Good day, and thank you for standing by. Welcome to the PIVOT- HD 12-month Interim Results Conference Call. At this time, all participants are on 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 11 on your telephone. You will then hear an automated message advising your hand is raised. To withdraw your question, please press star 11 again. Please be advised that today's conference is being recorded. I would now like to hand the conference over to your speaker today, Dr. Matthew Klein, Chief Executive Officer. Please go ahead.
Thank you all for joining the call this morning. I'm excited to share the encouraging data from the 12-month interim readout of the Phase 2 PIVOT-HD study of PTC518 in Huntington's disease patients. PTC518 comes from PTC's pioneering splicing platform and has been following the successful discovery and development path of Evrdi, the first ever approved small molecule splicing modifier, and now the global leading SMA therapy. We look forward to similarly advancing PTC518 for the over 130,000 symptomatic Huntington's disease patients around the world who desperately need a disease-modifying therapy. Before I begin, I refer you to our forward-looking statements on this slide, which are also posted on our website, as well as our risk factor section in our most recent 10-K. Last summer, we shared the 12-week results of the initial cohort of Stage 2 Huntington's disease patients enrolled in PIVOT-HD.
We achieved all the 12-week study objectives, including demonstrating dose-dependent lowering of Huntington mRNA and protein and blood cells, excellent CNS exposure, and a favorable safety and tolerability profile with no evidence of treatment-related NfL spikes. These data confirmed that PTC518 demonstrates the selectivity and specificity for the huntingtin mRNA and broad CNS bioavailability required for a safe and effective HTT lowering agent. The initial cohort of patients have now completed 12 months of treatment, and the objectives for the 12-month interim readout include demonstrating durable dose-dependent lowering of HTT protein and peripheral blood cells, demonstrating evidence of early signals of favorable CNS effect on disease biomarkers and functional clinical scales, and, importantly, continued safety and tolerability at the 12-month time point. I am proud to report we have achieved all these objectives.
We see durable HTT protein lowering in blood cells at 12 months, with protein lowering of over 40% at the 10-milligram dose level. We see dose-dependent lowering of CSF mutant Huntington protein, with over 40% lowering at the 10-milligram dose level. We see dose-dependent trends of early clinical benefit on key disease functional measures, and we see continued favorable safety and tolerability of PTC 518. I'm also happy to report that, based on the Pivot HD data collected to date, the FDA has lifted the partial clinical hold on the program. Before going into more detail on the study results, I will review the Pivot HD study design. Pivot HD is a 12-month placebo-controlled study in two parts. Part one is 12 weeks in duration and focuses on PTC 518 pharmacology and pharmacodynamic effect. Part two is 9 months in duration and focuses on disease biomarkers and HD clinical scales.
The study includes two dose levels, five milligrams and 10 milligrams, and we are studying two patient cohorts: Stage 2 patients and early Stage 3 patients. Following completion of PIVOT-HD, all subjects are eligible to participate in a long-term open-label study. Now, I will review the 12-month interim results. This slide highlights the baseline characteristics of the Stage 2 subjects included in the 12-month interim readout. The dosing cohorts are well-matched for age and CAG repeat length, and, as expected, all have a normal total functional capacity score of 13, which is a defining characteristic of Stage 2 disease. Let's begin with the results of peripheral blood cell lowering. As a reminder, at week 12, we reported a dose-dependent lowering of HTT protein and blood cells, with lowering of 21% at five milligrams and 30% at 10 milligrams.
Now, at 12 months, we see durability of HTT lowering of blood cells, with lowering reaching 22% at 5 milligrams and 43% at 10 milligrams. After week 12, there was progressively greater lowering of HTT protein over time that reached a steady state between six and nine months. Now, let's look at the biomarker and clinical scale results. As we have discussed, the objective here is to capture evidence of early signal of effect on either disease-relevant biomarkers and/or clinical scales. As you will see, we achieved this objective with evidence of favorable effect on both. At month 12, we see dose-dependent lowering of mutant Huntington protein in the CSF, reaching over 40% lowering at the 10-milligram dose level.
I want to highlight that the magnitude of CSF lowering observed at both 5 mg and 10 mg dose levels is consistent with the magnitude of lowering in peripheral blood cells, supporting that we are likely reducing mutant protein levels within the brain by at least 20% and 40% at 5 mg and 10 mg, respectively. The actual lowering in brain cells may be even greater, based on the PTC518 exposure data. As we cannot biopsy the brain and directly measure the changes of Huntingtin protein in the neurons, measuring mutant Huntingtin protein changes in the CSF provides the best direct evidence that we are lowering mutant Huntingtin protein in the central nervous system. Moving to NfL, on the left side of slide 13, we see decreased NfL levels across placebo and both dose groups from baseline to month 12.
I want to point out that, based on natural history studies, NfL increases on average 10%-12% per year in Stage 2 patients and that there can be fluctuations in NfL levels over time. On the right-hand side of the slide, from a safety standpoint, we again see that there have been no treatment-related NfL spikes recorded over time in either dose group. On volumetric MRI analyses, we see consistency in brain volume changes over time across all three treatment groups. Shown here are the results for the striatum, and the overall brain volume results are similar. These results are expected given the slow rate of progression of brain volume changes. This will be a measurement that we will continue to follow in the open-label extension study in order to discern treatment effect over time. Now, moving on to the clinical scales.
At month 12, we see dose-dependent treatment benefit on the Total Motor Score, with treatment at 10 milligrams reducing progression on the TMS by over 70%. Of course, I want to highlight that these are early data on a relatively small number of patients, but in Stage 2 patients, the TMS is one of the disease measures that tends to be the most relevant in measuring disease progression, and to see this signal of favorable CNS clinical effect in such a small number of subjects at month 12 is clearly encouraging. We also see evidence of clinical benefit on both the composite UHDRS scale and the Total Functional Capacity scale. Again, these are early data in a small number of subjects, but the data are quite encouraging and provide a signal of favorable CNS effect.
I want to point out that the average per-year change on the cUHDRS is approximately one point, so the PTC518 treatment effect relative to placebo in this initial group of subjects is notable. The demonstration of CNS biomarker effect in early clinical signals of effect achieved the main objectives of the month 12 readout. In addition, we are also seeing continued evidence of favorable safety and tolerability. At month 12, there remain no reports of dose-limiting toxicities. The most common adverse events are similar to those reported previously at week 12, with equivalent frequency across dose groups and placebo subjects. As shown on this AE table, the frequency of events is also consistent across each dose group, and there have been no grade 4 nor 5 adverse events reported in the 12-month cohort of patients. In summary, we have achieved all the objectives of the 12-month study readout.
There is durable dose-dependent lowering of blood HTT levels. There is dose-dependent lowering of CSF mutant Huntington protein levels, reaching over 40% at the 10-mg dose level, and we see early signals of dose-dependent benefit on key disease functional scales. PTC518 continues to be safe and well-tolerated, and, as mentioned earlier, based on the PIVOT-HD data, the FDA has lifted the partial clinical hold on the program. Finally, we will share 12-week results on the subjects who have completed this time point across both Stage 2 and Stage 3 cohorts. This table summarizes the patient and disease characteristics of the additional subjects included in this readout. As you can see, patient age, CAG repeat, and TFC score are similar across each dose group.
With the addition of Stage 3 subjects, we see average TFC is slightly below 13, as the enrollment criterion for early Stage 3 is a TFC of 11 or 12. In terms of blood HTT lowering, we again observe dose-dependent lowering at both 5 milligrams and 10 milligram dose levels. We expect lowering to continue and to reach steady state between month 6 and 9, like in the initial cohort. The safety profile in these additional subjects is also consistent with what we have observed previously, with similar adverse event profiles across all treatment groups, including placebo. In conclusion, the 12-month interim PIVOT-HD results met all the key objectives, with durable HTT lowering in the blood and favorable biomarker and early clinical effect recorded.
We observed mutant Huntington protein lowering in the CSF of over 40% at the 10 mg dose level, and we see a clear early signal of dose-dependent benefit on the TMS score, which is a particularly relevant functional measure for Stage 2 HD patients. We will continue to follow the patients progressing through Pivot HD, as well as those now enrolled in the long-term extension study. And with these promising results in hand, we will begin work on the design of the phase 3 efficacy trial of PTC518, which, as we have previously said, can either serve as a confirmatory study in the context of an accelerated approval based on Pivot HD or serve as a registrational trial. Finally, I want to thank the patients and their families who are participating in the Pivot HD study.
We remain committed to advancing PTC518 for all those patients affected by HD who may benefit. I will now turn the call over to the operator for questions on the PTC518 HD program. Operator? Thank you. As a reminder, to ask a question, please press star 11 on your telephone and wait for your name to be announced. To withdraw your question, please press star 11 again. Questions on today's conference call will be limited to PTC518 and the HD program. Please stand by while we compile the Q&A roster. Our first question comes from the line of Kelly Shi with Jefferies. Your line is now open. Thank you for taking my question and congrats on the progress. So did you have a statistical analysis on TMS, the total motor score, across the control and the 5 milligram group? And is the difference considered clinically meaningful?
Also, moving forward, how do we think about the trend change beyond 12-month landmark analysis? Thank you. Thank you very much for the question, Kelly. So we did not do a formal statistical analysis on the TMS changes, but I'll say, you know, with 30 subjects at 12 months in HD, to be even able to detect the dose-dependent difference that we're observing is truly notable. And we were incredibly encouraged by those findings. In terms of, is that clinically meaningful, I think when you consider the change at the 10-milligram dose group representing a 70% slowing in disease progression over 12 months, I think most would agree that would be incredibly meaningful if those results held over time. So we will, of course, continue to follow the patients over time.
As we said, the objective here at 12 months was, can we simply see any signal of effect on these measurements and be able to see this dose-dependent trend in a small number of patients at the 12-month time point of this disease? Again, it is incredibly encouraging. Terrific. Thank you. And also, I apologize if I missed what you have discussed on this point. So given the dose response and also the good safety observed so far, what is the plan with the 20-milligram dose? Good question. We said all along, Kelly, that the goal was to achieve a lowering of between 30% and 50% of Huntington protein. The reason for that is we understand that that's really the spot to be in in terms of getting optimal clinical effect as well as safety.
With the 5- and 10-milligram doses, we're continuing to see that we're sitting right in the therapeutic window where we want to be and therefore have no plans to go beyond the 10-milligram dose level. We're confident that 5 and 10 would be the doses that we would bring forward. Okay. Terrific. Thank you, Matt. Congrats again. Thank you. Thank you. Our next question comes from the line of Kristen Kluska with Cantor Fitzgerald. Your line is now open. Hi, good morning. Let me also add my congratulations on the data, as well as getting the partial hold lifted. So encouraging to see some of these clinical outcomes that you're seeing, a dose benefit favoring drug over placebo. Based on the patients that you enrolled, can you remind us, maybe across some of these endpoints, what you would have expected from natural history?
And I know you shared that data with us on NfL. And again, is that NfL data, would you say, in line with the specific inclusion/exclusion criteria of the patients enrolled in the study? Thanks for the question, Kristen. So we've talked a lot about how, in designing the PIVOT-HD study, we were incredibly thoughtful about the inclusion criteria, wanting to include patients who are at a stage of disease where they weren't so advanced that targeting the upstream cause of the disease wouldn't register a meaningful effect on progression. And that's so early that the patients aren't progressing enough to be able to register a meaningful effect. And so when we think about these patients, these 30 or so patients at the 12-month time point, they're all Stage 2 patients.
And as we mentioned on the call, that's a group where total motor score is really the clinical instrument that's most relevant to functional changes over that time period. Now, the natural history data on these stages of subjects is a little bit variable. Most recently, there was a report, the SHIELD-HD, or SHIELD-HD study that was presented at CHDI, where there was about a 2.3-point change per year, point change per year. There's others where it could be higher, a 4 or 5 point change per year. But that's also, I think, the value of having the placebo arm up to these 12 months, because it really allows us to understand the treatment effect we're seeing in patients who are more specifically matched for the age and severity characteristics of those who are receiving active therapy.
So I think what we're seeing across the board are changes that are in line with natural history. And certainly on the cUHDRS, where we're seeing basically almost a 1-point change per year in the placebo group, that's pretty much in line with natural history at this severity, which also makes the changes we're seeing, while seemingly small treatment differences, potentially clinically meaningful. My experts talk about even a 0.1 or 0.2 treatment effect over 1 year could be considered clinically meaningful because it would represent approximately 20% slowing of progression on that composite score. So overall, we're seeing on the clinical endpoints placebo changes in line with, in most cases, natural history. And we did point out that NfL difference, which was notable on the plasma NfL, but also what's clearly acknowledged about NfL and HD, is that there is a lot of variability over time.
And so it's really going to be a larger number of patients probably over a longer period of time to see clearer changes. Okay. Thanks for that. And I don't want to jump too ahead, as obviously you'll be meeting with the regulators next. But what is your sense about, in general, the latest regulatory guidance on pivotal trials and primary endpoints used in this patient population? I think to an extent it's still a disease where a lot of these endpoints and meaningfulness, some of them aren't totally understood yet. But how are you thinking about that as you digest these data? Thank you again. Yeah, Kristen, good question. And there's two parts to that.
There's, of course, the efficacy trial endpoints, which the FDA's guidance is consistent, which is you have to be able to bring them an argument for an endpoint that reflects how a patient feels or functions in everyday life. That endpoint's got to be consistent with the stage and type of patients that you're enrolling in the trial. I think certainly when we look at Stage 2 and knowing the importance of, and even the early Stage 3, looking at the importance of the Total Motor Score in those patients, I think we could certainly put in a strong argument together to support that as an endpoint.
And then I think on the accelerated approval side, look, I think, again, our job as sponsors is to present an argument to the agency of why are certain biomarkers likely to predict clinical benefit, which is what the bar is for a surrogate endpoint. And I think when we certainly look at mutant Huntington protein, whether that's in the blood or CSF, I think we could certainly put that argument together, given the extensive literature now demonstrating that supporting that changes in mutant Huntington protein could provide benefit to patients. So as you say, we look forward now with data in hand to begin having those types of conversations around both potential paths to accelerated approval and also endpoint strategy and study design for the efficacy trial. Thanks, everyone. Thank you. Our next question comes from the line of Brooke Schuster with William Blair. Your line is now open.
Hi. Congrats on the data. We were wondering if you could elaborate more on the patient-to-patient variability, specifically with the CSF measurements and the NfL and the MRI volume measurements. Yeah, I think we're at 12 months in a small number of patients, so there'll always be some variability. But I think that's why, in such a small number of subjects at that time point, to be able to see the signals we see on mutant Huntington's CSF protein are incredibly encouraging. And we see levels of reduction in that protein in line with the lowering or achieving the blood, again, is incredibly encouraging, Brooke. Obviously, you see that we recorded the medians out there for the biomarkers. We believe that's the appropriate way to report out those biomarker data on a small number of subjects.
And again, really give us a strong sense that we are having, certainly on the CSF protein, marked impact on reducing the protein levels in the CSF. And as we commented on both the NfL and the brain volumes, we're not seeing any detectable differences at this standpoint. But we actually believe, certainly in the case of brain volume, it's probably too early to really appreciate treatment effect in such a small number of subjects. Okay. Thank you. And I guess one additional quick question. Congrats with the FDA lifting the hold. We are curious about, would you need to dose a certain amount of U.S. patients before discussing them about a potential registrational trial? No. I think we're in a disease with Huntington's disease. It's a monogenic disorder. And I think we will come with data from Huntington's disease patients.
There's no reason that the geographic, the country the patient's living would make any difference in that regard. Okay. Cool. Thank you. Thank you. Our next question comes from the line of Eric Joseph with J.P. Morgan. Your line is now open. Thanks for taking the questions. I'm just wondering, Matt, if you can comment on the kinetics of HTT lowering that you're seeing both in the periphery and CSF. Do you have a sense of whether you achieved a nadir or a steady-state level with protein lowering and sort of in what time frame that's achieved? And then secondly, if I heard correctly, the plan is to still evaluate both 5 and 10 milligrams going forward. I mean, you've got a pretty good dose response and safety margin here.
Can you talk about sort of the rationale for sort of still advancing both doses rather than sort of then concentrating on 10 milligrams here on a—thank you. Thanks for the questions, Eric. First, on the kinetics of protein lowering, I'll say one slightly unexpected finding here was that we saw continuing lowering in the blood beyond the 12 weeks. What we did observe in the serial blood levels is that we reached steady-state lowering between about six and nine months. So we believe now at 12 months, we're certainly at the point where we're seeing the steady-state of lowering that we had. And CSF, as we've talked about in the past, we didn't expect—we expected it to be several months before we reached steady-state.
I think if we're seeing steady-state in the blood between 6 and 9 months, our assumption is that we're likely going to be seeing steady-state shortly thereafter in the brain. We've spent a lot of time talking about what's the relationship between blood CSF, blood HTT changes, brain HTT changes, and CSF HTT changes. I don't think anyone exactly understands how those kinetics work other than to say it's incredibly encouraging to see consistent magnitude of changes in the blood and in the CSF because that absolutely supports that we're seeing at least those levels of decrease in HTT protein within the brain cells itself, which, of course, is the most relevant activity we need in order to affect disease progression.
Regarding the dose levels of 5 and 10, as you say, Eric, what we're seeing with 10 is absolutely where we feel we want to be and the effects we're seeing there. But again, we're also seeing changes at 5 milligrams. So I think certainly until we get more data out at 12 months on both levels, I think we're very comfortable moving both forward and understanding more of what the relative efficacy could be at those two different dose levels. Appreciate it. Congrats with the data. Thanks for taking the question. Thanks. Thank you. Our next question comes from the line of Jeffrey Hung with Morgan Stanley. Your line is now open. Thanks for taking my questions. I guess first, what gives you confidence in clinical benefits beyond 12 months when lowering of HTT protein reaches steady-state at 6 to 9 months?
And then the mHTT lowering in blood and CSF were very similar. So was this a surprise to you since CSF levels are often more preferred in the reflection of clinical progression? Just curious your thoughts on those results and how that can be incorporated into the Phase 3. Thanks. Yeah. Thanks. Thanks for the questions, Jeff. Just again, can you just, your first question, just repeat that again? Yeah. I was just curious, what gives you confidence in clinical benefits beyond 12 months when lowering of HTT protein reaches steady-state at six to nine months? Yeah. I think that's exactly what gives us confidence. If you're achieving optimal lowering between six and nine months, it suggests now that you're having an ongoing effect on the disease that can counter the otherwise disease progression that one would observe.
So I think what that actually suggests is that we're not near optimal clinical benefit yet. It's only going to be over time that we start to see it. If you think about the pathophysiology of this disease, it's a disease that results from the production of a mutant protein that aggregates, causes inflammation, cell injury, and ultimately cell death. And so by intervening upstream at the source of the disease and lowering the amount of that toxic protein, you would then naturally expect over time for that to progressively decrease that whole cascade, decrease inflammation, decrease cell injury, decrease cell death, and that would ultimately manifest itself in observable clinical benefit.
I think that's why we say to be able to see what we're seeing at 12 months on the clinical scales in terms of the dose-dependent benefits that could be considered clinically meaningful is incredibly encouraging because we expect those trends to get even stronger over time as the drug continues to exert its favorable effect. Great. Thanks. And then on the blood versus CSF HTT. Yeah. Look, I think it was good to see that we're seeing consistent decreases in both. I think, again, in an ideal world, we would be able to directly measure the decrease levels or the lowering we achieve in the brain cells themselves. Obviously, we're not able to do that because we can't biopsy the brain, and there's no radiographic markers that would allow us to do that in an accurate and precise way, or quite frankly, even at all at this point.
And so what we rely on is reflective measures in the CSF of what could be going on in the brain cells. It's well understood that over time in Huntington's disease, there's a progressive increase in the amount of mutant Huntington protein in the CSF that is believed to be consistent with the neurodegeneration process. So the ability to be seeing lowering of those levels between the over 40% that we observed is incredibly supportive that we're at least lowering the levels of Huntington protein in the brain cells to that amount. We're also benefiting here. You have to understand, we have the benefit of an oral medication that has systemic exposure. And it's terrific to be able to sample blood and get an understanding of what's going on in the CNS. You don't have that luxury with an intrathecally administered or central nervous system administered therapy.
This is something that was incredibly valuable in understanding the pharmacokinetic and pharmacodynamic profile of Evrysdi during its early development. Similarly here for PTC518, it's incredibly useful to be able to have a compartment that you can sample frequently that's a low burden to patients and can provide very valuable information on that pharmacodynamic effect. Again, seeing now this relationship between the blood and the CSF is really helpful to us as we move forward and support our continued use of the blood cells to give us an understanding of what is going on in the central nervous system. Great. Thank you very much. Thank you. Our next question comes from the line of Brian Abrahams with RBC Capital Markets. Your line is now open. Hey. Good morning, guys. Thanks so much for taking my questions. Two from me.
First, I was wondering if you could talk about any potential correlations that you're seeing between CSF mHTT lowering and some of the clinical scores, just given the potential for that correlation to help validate the biomarker as a potential surrogate for accelerated approval. And then on the TMS changes, I'm just wondering, any additional granularity around those changes? Were all the patients, all 32, included in that analysis? And any outliers that you may have seen there, particularly in the placebo group? Thanks. Yep. Thanks for the questions, Brian. So first, on the potential correlation. So we're reporting the group-level data here, so we did not get into the individual subject changes that would allow us to look specifically at those correlations. Clearly, it's encouraging to be able to see that in general, we're seeing consistent decreases, a magnitude of decrease in both the CSF and the blood.
Obviously, there's a range there as well. There's some that are higher, some that are lower than the median reported. Again, we have not looked at any specific correlations. I think, and then correlation with the TMS changes, as you suggested, I think what gives us encouragement in terms of the discussion around accelerated approval is the existing, a couple of things. One is just the general first principles. This is a disease that's caused by production of a mutant protein that's toxic to cells. I think most would accept that decreasing that is likely to be beneficial to patients. And there's certainly a literature supporting a range of decreasing levels of that protein in the brain of between 20% and 50% as being associated with potential clinical benefit.
So the way we see these data is they're certainly giving us now evidence that we are lowering those levels of protein at a magnitude that is what the literature supports is likely to predict clinical benefit. But of course, this will be the discussions that we begin to have as we explore the potential for accelerated approval. On the TMS scores, that included all the subjects out at 12 months. What we saw on those scores in terms of mean changes and median changes were pretty consistent, which gives you an idea that there's not outliers driving things in either direction. Again, it's a small number of subjects, but those clear trends, I think, are really quite encouraging given that small number of subjects. That's really helpful. Thanks, Matt. Congrats on the data. Thanks. Thank you. Our next question comes from the line of Peyton Bohnsack with TD Cowen.
Your line is now open. Hey. Good morning, guys. And thanks for taking our questions. I guess, could you give a little more kind of guidance on when you would complete enrollment in PIVOT-HD? And based off that, when would you approach the FDA for an accelerated approval plan versus going with full PIVOTAL program? And then I'll—Yep. So thanks for the question. The study is completely enrolled. The study is fully enrolled, and we will expect to have all patients coming through and completing the 12-month part of PIVOT-HD in the first half of next year, just doing the math of it being fully enrolled and the time it'll take to bring everyone through the trial. We're going to start plans right away for how we're thinking about phase 3 and also start right away with interactions with the agency.
Look, we're in a position here where we have a dataset now at 12 months showing safety, tolerability, biomarker effect, and early clinical signals. That's a pretty unique place to be and a pretty special place to be. We're going to take these data and move as quickly as we can to advance the program, in parallel, moving towards Phase 3 and working as fast and as hard as we can to get this drug to patients who desperately need one. In parallel, we'll also explore the accelerated approval route as we interact with the regulators. Great. Thank you. And then I guess, kind of following up on that, how are you thinking about maybe taking this forward yourself in terms of worldwide? Or would you be looking to partner this as what was happening with the Evrysdi? Yeah.
So we have worked very hard to build the clinical R&D and commercial infrastructure to support the development and ultimately commercialization of this therapy worldwide. We also have a balance sheet that also enables us to do this all ourselves, and we're pretty proud of that. Also, even just as we talked about in designing PIVOT HD, the idea that we looked at inclusion criteria different than has traditionally been done in order to make sure that we have a population that we believe is appropriate for assessing the therapeutic benefit of a potential disease-modifying therapy. Those elements of innovation and pioneering is a strong part of who we are, and that's why we would be incredibly keen, and we are obviously incredibly capable of moving this program forward and commercializing it ourselves. Great. Thank you very much for taking our questions. Thank you.
Our next question comes from the line of Paul Choi with Goldman Sachs. Your line is now open. Hi, everyone. Can you hear me? Yes. Great. Hi. This is Khalil calling in for Paul. Thank you so much for taking our questions. I guess a couple of quick ones from us real quick is, one, if you could share any additional color on what led to the FDA's decision to lift the clinical hold, and by the way, congratulations on that, whether it was driven more by the early clinical signals or whether it was more on the safety side. And then I guess a quick follow-up to that is, if you have any anecdotal examples of some of the clinical benefit seen in some patients and whether there are any baseline characteristics you'd call out in those patients, that'd be really helpful for us as well.
Thank you so much. Thanks for the question, Khalil. We presented the data we had. It included the safety data, the tolerability data, as well as some of the clinical data we have to the FDA. I can't speak to which factors were influential. Obviously, we're talking about a safety hold, and I think it's incredibly important. I think all would agree with huntingtin lowering therapies to be able to have this strong safety and tolerability profile after 12 months. No evidence of NfL spikes. We had no dose-limiting toxicities. The very favorable safety profile we have, of course, was influential to the extent that they saw these early signs of clinical benefit and how that factored into decision, I can't say other than to say that we did provide them all of the data that we had.
And then in terms of individual characteristics that had changes, I think, Khalil, this is a pretty small sample set of about 30 patients. Obviously, we stratified and balanced the dosing groups pretty consistently for patient and disease characteristics. So at this point, I would say there's nothing that stands out. And plus, as we said, these are group-level data. The study is still blinded, so we're not digging deep into individuals and how their characteristics might influence treatment response at this time. Got it. Okay. Thank you so much. Thank you. Our next question comes from the line of David Lebowitz with Citi. Your line is now open. Hi, John. I'm for David. Thanks for taking our question, and congrats on the data.
Just given the dose dependency you're seeing in HTT reduction and some of the clinical outcomes, can you talk to the dose effect and total functional capacity and why that's not also showing a similar dose response? Yeah. John, I think I'd look at this differently. I think what we would say is it's incredible at 30 patients in this disease that you're seeing dose-dependent response on any clinical measure at 12 months. And where we're seeing it most clearly is on that total motor score, which for this disease severity, Stage 2, is the most meaningful endpoint. We are seeing benefit on TFC. Again, and that's more of a Stage 3 entity. But I think the fact that we're seeing dose-dependent effects on cUHDRS and UHDRS and TMS is actually the story here.
That would be an unexpected finding in such a small group of patients at the 12-month time point. Got it. Thank you. Thank you. Our next question comes from the line of Gina Wang with Barclays. Your line is now open. Thank you for taking my questions. I have three quick questions. First, Matt, I wanted to say, if you remember, we debate on why CSF huntingtin should be or should not be measured. So I'm very glad to see the CSF huntingtin protein level knockdown of 43%. That's comparable to the blood. So on the other hand, I wanted to ask you, what is your estimation on the brain tissue knockdown? I remember previously we saw the level of the drug crossing blood-brain barrier that should be 2:1. So in theory, in brain, it should be higher percentage knockdown. And a related question is, what is the sweet spot?
As you said, it's 30%-50%. In reality, we wanted to aim for 50% so that you have a maximized efficacy but also minimize safety issue. That's my first question. Gina, thank you for the question. I think there's a couple in there. In that first question, there's a couple of sub-questions. Let me make sure I can get to all of them. We've had many conversations about CSF huntingtin protein, as you alluded to. I think as we've talked about, we didn't share those data at 12 weeks because we thought it was too early and wouldn't be a steady state and they wouldn't be interpretable. I think that's why we said it would be a 12-month endpoint. Obviously, happy to be sharing those data now.
We agree that they certainly do provide a strong level of evidence that we're having activity in the central nervous system, which we understand is incredibly important, given that ultimately the goal here is to lower Huntington protein in the brain and exert favorable effects in the central nervous system. You referenced as well the fact that we previously reported that we're having greater free drug exposure in the CNS or CSF relative to the plasma and that holds. We reported that at the 10-milligram dose level, that's roughly 1.5 to 1 and 1.1 to 1 at the 5-milligram dose level. 1.5 at 10 milligrams, 1.1 at 5 milligrams. When we look at these data, we still don't know for sure how much lowering we're getting exactly in the brain cells.
But I think when we're seeing the reduction in blood of over 40%, and we're seeing reduction in the CSF over 40%, that gives us confidence that we're reducing the levels in the brain by at least 40%, and it could be higher. Of course, that's also a median level, which means we, of course, will have subjects who are getting reductions of 50% and maybe even higher and some that are lower. But I think in general, we have confidence now that we're reducing within the brain at least that 40%, which, as you alluded to, is exactly where we believe we need to be for therapeutic benefit. Okay. The second question more regarding the neurofilament, when I look at the 12-week data, actually, I think the 5-milligram and 10-milligram show much higher reduction. I think if I look at the bar, it's about 10%.
So there's a little bit decrease regarding the drug arm, and you have an increase, actually, reduction from the placebo arm. So thoughts on the neurofilament? I understand it's monoclonal, and there is some noise there. Maybe try to give a little bit more color regarding the trend, what we've seen here. Any question or concern there? Yep. So first, let me say there's no concern there. I think one of the most important things for CSF, and it's becoming increasingly acknowledged by the HD experts, is as a measure for safety in this regard. The fact that we're not seeing the spikes is incredibly important and speaks to the fact that we're not inciting any neuronal injury or anything for concern. So I'd say first, that's probably the most important message on the NfL.
In terms of what we've observed in the differences of 12 months to 12 weeks, as I mentioned, it's acknowledged that these NfL levels do tend in the short term to fluctuate, and it may be that over a longer time that you see more of a general trend. I'll note that according to natural history, when you look at the plasma NfL, it should be going up 10%-12%. So if I were seeing it down in placebo and down in treatment, this may, in fact, just be this fluctuation. And there's a literature around this, and I think what the literature is increasingly supporting is that in Huntington's disease, while it is acknowledged that patients progress over time, that Huntington, I'm sorry, NfL levels tend to increase as they do in other neurodegenerative diseases.
It's not as clear that there's a close correlation between these NFL changes and clinical course. In fact, there was a publication in 2021 by Jody Corey-Bloom that looked at this specifically and said, "Look, NFL is probably really good at baseline to understand where a patient is at the stage of their disease, but it may be less reliable as a correlate to clinical changes, and that's, of course, then as a correlate to treatment effect." And I think that's something that we're all learning about in this disease. I know that there's been certainly the experience with tofersen and NFL and ALS has substantiated NFL as a surrogate marker in that disease.
It may be in Huntington's disease, certainly over the shorter term, it's not as robust a marker, probably because the disease is not moving as fast and the fact that there may, in fact, be some fluctuations over time. Okay. Thank you. Last quick question. Sorry. Actually, it's not quick. Regarding the safety slides, I know you listed only the subject with the treatment-related AE, but did not say what kind of AEs. Can you give us color, especially the one that show a little bit higher percentage in the drug arm, like drug-related AEs? What are the most common AEs that were listed? Actually, it showed up in the drug. Yep. So I think the profile, the frequency, and the type of AEs were consistent across all groups.
And those were very common things like cold and flu, headache, and there was nothing that looked different in any of the groups. Nasopharyngitis was one of them. So again, there was nothing here that stood out as being something we saw in the treatment arms that we didn't see in the placebo. And again, things that are very common that you see in clinical trials. Okay. Thank you very much. Thank you. Thank you. Our next question comes from the line of Joseph Schwartz, Leerink Partners. Your line is now open. Great. Thanks, and congrats on the progress. I was wondering if you could talk a little bit more about how the PIVOT-HD data compares to natural history in terms of the biomarker of striatal brain volume.
It seems like there's not as much separation between the treatment and placebo arm on this measure, and I'm just wondering what to make of that. Yeah. I think, Joe, thanks for the question. We've talked a lot about how brain volume changes occur pretty slowly over time. That's why we said as well we would expect that to be, of all the biomarkers we're measuring, certainly one that's going to probably take longer than 12 months to begin to see a treatment effect. I think what we're seeing at 12 months, what's important of what we're seeing at 12 months, is that there's no differences. We're not having any adverse effects here, which is something that other therapies in development have shown. I think we're seeing changes that are in line with natural history across all three study groups.
I think that's fully expected at the 12-month time point. And again, as we've talked about, what we really wanted to see at 12 months in this study is registering some favorable effect on a key biomarker, which we've absolutely done with the mutant Huntington protein levels. And then, of course, being able to see these signals of early clinical benefit, particularly on TMS, as I mentioned, slowing the progression by about 70% in the high-dose group relative to placebo. So I think when you look at the data holistically, you're seeing the exact signals of favorable CNS effect that one would want to see at this stage in terms of supporting further development and the promise of this therapy. Thank you. Thank you. Our next question comes from the line of Eric Joseph with J.P. Morgan. Your line is now open. Eric Joseph, your line is open.
Please check your mute button. Oh, sorry. Sorry. Thanks for having me back in queue. A little bit fuzzy on my end. I just wanted to come back to sort of duration of follow-up, both in the or continued dosing, basically, in PIVOT HD and also touch back on the additions to the lift of the partial hold. I guess, how far do you expect to follow patients in the open-label portion of PIVOT HD? And as it concerns the lift of the partial hold, previous discussion, it seemed like these data would allow for 12 months. Are you able to dose for 12 months in phase 3 conducted at U.S. sites going forward? I guess any conditions, basically, on the length of treatment with the lift of FDA's hold. Yeah. So thanks again for the questions, Eric. In terms of duration of follow-up, the open-label extension is ongoing.
It's going to go on for a period of time. We don't have, as of yet, a plan for when that will be definitively stopped. And so it could allow us to do exactly what you outlined, continue to follow patients over time, and, of course, give an opportunity for those patients who are on placebo to now receive therapy. So we look forward to being able to follow the patients and give access to the drug for all those who participated in PIVOT-HD. In terms of the partial hold, it was a release of the partial hold, and there were no restrictions given. Excellent. Thanks for taking the follow-up questions. Thank you. And I'm currently showing no further questions at this time. I'd like to hand the conference call back over to Dr. Matthew Klein for closing remarks. Thank you.
Thank you all again for joining the call this morning. We're incredibly excited about these results. We had very clear objectives for the 12-month readout. And as we've discussed, we've met all of them, which really supports the promise of PTC518 for patients with Huntington's disease. We look forward to continuing to move this program forward and continuing to do all we can to deliver a therapy for Huntington's disease patients who desperately need one. Thank you all again, and have a good day. This concludes today's conference call. Thank you for your participation. You may now disconnect.