanded into one that could have natural history control? Or is that a different trial altogether in your mind or in your potential proposal. And then three, I mean, certainly, the cUHDRS data is interesting. Was this the endpoint that at the outset you had proposed to be the most sensitive for this type of therapy? I guess I had been under the impression that something like TMS or something that's more biased towards motor symptomatology might be the best measure for this mechanism, given deep brain delivery. So just curious on your thought process there.

Thanks a lot. So two questions, I'll tackle them in order. First, in natural history, I think it's clearly now the case that we're going to be relying more and more as our patients continue to invest in therapy on comparing to an external natural history cohort. So our objective is to build this natural issue to make it more robust by including additional databases that we could have access to by working collaboratively with cUHDRS, among others. But more importantly, when we meet with the FDA, we want to incorporate also their input on how to best construct these external natural history cohorts to be able to robustly compare to our therapy. So more to come as we have more information on this. Regarding the endpoint, the cUHDRS has been shown by an independent study that it has the best signal-to-noise ratio. If you look in our own data, you see that there are some differences between each component score. And sometimes when you look at patient level data, you also see a difference within the same patient, where they might have gone maybe a little bit worse in one visit compared to the previous one on one of these subscales better on another one. And that's truly where is the power of the cUHDRS, especially when you're dealing with smaller trials to take these individual variability and combine them to a composite score that is better designed to measure sensitively these changes. And actually, they successfully were able to show it in recent trials and in HD how they can quickly detect changes. In that case, it happened to be worsening of symptoms in HD. So in terms of priority choosing this at the beginning, look, this was a Phase I trial at the beginning when we started the primary endpoint, and I think I mentioned this in my presentation, is only going to be safety and tolerability. That's the first thing we think about. But of course, this is a gene therapy, one and done therapy where we continue to follow patients for years after therapy, we measure important endpoint, clinical endpoints, which these components are key, cUHDRS as the main one with its subcomponents as well as the biomarker data, NfL and others. And those were the decisions that we made at the beginning. So I do believe that while TMS could, in one case, show positive results in some cases, will not or changes between visits, cUHDRS is much more stable, particularly when you have a smaller number of subjects.

Yes. Just 2 quick points, Paul. One is we have a high degree of confidence that cUHDRS potentially could be improvable end point at least in certain geographies. It's less clear about a particular individual component or domain of the score. The second is if you really talk to Huntington's patients, obviously, the material symptoms are important, but so are the behavioral and cognitive symptoms. So I do think looking at a compose it makes a lot of sense.

And our next question will come from Joseph Schwartz of Leerink Partners.

Great. And let me add my congrats on the data. A couple of questions. First, could you walk us through your thinking when it comes to the development scenarios that you might face going forward? How much would you be willing to undertake on your own versus if you would require a partner for continued advancement?

Yes. Joe, thanks for the question. We are very willing to take this program forward, particularly under an expedited scenario. Obviously, to the extent that the regulatory agencies require a very significant expensive long-term Phase III study. That is something that we clearly would have to discuss potential partnering or other scenarios. I think we've been pretty clear that if we're going to be looking at hundreds of millions of dollars in 5 to 6 years of a Phase III study, that is something that is likely going to be beyond our means at least today. But I really do believe, particularly under RMAT designation that there is a lot of support for expedited clinical development pathway, particularly in Huntington's disease. And I think with the ability to collect long-term outcomes from an early clinical study in conjunction with a potentially surrogate biomarker like CSF, NfL. I really do think and encouraged for having discussions with the FDA later this year to discuss those faster pathways.

That's helpful. And then can you talk about the clinical relevance of these changes in cUHDRS, how does the clinical impact that you're detecting compared to any minimally clinically relevant differences that have been established to date.

Yes. Thank you. I'll take that question. The field has been very active in this space. Actually, most recently, there's a paper that came out in '23 by CHDI with a lead author, Jamie Hamilton, depicting what would be a clinically meaningful worsening on each of the cUHDRS and this upscale for a given stage of the disease. And actually, we've used this particular analysis to compare our data to. And what we're able to see is that the high dose has a 60% odds of reducing the auth of worsening for patients who are treated with a high dose compared to the natural history cohort. So we believe this is very clinically meaningful data and powerful.

And our next question will be coming from Ellie Merle of UBS.

Congrats on the data. Just for the NfL data, it looks like the low dose is getting slightly better than the high dose, but in the cUHDRS data. The high dose is performing better than the low dose. I guess how should we interpret this? And how are you thinking about the dose response more broadly?

Yes. Thanks, Ellie. Great question. If you recall, when you look at our time course, we've had, although a similar spike between the low dose and the high dose, which we attribute to the actual effect of the surgery itself. The return to baseline over time took longer at the high dose than at the low dose. And we believe those have been confounded by some of the inflammation that we've observed a bit with the high dose. And those were corroborated in individual cases when we look at individual time points where they have a spike in inflammation and that responds to therapy for that. So I do believe that the 2-year period is long enough after the intervention and after these effects to start to see a return to baseline, and we're very pleased with the fact that we have a return below baseline for the high dose. If I were to predict, my predictions would be that in the 3-year, the high dose should have a larger reduction from baseline and then the low dose on NfL. So the bottom line, we believe the high dose data are compounded by the inflammation, which the longer we go away from the intervention, the less we see those effects of the confounding tractors.

And our next question will be coming from Joseph Thome of TD Cowen.

Congrats on the update. Maybe one for Dr. Sung. I guess in terms of implementing this therapy broader into your patient population, should it be approved, I guess, what additional data would you like to see versus what we're seeing today, maybe to make you comfortable with the therapy, if anything or if the profile right now enough to kind of get you to use it more broadly if that were approved today. And then maybe second for the company, a little bit of a follow-up to the prior question, but I know in your fiscal year '23 press release, you did indicate a partner before Phase III, I guess how have partnership discussion has been progressing if at all? And if there is that accelerated pathway, do you think you could go forward with an approval on a launch internally? Or would you still want to partner for commercialization as well.

Thank you for the question. I'll start first. So I think, in general, this profile is very strong with cUHDRS, which I'm very familiar with and comfortable with both the components and as a composite and the NfL data is also extremely compelling. So generally, I feel comfortable with it from my patients as it stands. The one thing that I think I would love to see are, since it's really appearing that the high dose is more impactful overall functionally, and that's where we saw more inflammation. But in the plans for the next cohort, there are plans with a new immunosuppression protocol to kind of suppress that inflammation. And I'd like to see the data on that and how successful that immunosuppression plan is for the actual implementation of the therapy. But otherwise, overall, the profile I'm pretty satisfied with.

Thanks, Victor. Yes. And regarding your second question on partnering. Right now, we are focused on initiating our interactions with the FDA under RMAT. We expect an RMAT kickoff meeting, a multidisciplinary meeting, where we can engage with them meaningfully and frequently to understand the path forward. As I mentioned in one of the prior questions, I do believe and particularly with more focused operations and preservation of capital initiatives that we recently announced that we do have the ability to take this forward under an expedited pathway and based on the feedback that we get from the FDA, we'll make an appropriate determination if the partner is required.

Our next question will be coming from Salveen Richter of Goldman Sachs.

Two questions for me. Could you speak to the variability that seen across patients per dose cohort compared to natural history. And then help us understand, as you meet with the FDA later this year, just frame expectations as what you would view as a positive outcome?

Okay. So on the variability, again, I think what we're dealing with are endpoints that measure cognition, motor symptoms, and total functional capacity is a scale where it's an integer-based scale so essentially to scale from 0 to 13, with 13 being normal. So people can only have a reduction of 1 or 2 or more on that scale and those sometimes could be affected by somebody losing a job or somebody having a breakup with a partner and things like that. So when you do smaller studies like this is necessary in gene therapy, the variability is -- on individual scales will become much more prominent. And that's why the whole cUHDRS was developed specifically to improve that signal-to-noise ratio and reduce that individual variability into a composite score and allow us to draw better conclusions on our data. And for the second question on the FDA?

Yes. I mean on the second question, Salveen, I mean really this is the beginning of what's going to likely be a series of meetings under RMAT to kick us off to set a plan going forward with the FDA, we'll be in a position to raise certain questions and begin the dialogue, and we're committed to providing an update at the very least procedural update on what to expect going forward. And once we align with the FDA on a path forward, that's when we'll provide more detail.

And our next question will be coming from Luca Issi of RBC Capital.

Great. Congrats on data. Maybe, Matt, I appreciate a difficult question to answer. But in your head, what's the likelihood that this data as is, is sufficient for accelerated approval? Is that number above or below 15%. And then maybe second question on the subgroup. I appreciate small end, but any subgroup where the benefit is more pronounced here? I know Roche is focused on patients with low age and low cap. So wondering if what you're seeing is consistent with what they are seeing. Again, I appreciate different models there. But any color there much appreciated.

Luca, thanks for the questions. I'll let Walid to answer the second question. Yes, on the first question, it's very hard for me to handicap and provide a probability that based on this data alone, we could get accelerated approval. In my heart, I really am encouraged and really believe that we're seeing a potential therapeutic and clinical benefit here at AMT-130, particularly given the trends that we're seeing over a 2-year period. I mean you heard Dr. Sung talk about at 2 years, you really would expect to see this disease progress. And we're generally seeing stability across numerous clinical measures that are supported by the CSF, NfL data. The most important thing is not what's in my heart, right? It's in the minds of the FDA. And the great thing is that we're under RMAT, and we expect in the relatively near term to begin very significant interactions with them about potentially accelerated approval. Walid, do you want to answer the second question?