Uniqure NV

NASDAQ:QURE

Earnings Call Transcript 2022-Q2

[Operator]

Good day, and thank you for standing by. Welcome to the AMT-130 Huntington's Disease Program Update.

[Operator Instructions]

Please be advised that today's conference is being recorded. And I would now like to hand the conference over to Ms. Maria Cantor, Chief Corporate Affairs Officer. Ms. Cantor, please go ahead.

[Maria Cantor, executive]

Good morning, and thank you for joining us. This morning, uniQure announced that it has postponed patient enrollment in the higher-dose cohort of the Phase I/II clinical trial of AMT-130 in Huntington's disease based on reported SUSAR events at this dose. We will discuss these events and provide an update on the program during this call. Joining me for the investor event and webcast are Matt Kapusta, our Chief Executive Officer; and Dr. Ricardo Dolmetsch, our President of Research and Development.

We'll be making forward-looking statements during this investor call. All statements, other than those of historical fact are forward-looking statements. They are based on management's beliefs and assumptions and on information available to management only as of the date of this conference call. Our actual results could differ materially from those anticipated in these forward-looking statements for many reasons, including the factors described under the heading Risk Factors in uniQure's quarterly report on Form 10-Q filed today, August 8, 2022, and other securities filings. Given these risks and uncertainties, investors 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.

[Matthew Kapusta, executive]

Thank you, Maria, and good morning, everyone.

On June 23, we announced encouraging 12-month follow-up data from the low-dose cohort of our U.S. Phase I/II study that showed AMT-130 was generally well tolerated with neurofilament light levels near baseline in treated patients and meaningful lowering of mutant Huntington protein supportive of target engagement. As announced in our press release this morning, in July, we were informed of 2 suspected unexpected serious adverse reactions or SUSARs in the higher-dose cohort of our open-label Phase Ib/II clinical trial of AMT-130 in Europe. Both of these patients, which were the first 2 patients dosed at a single clinical study presented with globalized inflammatory responses and other related symptoms within 1 to 2 weeks after their procedures.

A third patient who had previously been treated with a higher dose of AMT-130 in the U.S. in March of this year experienced severe headache and other related symptoms also shortly after their procedure. That event was initially deemed by the investigator as not related to AMT-130, but related to the procedure. Upon further review and discussion with the clinical trial independent Data Safety Monitoring Board, or DSMB, we have reclassified and reported that patient's reaction as SUSAR. Importantly, these 3 patients are no longer hospitalized and have since fully or substantially recovered.

The DSMB does not view these events as a dose-limiting toxicity. And thus far in our investigation, we have not yet identified the root cause of these events. Nevertheless, we have the DSMB believe it is prudent to voluntarily and temporarily delay the enrollment in dosing of additional patients with a higher dose until we complete a comprehensive safety review in conjunction with our DSMB.

During that time, we will continue our investigation to consider potential risk mitigation plans. We expect to do this over the next 60 to 90 days. This delay does not apply to any future procedures at the low dose where no significant adverse events related to AMT-130 have been reported. Thus far, a total of 36 patients have been enrolled across our U.S. and European clinical trials, including 26 patients treated with AMT-130 and 10 control patients. Of those treated, 14 patients have received a higher dose with some having -- now we followed for up to 1 year.

An additional 12 patients have received a lower dose with some having now been followed for up to 2 years. Over the course of our studies, the independent DSMB has conducted 6 separate safety reviews. And aside from these 3 events, no other SUSARs have been reported. We do not expect this delay will have any impact on the data readouts in 2023. In the U.S. Phase I/II study, all 26 patients in the first 2 dose cohorts have been enrolled. And the company continues to expect to present 1- to 2-year follow-up data in the second quarter of 2023.

And the European Phase Ib study -- Phase Ib/II study, the 6-patient lower-dose cohort is fully enrolled, and the company continues to expect to present 1-year follow-up data in 2023. 4 of 9 patients in the European study have been enrolled in the higher-dose cohort. Before I hand the call over to Ricardo, I want to stress that patient safety and well-being will always be uniQure's top priority, and we are committed to working with the DSMB to complete our investigation as soon as possible. Now let me turn the call over to Ricardo.

[Ricardo Dolmetsch, executive]

Thanks, Matt, and good morning.

In mid-July, uniQure notified the health authorities of serious unexpected suspected adverse events related to 2 subjects in Europe treated with the higher dose of AMT-130 at a single clinical site. The first patient experienced onset of motor and other striatal symptoms within 12 days after the procedure, following admissions of a hospital and MRI, which showed enhanced T2-weighted MRI signal along the tracks of the infusion in the striatum caudate, consistent with edema or swelling in the brain. Treatment with steroids was initiated and tapered through a final dose of 10 days later.

The subject is now fully oriented and has a nonclinical neurological exam, but still have couple deficits in terms of fluency, memory and attention relative to its pre-automated state.

The second patient experienced vomiting and raised intracranial pressure as presented 12 days after the procedure. Following admission to the hospital [Technical Difficulty]

[Maria Cantor, executive]

I'm sorry, if you don't mind going back in your remarks just a little bit because we were losing you on the audio just a bit. You were fading out. So I apologize interrupting you. But if you can go back a little bit to reiterate and just for real clarity.

[Ricardo Dolmetsch, executive]

Absolutely. So I apologize. Let me start again. So in mid-July, uniQure notified the health authorities of serious unexpected suspect adverse events related to 2 subjects in Europe treated with a higher dose of AMT-130 at a single clinical site. The first patient experienced onset of motor and other striatal symptoms within 12 days after the procedure. Following addition to the hospitals and MRI was performed that showed an enhanced T2-weighted MRI signal along the track of the infusion and in the striatum and in the caudate consistent with edema or swelling in the brain. Treatments with steroids was initiated and tapered through a final dose 10 days later. The subject is now fully oriented and has nonclinical neurological exam, but still has several deficits in terms of fluency, memory and attention motive to its pre-automated state.

The second patient experienced vomiting and raised intracranial pressure that presented 12 days after the receiver. Following admission to the hospital, the patient was found to have papilledema or optic disc swelling, but the MRI did not show any evidence of edema in the striatum or longer-tract infusion. A lumbar puncture to remove 20 ccs of cerebral spinal fluid was performed and the symptoms fully resolved...

[Maria Cantor, executive]

Yes. I'm sorry, you were cutting out again, and I just feel for the benefit of all of those listening into the call, the content of what you're sharing is so important that it may be better to have Matt provide your remarks, and then we'll go to you in the Q&A session. Again, I think that, that matters for everyone listening in. Thank you. So we'll have Matt pickup from that.

[Matthew Kapusta, executive]

Okay. Yes, Matt Kapusta, everybody. So let me start off with the second patient experience, vomiting and raised intracranial pressure around 12 days after the procedure. Following admission to the hospital, the patient was found to have papilledema or optic disc swelling, but the MRI did not show any evidence of edema in the striatum or longer tracts. A lumbar puncture to remove 20 ccs of cerebral spinal fluid was performed and the symptoms fully resolved leading to discharge. The subject also received prophylactic antibiotics.

A subsequent review of the safety data from the previous treated patients identified a third patient who received a higher dose of AMT-130 in March of this year and U.S. segments. This patient had a serious adverse event that was initially deemed by the investigator to be related to the procedure and not AMT-130.

The patient was admitted to the hospital 7 days after the procedure with severe headache and vomiting. The patient was treated with analgesics and discharge from the hospital, but returned to the hospital 2 days later with the recurring headache, this time contributed to a CSF leak from a diagnostic lumbar puncture conducted at the prior visit.

The patient was treated with a blood patch, which is the procedure by which blood is injected into the spinal canal to patch a hole through which cerebral spinal fluid is leaking. The patient was then discharged from the hospital and is now fully recovered. While the CAT scan taken on day 7 did not reveal any abnormalities, MRI taken on the patient's 14-day follow-up visit showed some edema or swelling in the striatum and the infusion tracks, which largely resolved by the patient's 30-day follow-up visit.

Upon discussion with the DSMB following the events observed in European study, we have reclassified and reported this patient event as a SUSAR and reported to the authorities in mid-July. In compliance with our study protocols, uniQure has reported these events in the appropriate regulatory agencies, review them in detail with our DSMB and initiated a comprehensive investigation. While our investigation is not yet complete, we have thus far found no evidence that these events are related to quality of the clinical loss of AMT-130 or the shipping and handling of the drug or we haven't found any evidence that they were related to a non-lease and pharmaceutical preparation for the surgical procedures.

As part of our investigation, we are also evaluating if there's any evidence that medical history or genetic predisposition may make some patients more susceptible to acute inflammation. We will share the results of our investigation in a timely manner with regulators and with the medical and scientific community when possible. As all 3 events occurred within the first 1 to 2 weeks after the procedure, we believe that enhanced patient monitoring during this period has the potential to satisfactorily address any patient risk.

We have developed additional risk mitigation protocols, including closer patient monitoring procedures and treatments, which we are currently discussing with our DSMB. The DSMB does not view these events as a dose-limiting toxicity. However, we and our DSMB believe it's prudent to temporarily pause additional patient dosing with a higher dose until we complete our safety review and investigation and has put the observation and risk mitigation plans in place.

We expect this will occur sometime in the early fourth quarter. It's important to note that the delay does not apply to any future administration of the low dose of AMT-130. Thus far, no significant adverse events related to AMT-130 have been reported by any of the 12 patients treated with a lower dose, who have now been followed up for up to 2 years. The DSMB has allowed us to continue enrolling at the lower dose of AMT-130 for patients crossing over from the placebo group in the U.S. study, which is expected to take place in the third quarter.

We are optimistic this matter to be resolved in a timely manner and dosing of the 5 remaining patients in the European higher-dose cohort can be resumed. I want to reiterate, we do not expect that this will have any impact on previously guided data readouts in 2023.

With 36 patients enrolled to across both clinical trials, we expect to have sufficient data to maintain our time lines for regulatory discussions and decisions regarding potential registrational pathway. We also continue to be very encouraged by the 12-month update we provided in June on the patients in the lower-dose cohort of the U.S. study. These data show neurofilament light chain levels in your baseline and lowering a mutant Huntington protein levels suggested a meaningful target engagement. We believe this notes has the potential to provide benefits to patients suffering from Huntington's disease and we look forward to working with the HD community to develop a treatment for this devastating disease.

Now I'd like to open up the call for analyst questions, operator. Thank you.

[Operator]

[Operator Instructions]

Our first question will come from Paul Matteis of Stifel.

[Alexander Thompson, analyst]

This is Alex on for Paul. I just wanted to ask, have you share these updates with the FDA yet? What has your dialogue been and is there any risk to be placed on a clinical hold?

[Ricardo Dolmetsch, executive]

Right. This is Ricardo. So absolutely. So right after we brought these reports from the sites, we shared them with both the EMA and the FDA. And so far, we have heard nothing. [Technical Difficulty]

[Matthew Kapusta, executive]

Yes, I think your audio is still muffled. But just to repeat it, all of these events have been shared with the appropriate regulatory agencies in accordance with our protocols and regulations and we have not had any specific dialogue with them or outreach that we received.

[Operator]

Our next question will come from Joe Schwartz of SVB Securities.

[Unknown Analyst]

This is Beth on for Joe. So I know you said that no clear root cause of these serious adverse events have been identified yet, but just curious what your initial hypothesis is on what could be driving it? Is there any sort of reason to believe that it could be associated with the degree of wild-type Huntington's protein knockdown? And just in the serious adverse events occurred so closely to the administration period, curious if that could be playing any sort of role as well?

[Matthew Kapusta, executive]

Yes. I think that obviously, we need to complete our investigation before we weigh in specifically on the hypothesis. But I will say that the proximity of these events, which have happened within days of the procedure lead us to believe that it's probably unlikely that it's a mechanism of action related and that it is probably something related to either the immune response or inflammation associated with the product or the procedure itself.

[Unknown Analyst]

Got it. And I guess just as a quick follow-up for the 3 patients who appears as serious adverse events, how are they doing now? And just in terms of their NfL signal, have you been monitoring that and notice any sort of differences in how it's maybe the time it takes return to baseline compared to others?

[Matthew Kapusta, executive]

Yes. The 3 patients are no longer hospitalized. 2 of the 3 patients have fully recovered. One of the patients have substantially recovered. I think there's some subtle deficits that are continuing to be monitored. And we have been doing the battery of follow-up tests, including neurofilament light. All of that information is going to be shared or is being shared with the data safety monitoring board in part of the comprehensive investigation.

[Operator]

Our next question will come from Debjit Chattopadhyay of Guggenheim Partners.

[Debjit Chattopadhyay, analyst]

Just a couple of clarifications. What was the volume of administration between the low and the high dose? And is there any difference in the rate of infusion between the 2 doses?

[Matthew Kapusta, executive]

The volume, I think, is roughly the same. I think it's just the concentration that is different. I don't know, Ricardo, if you have changed your audio. But I believe that's the case. And the rate of infusion, I think, is consistent with the low-dose procedure as well.

[Ricardo Dolmetsch, executive]

So yes, so the volume is exactly the same at the low dose and the high dose. It's basically a total of 3 mills in -- for both. And the data input is exactly the same.

[Debjit Chattopadhyay, analyst]

And did you measure neutralizing antibodies at baseline?

[Ricardo Dolmetsch, executive]

Yes, and none of the patients have neutralizing antibodies.

[Operator]

Our next question will come from Joseph Thome of Cowen.

[Joseph Thome, analyst]

It seems like the disease course or the response course is a little bit different in the European patients than the U.S. and then that U.S. patient had the CSF issue. So have you ruled out that this is a potential physician or administration error versus something like AMT-130? And then second, what do you expect to learn, I guess, between now and that Q4 safety review?

[Matthew Kapusta, executive]

So we -- until we finish our investigation, it's probably difficult to rule anything out at this juncture. Having said that, there's been no specific evidence that we have found that's directly implicated the procedure or the way that the procedure has been done. And it's not clear if that's something that we'll be able to identify. But it is true that 2 of these particular SUSARs happened at 1 clinical site and they were the first 2 procedures that were performed at that clinical site. So we'll continue to investigate that, but as I said, we know there's no evidence that supports that thesis right now.

Between now and the next Data Safety Monitoring Board meeting, we're going to complete our investigation associated with reviewing all different aspects and factors that could contribute to the root cause. And we will, in addition, have some further follow-up associated with the 14 patients in the high-dose cohort. I'll just remind everybody that we have treated 14 patients in the high-dose cohort and one of those 14 patients have not reported any significant adverse events related to AMT-130 to follow-up up to 1 year.

So all of that information will be compiled and pulled together for the DSMB as part of the review that we expect to have next month.

[Operator]

Our next question shall come from Salveen Richter of Goldman Sachs.

[Elizabeth Webster, analyst]

This is Elizabeth on for Salveen. A few from us. So have any more procedures being performed at that same site in the EU where the first 2 procedures were performed?

And then do you intend to message to the Street after the safety review in 4Q? And then what are kind of the exact evaluations that are going to be performed during safety investigation? And if you could give more color on some of the specific things you're going to be looking at?

[Matthew Kapusta, executive]

Okay. So the answer to your first question is no, there's been no additional procedures that have been performed at that particular site or any site for that matter. So just to make that clear.

Second is that we will provide an update after we complete our review with the Data Safety Monitoring Board. And then third, as I mentioned, there's various different factors and analysis that we'll be looking at. One is that we're going to continue to complete our investigation of the critical quality attributes to the product. As I said, there's nothing thus far that suggests that there's any CMC-related issues or critical quality attributes, but we want to finalize that analysis. We will continue to review the pharmaceutical preparation and shipping and handling associated with the product.

Again, there's no evidence that suggests that. There's additional data that will be approved on follow-up visits. Again, remember that we have 26 patients that have been treated thus far that are doing quarterly follow-up visits. And in particular, in the high-dose cohort, a number of those analysis are batched. So we will aggregate that data and review that data with the DSMB, and we expect to do that over the course of the next 60 to 90 days.

[Operator]

Our next question shall come from Eliana Merle of UBS.

[Sara Khan, analyst]

This is Sara Khan on for Eliana. As you're thinking about building out the pipeline beyond hemophilia and Huntington's, how are you thinking about potential business development there?

[Matthew Kapusta, executive]

So the pipeline beyond Huntington's disease. I mean, we're always looking at business development. Business development is something that is going to be part of our strategy. I think what we're committed to is being disciplined about business development and making sure that any transaction that we might consider is strategic and that we believe can drive value for our shareholders. So beyond that, it's not something that I can really comment on.

[Operator]

Our next question will come from Danielle Brill of Raymond James.

[Alex Nackenoff, analyst]

This is Alex on for Danielle. Is there any way this could be related to the duration of the surgery? We're just kind of curious if there's any way that this could be rectified by the planned shortened surgical procedure. And then a quick follow-up or a separate question on the control crossover. Was it ever an option for the patients or for you as a company to provide the low-versus-high dose for the placebo crossover patients who chose to crossover?

[Matthew Kapusta, executive]

Yes. In relation to that question with respect to duration, again, our investigation isn't complete yet, but I'll just remind, I mean, we've done 26 procedures that have been generally consistent in terms of duration. And this is the first 3 SUSARs or events like this that we've seen. So it's -- our thesis is that it's probably not related to the duration of the procedure, but it's something that we'll continue to look at.

With respect to the crossover, listen, it's difficult to enroll patients in the first-in-man study where they have the possibility of sham control unless they have the potential to crossover to treatment. So I think that, that was always something that I think, was an option that was less open. Of course, it became something that we have to establish safety.

So I think that now we can offer that the DSMB has evaluated the information and believe that, that's something that we should provide to the patients that had a control.

[Alex Nackenoff, analyst]

If I could follow up though. In terms of the crossover, I understand they could crossover. But in terms of -- was that always an option of that they could receive the high dose and now that's off the table, or was that going to be determined after the normal safety and advocacy data?

[Matthew Kapusta, executive]

I don't think there was any specificity about exactly which dose they got. I think that, that was something that would be determined based on the information that the DSMB had at the current time. So the bottom line is there is an option for crossover patients to get the high-dose cohort, but it will depend.

[Operator]

Our next question shall come from Sami Corwin of William Blair.

[Samantha Corwin, analyst]

Based on the biomarker data from the low-dose cohort and now the 2 stars in the high-dose cohort, are you guys rethinking your development strategy for AMT-130 at all? And like in particular, are you reevaluating possibly expanding the low-dose cohort?

[Matthew Kapusta, executive]

We have not made any decisions yet. It's a little too early for that. I think we want to complete our investigation and have our review with the DSMB. And at that point in time, we'll be better reformed to weigh in on how we might bring forward the product and how that might impact the dose that we move forward.

[Samantha Corwin, analyst]

Okay. And then are there any changes in the time line for conducting the procedures with the new surgical procedure?

[Matthew Kapusta, executive]

Well, we wanted to complete dosing of the higher-dose cohort. So that was something that we messaged in the June call. That was really what we're focused on. So we're probably not going to be moving forward with the third-dose cohort until we complete the enrollment of these remaining 5 patients. We think, again, this is something that's a decision that we'll be able to make in the next 60 to 90 days. So we think any impact on the third-dose cohort will be minimal.

The other part that I'll mention is that, again, the third-dose cohort, it's not really a dose cohort, it's a surgical-adaptive cohort, where we're going to be mostly focused on understanding the feasibility and CP, the procedure. So we don't think that, that impact is going to impact late-stage development in a material way at this juncture.

[Operator]

Our next question will come from Robyn Karnauskas [indiscernible] of Truist.

[Alexander Xenakis, analyst]

This is Alex on for Robyn. I just wanted to clarify, if the DSMB concludes that the SAEs observed were procedure-related, would this third-dose cohort with a different procedure to qualified to establish a new procedure that might be better? Or would you need additional clinical trials? And would you apply that to the low-dose cohort if you wanted to expand that trial and carry that forward?

[Matthew Kapusta, executive]

Yes. Again, it's going to be difficult to hypothesize or conjecture about what might happen. I would say again that it's probably unlikely that it's generic procedure-related. We haven't seen any significant adverse events related to AMT-130 or the procedure and the entire low-dose cohort of 12 patients, and there's 11 of the 14 in the high-dose cohort where we haven't seen it as well. It might be something related to the specific procedure right, of that particular patient. But I think it's unlikely that there's some generic issue with the procedure itself, given the safety track record that we have over the last 2 years. But any learnings that we get from this to the extent that they're applicable across the board, they certainly will be applied for the benefit of all patients. And that would include risk mitigation or closer-patient monitoring procedures.

[Operator]

Up next, we have Luca Issi of RBC Capital Markets.

[Luca Issi, analyst]

I know this was discussed a little bit earlier, but can you just help us understand how adverse events are dichotomized as related to the procedure versus related to the actual drug, is that a pretty clear cut? Or is this more like a fine line that comes down to clinical judgment? So again, any color there would be great.

And then in terms of resuming the dose, what are your options here that you're contemplating in order to resolve the issue at a high dose in addition to more frequent monitoring, what are the other levers that you can pull? How you're thinking about potentially refining inclusion-exclusion criteria? Are you considering maybe putting all patients on stereo-prophylactically? Any additional color there would be great.

[Matthew Kapusta, executive]

Yes. So adverse events are really characterized by the investigator. So those events are documented and the specific investigator that is managing that patient really weighs in and attribute that to either the procedure or the product or unrelated to the best of their ability. So it's really a judgment call that is really clinician-directed. It's also something that we would review with our Data Safety Monitoring Board and to take into opinion their evaluation and recommendations as well.

And then just remind me your second question?

[Luca Issi, analyst]

Yes, what are your options going forward here to kind of solve the issues? You obviously talked about more frequent monitoring, but I was wondering if there's any other components here that you're contemplating?

[Matthew Kapusta, executive]

Yes. No, it's really -- I mean just as to remind you -- all of these really happened in the first 1 to 2 weeks, right? So these are things that we can check in with patients on a daily basis. Before they're discharged from the hospital, we can do specific evaluations to make sure that they are meeting certain standards for discharge. There's a possibility that we could do, if there's anything we have normal or unusual, we can do an additional MRI procedure. And then if there are any symptoms of edema or inflammation, we can much more rapidly bring them in for suppression or steroid treatment. So that's really what it is that we're focused on. If there's any reactions that happen quickly, we can identify those reactions and then get the patient treated. And with that, we think we can substantially mitigate any risk to the patients.

[Operator]

Our next question will come from Kristen Kluska of Cantor Fitzgerald.

[Kristen Kluska, analyst]

Just to switch gears on hemophilia B. Is there any color behind the decision that the review could not be done in Europe on an accelerated basis? And when in the U.S. and Europe and CSL bearing expect approval decisions to take place at this time? And then can you remind us of the near-term milestone payments you are eligible for?

[Matthew Kapusta, executive]

Yes, sure. So with respect to the interactions with EMA that is being handled completely by CSL. What we have heard from CSL is that there was no specific issue that was identified in the review that led to the switching from accelerated-to-standard review that this is simply just a bandwidth issue and for EMA and as a result, that they needed some additional time for the review, but there was nothing specific.

With respect to the timing of approval, I think that again is something that CSL will have to provide. I think what we've said is that we would now expect approval probably early next year, early in the first quarter of next year. That's based on the standard review. So that's what we would [Technical Difficulty] With respect to milestones, we have stated that there's $175 million that would be received upon commercial launch of the product in the United States and Europe. And then there's additional milestones that are commercial related to certain net sales thresholds as well as commercial launch in Japan.

[Operator]

Our next question will come from Judah Frommer of Credit Suisse.

[Judah Frommer, analyst]

First, maybe just following up on kind of the hypothesis that CMC or quality control and handling our product could have potentially been an issue here. Would those have been the same for the EU and the U.S. product, where those have come from the same batch or potentially been handled the same way just by being conducted at different sites?

[Matthew Kapusta, executive]

Precisely the analysis that we do, right? We just look to see if there's any loss, a lot of differences in any of the critical quality attributes. And based on that assessment, we do not believe that the -- that this is likely to be anything related to CMC.

[Judah Frommer, analyst]

Okay. And then just if we do end up in a situation where there was a dose-limiting toxicity here, kind of -- can you assess kind of how that would affect your confidence in the program, if you were maybe only going forward with the low dose? Maybe just remind us of your preclinical work and how the potentially confer functional benefit if we are going to be in a functional study at some point ideally with that least or low dose?

[Matthew Kapusta, executive]

Yes. This doesn't impact my confidence in the program, honestly. I mean the purpose of a dose-finding study is exactly that to find the right dose. We are really pleased with the data that we presented thus far from the first 10 patients in the U.S. study. We haven't seen any significant adverse events related to the low dose. We saw suppression of mutant protein and through the spinal fluid that, quite frankly, was more meaningful than what we saw in the preclinical work. So that was over 50% depression mutant protein. At 12 months, we've seen neurofilament light levels near baseline. So we're really encouraged by that data. And even if there is a dose-limiting toxicity, we'll have to obviously continue to follow patients that received the low-dose cohort, but we continue to be really pleased and encouraged about that dose.

[Operator]

Our next question shall come from Yanan Zhu of Wells Fargo.

[Yanan Zhu, analyst]

So I think in 2021, FDA convened an Advisory Committee meeting reviewing AAV gene therapy safety. And one of the topics was MRI abnormalities arising in patients who received intra-parenchymal injections of AAV. So I'm wondering, based on those, the information presented there, how do you feel your -- the cases you have been seeing similar or different from those cases, for example, in terms of timing of onset and whether patients are symptomatic or not?

[Matthew Kapusta, executive]

Yes. It's hard for me to compare it against what was presented at the panel, but as I say, these are pretty acute cases. All the patients have been treated, have either fully recovered or substantially recovered. The most important thing is, obviously, the clinical prognosis for these patients. We're still learning a lot around what we're actually seeing in the MRI. What is this related to? In some cases, it's the drug working, and it's not a best thing. But what is the best thing, obviously, if there's any safety implications for the patients, but the most important thing is that these patients can be treated, they can be monitored more closely and that they can recover, right? So that's really the most important thing that we're focused on. And so we're pleased in that regard.

[Yanan Zhu, analyst]

Got it. If I may have a quick follow-up. In the low-dose patients, have any of them been followed up with MRI? And whether are there any MRI findings in those patients, of course, those will be nonsymptomatic.

[Matthew Kapusta, executive]

All of them, every simulation is followed up with an MRI. Those MRIs happen, I believe, quarterly. And the -- I think what we've reported at the time that we presented this data on the low-dose cohort patients is that there were no structural abnormalities on the MRI, but a full safety update will be provided when we present comprehensive data next year.

[Operator]

Our next question will come from Yun Zhong of BTIG.

[Yun Zhong, analyst]

This is a follow-up question on the low dose. Given the data, like you said, Matt, expect -- exceeded our expectations. So I wonder how much effort and time would you like to spend to figure out the high dose before deciding maybe low dose is the optimal dose to move forward?

[Matthew Kapusta, executive]

Yes. I mean I'll remind everybody. So we have 14 patients that have received treatment with the high dose. So -- and there's remaining 5 patients in the European study that have not been treated thus far. This is in the first 2 dose cohorts. So I mean, we can follow the 14 patients that we've treated and have very robust data to, I think, evaluate the high dose and the low dose next year. So I'm not sure we concerned that we'll be spending a lot of energy or a lot of time evaluating this.

I think to the extent that the DSMB continues to have pause when we do our safety review, we always have the possibility of contemplating, treating those remaining patients with a low dose. But as I said, we'll cross that bridge when we have that discussion and provide an update after that time.

[Operator]

And we have a follow-up question from Debjit of Guggenheim Partners.

[Debjit Chattopadhyay, analyst]

A clarification. Is the EU segment enrolling subjects with similar disease stage and caudate putamen volume as the United States?

[Matthew Kapusta, executive]

Yes.

[Debjit Chattopadhyay, analyst]

Got it. And do you have a sense where the NfL lines up in these patients? I know it's early, but given the U.S. patient who had SAE back in March, do you have a sense of where NfL lines up in these patients with SAEs versus those who have not experienced an SAE?

[Matthew Kapusta, executive]

Yes. What I'll say is that we're not providing any of that specific details, but the information is being reviewed by the Data Safety Monitoring Board.

[Operator]

And we have a follow-up from Luca of RBC Capital Markets.

[Luca Issi, analyst]

Great. I'll be quick. Just circling back on the hemophilia B delay in Europe. Is this related to the companion diagnostic? Or how should we think about that?

[Matthew Kapusta, executive]

No. I answered that part before. There's no specific issue that was cited by the European authorities related to it at all. So this is not like there's a specific issue that they've identified and feel they need more time to review that specific issue with just a bandwidth issue with the agency that they feel they just need more time to complete the review.

[Operator]

And I'm seeing no further questions in the queue. I would now like to turn the conference back to Matthew Kapusta for closing remarks.

[Matthew Kapusta, executive]

Thank you, operator. In summary, we remain confident in the potential of AMT-130 in Huntington's disease, continue to be very encouraged by the data we recently presented. We hope to resume higher-dose enrollment with minimal delay. We do not expect any impact to the previously guided data readouts for next year. As mentioned earlier, patient safety will always be our top priority, and I'd like to express my gratitude for patients, their families and physicians who have been part of our clinical trial to date for their trust in us and their dedication to pursuing new treatment options. Thank you for attending this call, and we look forward to providing further update as soon as possible. Thank you.

[Operator]

Thank you. This concludes today's conference call. Thank you all for participating. You may now disconnect, and have a pleasant day.