PTC Therapeutics, Inc. (PTCT) Earnings Call Transcript & Summary

Good day, and thank you for standby. Welcome to the PIVOT-HD 12-month Interim Results 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, 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 II 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 Evrysdi, 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 Factors 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 Huntington target and broad CNS bioavailability required for 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 in peripheral blood cells; demonstrating evidence of early signals of favorable CNS effect on disease biomarkers and functional clinical scale; and importantly, continued safety and tolerability at the 12-month time point. I am proud to report that 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 huntingtin 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 PTC518. 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 2 parts. Part 1 is 12 weeks in duration and focuses on PTC518 pharmacology and pharmacodynamic effect. Part 2 is 9 months in duration and focuses on disease biomarkers and HD clinical scale. The study includes 2 dose levels, 5 milligrams and 10 milligrams, and we are studying 2 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 link. 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 in blood cells with lowering of 21% at 5 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 6 and 9 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 scale. 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 huntingtin 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 milligrams and 10 milligram 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 and 10 milligrams, 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 slide 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% to 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 dosing. On volumetric MRI analyses, we see consistency in brand volume changes over time across all 3 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 scale. 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, a 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 1 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 or 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 huntingtin protein levels reaching over 40% at the 10-milligram 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 observed dose-dependent lowering at both 5-milligram 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 huntingtin protein lowering in the CSF of over 40% at the 10-milligram 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 III 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?

[Operator Instructions] Questions on today's conference call will be limited to PTC518 and the HD program. [Operator Instructions] Our first question comes from the line of Kelly Shi with Jefferies.

Congrats on the progress. So did you have a statistical analysis on TMS, the Total Motor Score, across clinical [indiscernible] and the 5-milligram group? And is the design considered clinical meaningful? Also, moving forward, how do we think about the trend change beyond 12 months landmark analysis?

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 with 30 subjects, the 12 months in HD, to be -- and was able to detect a 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 12 months was can we simply see any signal of effect on these measurements and to be able to see this dose-dependent trend in a small number of patients at the 12-month time point of this disease, again, is incredibly encouraging.

Terrific. And also, if I apologize if I missed, 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've set a lot, Kelly, that the goal was to achieve a lowering of between 30% and 50% of huntingtin protein. The reason for that is we understand that, that's really the spot to be in terms of getting optimal clinical effect as well as safety. And 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 be going forward.

Our next question comes from the line of Kristen Kluska with Cantor Fitzgerald.

Let me also add my congratulations on the data as well as getting the partial [ pool ] listed. So it's 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 the 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 questions, Kristen. So we talked a lot about how we're 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 they're -- the patients aren't progressing enough to be able to register a meaningful effect. And so when we think about these patients that -- these 30 or so patients in a 12-month time point, they're all Phase II 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 the stage of subjects is a little bit variable. Most recently, there was a report, the HD SHIELD or SHIELD-HD study that was presented at CHCI where there was about a 2.3 change per year, 0.1 change per year, there's been 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 you'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 border 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. 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 we've 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.

Okay. And I don't want to jump too ahead. And 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 the patient population. I think to an extent, it's still a disease where a lot of endpoints and meaningfulness, some of them aren't totally understood yet. But how are you thinking about that as you digest these data?

Yes, Kristen, it's a good question. And there's 2 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 feel or functions in everyday life, and that endpoint 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 early Stage 3, looking at the importance of the total motor score in those patients, I think we could certainly put 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 of sponsors to present an argument to the agency of why our 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 huntingtin protein, whether that's in the blood or CSF, I think we could certainly put that argument together, given the expense of literature now demonstrating that, supporting exchanges in the mutant huntingtin 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 path to accelerate approval and also endpoint strategy and study design for the efficacy trial.

Our next question comes from the line of Brooke Schuster with William Blair.

Congrats on the data. We were wondering if you could elaborate more on the patient-to-patient variability, specifically with the CSF measurements and NfL and MRI volume measurement.

Yes, I think the -- we're 12 months in a small number of patients, so there will 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 the mutant huntingtin CSF protein are incredibly encouraging, and we see levels of reduction in that protein in line with the lowering we're achieving the blood, again, is incredibly encouraging. But obviously, you see that we recorded the medians out there from the biomarkers, and 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, a market impact on reducing the protein levels in the CSF. And as you commented on both the NfL, the brain volumes, we're not seeing any detectable differences at this standpoint that we actually believe, certainly in the case of brain volume, it's probably too early to really appreciate treatment seeing effect in such a small number of subjects.

Okay. And I guess one additional quick question. Congrats with the FDA lifting the hold. We are curious about like how will 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 the disease, the Huntington's disease. It's a monogenetic disorder, and I think we will come with data from Huntington's disease patients, and there's no reason that the geographic, the country, the patients living would make any difference in that.

Our next question comes from the line of Eric Joseph with JPMorgan.

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 give a sense of whether you achieved a [ nator ] or a steady state level with protein lowering and sort of in what timeframe 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 being concentrating on 10 milligrams here on out?

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 of lowering between about 6 to 9 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 expect it to be several months before we reach steady state. And I think if we're seeing steady state in the blood between 6 and 9 months, our assumptions that we are 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 -- on blood HTT changes, brain HTT changes and CSF HTT changes, I don't think anyone exactly understand 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 you 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 effect we're seeing there. But again, we're also seeing changes in the 5 milligrams. So I think, certainly, until we get more data out of 12-month of both levels, I think we're very comfortable we move forward and understanding more of what the relative efficacy could be at those 2 different dose levels.

Our next question comes from the line of Jeff Hung with Morgan Stanley.

I guess, first of all, 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 a reflection of clinical progression. Just curious your thoughts on those results and how that can be incorporated into the Phase III.

Thanks for the question, Jeff. Just -- if you just -- on your first question, just repeat that again?

Yes, I was just curious, like what gives you confidence in clinical benefits beyond 12 months when lowering of HTT protein reaches steady state at 6 to 9 months?

Yes. I think that's exactly what gives us confidence. If you're achieving optimal lowering between 6 to 9 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 always going to be over time that we start to see it. If you think about the pathophysiology of this disease, this is 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 at upstream at the source of the disease and lowering the amount of that toxic protein, you would then naturally expect over time to have to progressively decrease that whole cascade, decreased inflammation, decreased cell injury, decreased cell death, and that would ultimately manifest itself 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. And then on the blood versus CSF HTT?

Yes, look, I think it was good to see that we're seeing consistent decreases in both. I think the -- again, we, in an ideal world, we would be able to directly measure the decrease level or the lowering we achieved 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 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 progressive increase in the amount of mutant huntingtin protein in the CSF that is believed to be consistent with the neurodegeneration process. So the ability to be seeing a lowering of those levels between -- I said, over 40% that we observed is incredibly supportive that we're at least lowering the levels of huntingtin protein in the brain cells to that amount. We are also benefiting here. You have to assume 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. We 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 pharmacokinetics and pharmacodynamics profile of Evrysdi during its early development, and 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. So 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 with the central nervous system.

Our next question comes from the line of Brian Abrahams with RBC Capital Markets.

Two for 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 on the placebo -- in the placebo group?

Thanks for the questions, Brian. So first, on the potential correlation. So we are reporting the group level data here so we did not get into the individual -- the individual subject changes that would allow us to look specifically at those correlations. Clearly, it's encouraging to be able to see that on -- in general, we're seeing consistent decreases -- magnitude of decrease in both the CSF and the blood. Obviously, there's a range there as well, and then there's some that are higher, some that are lower than the median reported. But again, we have not looked at any specific correlations. But 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 -- it's a couple of things. One it's just the general first principles. This is a disease that's caused by production of 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, they're certainly giving us now evidence that we are lowering those levels of protein, a magnitude that is what the literature supports is likely to predict clinical benefit. But of course, this will be the discussion that we begin to have as we explore the potential for accelerated approval. On the TMS score, that included all the subjects at 12 months. The -- 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.

Our next question comes from the line of Peyton Bohnsack with TD Cowen.

I guess could you give a little more kind of like 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 have a follow up.

Yes. So thanks for the question, Peyton. The study is completely enrolled. The study is fully enrolled, and we will expect to have all patients coming through and completing PIVOT-HD -- the 12-month part of PIVOT-HD in the first half of next year, just doing the math, that it is being fully enrolled and the kind of safety to bring everyone through the trial. We're going to start plans right away for how we're thinking about Phase III and also start right away with interactions with the agency. Look, we're in a position here where we have a data set now at 12 months showing safety, tolerability, biomarker effect and early clinical segment. That's a pretty unique place to be in 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 III 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. And then, I guess, kind of following up on that. How are you thinking about maybe taking this forward yourself in terms of like worldwide? Or would you be looking to partner that size, like what was happening with the Grade 3?

Yes. 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 look 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 ourselves.

Our next question comes from the line of Paul Choi with Goldman Sachs.

Can you hear me?

Yes.

This is Cleo calling in for Paul. 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 benefits seen in some patients and whether there are any baseline characteristics you'd call out in those patients, that would be really helpful for us as well.

Thanks for the question, Cleo. 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. They can't speak to which factors are more influential. Obviously, we're talking about a safety hold an I think it's incredibly important. I think all would agree with Huntington's lowering therapy, lowering therapies, to be able to have a strong safety and tolerability profile out to 12 months, no evidence of NfL spike, had no dose-limiting toxicities. The very favorable safety profile we have, of course, was intellectual, to the extent that they thought these early signs of clinical benefit and how that factor in the 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 has changed. I think this is a pretty small sample set of about 30 patients. Obviously, we've stratified and balanced the dosing groups pretty consistently for patients 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 that -- and how their characteristics might influence treatment response at this time.

Our next question comes from the line of David Lebowitz with Citi.

John on for David. And congrats on the data. Just given the dose dependency you're seeing in HTT reduction, some of the clinical outcomes, can you talk to the dose effect in total functional capacity and why that's not also showing a similar response?

Yes, John, I think I look at it differently. I think what we would say is it's incredible, in 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 is both clearly is on that total motor score, which for this disease severity of 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 TMS is actually the story here, that, that would be some unexpected finding in such a small group of patients at the 12-month time point.

Our next question comes from the line of Gena Wang with Barclays.

I have 3 quick questions. First, Matt, that I wanted to say like, 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 43% that's comparable to the block. So on the other hand, I wanted to ask you, like what is your estimation on the brain tissue knockdown? I remember previously, we saw the level of the drug crossing brain blood barrier that should be [indiscernible], it should be higher percentage knockdown. And the related question is what is the sweetspot, as you said, it's 30% to 50% in reality, we wanted to aim for 50% so that you have to maximize efficacy but also minimize safety issue. So that's my first question.

So Gena, thank you for the question. I think there's a couple in there in that first question. There's a couple of sub questions. So let me make sure I can get to all of them. I think we've had many conversations about CSF huntingtin protein, as you alluded to. I think as we 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. And I think that's why we said it would be a 12-month endpoint and obviously, happy to be sharing those data now. And 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 huntingtin protein in the brain and exert effects -- 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 in that whole, and we reported it at the 10-milligram dose level, that's roughly 1.5 to 1 and 1.1 to 1 at the 5-milligram dose level, so 1.5 at 10 milligrams, 1.1 at 5 milligrams. And so when we look at these data, it is -- 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 a reduction in blood of over 40% and we're seeing a reduction in the CSF over 40%, that gives us confidence that we're reducing the levels in the brain by at least of 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 reduction to 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 is, 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 weeks data, actually, I think at the 5-milligram and 10-milligram, much higher reduction in [indiscernible] when you look at it, the bar is about 10%. So there is 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 [indiscernible] and there is some noise there, like maybe try to give a little bit more color regarding the trend what we've seen here. Any question or concern there?

Yes. 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 in 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 in according to natural history, when you look at the plasma NfL, it should be going up 10% to 12%. So [indiscernible] we're seeing it down in placebo and down the treatment, which 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 a [indiscernible] that the patients progress over time that Huntington's -- sorry, NfL levels tend to increase as they do in other neurodegenerative diseases, they're not -- it's not as clear that there's a close correlation between the NfL changes and clinical course. In fact, there was a publication in 2021 by 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 the clinical changes and that, of course, that has 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 certainly the experience with tofersen and NfL and ALS had substantiated NfL as a surrogate marker in that disease. And 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 effectively may, in fact, see some fluctuations over time.

Okay. Last quick question. Sorry, actually, it's not quick. So -- but regarding the safety slide, I know you listed only the subject with the treatment-related AE, but did not say what kind of AE. Can you give us color, especially like the one that show a little bit higher percentage in the drug arm, like drug-related AE. What are the most common AEs that were listed as it showed up in the drug?

Yes. 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.

Our next question comes from the line of Joseph Schwartz, Leerink Partners.

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?

Yes. I think, Joe, thanks for the question. We've talked a lot about how brain volume changes occur slowly, pretty slowly over time. And that's why we said as well, we would expect that to be, of all the biomarkers we're measuring, certainly, when 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 is what we're seeing at 12 months is that there's no difference. We're not having any adverse effect here, which is something that other therapies in development have shown. So I think we're seeing changes that are in line with natural history across all 3 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 huntingtin protein levels and then, of course, being able to see the signals of early clinical benefit, particularly on TMS as eventual slowing the progression by at 70% in the high dose relative to placebo. So I think when you look at the data holistically, you're seeing that 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.

Our next question comes from the line of Eric Joseph with JPMorgan.

Sorry, thanks for having me back in the queue. A little bit fuzzy on my end. I just wanted to coming back to sort of duration of follow-up both in the -- or continued dose basically in PIVOT-HD and also you touch about on the decision to lift a partial hold. I guess how far do you expect to follow patients in the open-label portion of PIVOT-HD, and as a concern, to lift the partial hold because previous discussion it seems like the [indiscernible], are you able to dose beyond 12 months in [indiscernible] Phase III conducted at U.S. sites going forward. I guess, any conditions basically on the length of the treatment with the lift of FDA's hold?

Yes. 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 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 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.

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 all again for joining the call this morning. We are 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.