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

Good day, and welcome to the PIVOT-HD interim data update call. [Operator Instructions] As a reminder, this call is being recorded. I would now like to turn the call over to CEO, Dr. Matthew Klein. You may begin.

Thank you for joining this morning's call. We are excited to share the encouraging data from the 12-week interim analysis of the PIVOT-HD study. 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. The PTC518 Huntington's disease program comes from PTC's validated splicing classes. PTC pioneered the field of small molecule splicing And over the past 2 decades, -- we have built a robust platform to enable the identification of disease-relevant splicing targets and molecular scaffolds capable of favorably affecting splicing activity. In addition to our platform tools, we also have an outstanding team of scientists who have been leading our pioneering efforts. The first program from our splicing platform was our SMA program. The discovery and successful development of [risk] provided a blueprint for the successful development of a CNS-directed small molecule splicing therapy. This low print includes critical elements of drug design and development including the need for high levels of target selectivity and specificity, broad brain biodistribution, which is particularly important for HD, given the whole brain nature of the disease and the importance of leveraging the systemic exposure of an oral therapy such that blood cell [analyses] can be used to provide evidence of target engagement splicing mechanism of action provide important decisions around dose selection. The Phase I Healthy Volunteer Study of PTC518 confirmed we had succeeded in achieving many of these key elements in our HD program, as we demonstrated dose-dependent Huntington mRNA protein lowering and excellent CSF exposure. With those positive results, we initiated the PIVOT-HD Phase II trial of PTC518 in Huntington's disease patients. Let me begin by reviewing the key objectives of the 12-week part of the PIVOT-HD study. These included determine the level of reduction of Huntington protein and blood cells at dose levels of 5 milligrams and 10 milligrams confirm the relationship between HTT mRNA and protein lowering in steady state, define the ratio of CSF/plasma drug exposure in Huntington's disease patients following on the observation in Phase I that we were achieving higher levels of exposure in the CSF and importantly, to evaluate PTC518 safety and tolerability. We are very excited to share that we accomplished all key objectives of the study. PTC518 treatment resulted in dose-dependent lowering of Huntington protein and blood cells reaching an average lowering of 30% at the 10-milligram dose level with the expected approximate 1:1 ratio of mRNA to protein reduction at steady state. PTC518 remains demonstrated the targeted CSF exposure with higher concentrations of free drug in the CSF and plasma. PTC518 was well tolerated with no treatment-related serious adverse events no dose-limiting toxicities and no reports of peripheral neuropathy. And there were no treatment-related neurofilament light chain spikes recorded. Overall, CSF NfL levels remain stable after 12 weeks of treatment, with a trend towards lowering in PTC518 treated patients. I will now go through the study design and study results in more detail. The PIVOT-HD study is a 12-month placebo-controlled trial of PTC518 in Huntington's disease patients. The study includes 2 parts. Part 1 is 12 weeks in duration and focuses on PTC518 pharmacology and pharmacodynamic effects as well as biodistribution. Part 2 is 9 months in duration and focuses on blood-based, [CSF] base and [endographic] biomarkers of disease, including reductions in CSF levels of mutant Huntington protein and changes in brain volume. The study currently includes 2 dose plus 5 milligrams and 10 milligrams. We have received regulatory clearance in all countries in which the study is being conducted to include a third dose of up to 20 milligrams. When we initiated the study, we included only Stage 2 patients who met a set of specific disease severity criteria in an effort to ensure that we had study subjects who are likely to progress sufficiently during the course of the clinical trial to allow us to detect a potential treatment effect. We subsequently expanded the study inclusion criteria to include early Stage III patients who had similar disease characteristics as the original subject cohort with the exception of including patients with a total functional capacity score of 11 or 12. This change allows for the inclusion of slightly more severe patients and will provide important data on PTC518 treatment effect. The data presented today are from the original Stage 2 cohort of enrollees. The interim data analysis included 33 subjects who completed Part 1 of the study. The baseline subject and disease characteristics were similar across the placebo and the 5-milligram and 10-milligram treatment groups. Now let me share the results of the interim data analysis. Following 12 weeks of PTC518 treatment, there was a dose-dependent lowering of mutant Huntington protein in peripheral blood cells with a reduction of 21% in the 5-milligram cohort and 30% lowering in the 10-milligram cohort. These levels of reduction are even greater than our correct dates for the observed increase in protein levels in the placebo cohort. Importantly, we confirmed an approximate 1:1 ratio of mRNA to protein lowering, which was expected based on both the understood relationship between RNA and protein levels and our modeling of Phase I study results. In addition, the ratio of mutant protein lowering to total protein lowering was similar as expected, given that PTC518 is not [allele-selective]. It lowered both wild-type and mutant HTT protein. These HTT lowering results are important, both in terms of confirming the dose-dependent effects of PTC518 therapy and the fact that we are reserving on average, 30% lowering of HTT protein blood cells which is within the range of our ultimate target CNS protein lowering of 30% to 50% within brain cells. Turning to CSF drug exposure. In the Phase I healthy volunteer study, we observed higher levels of CSF exposure and plasma exposure, which confirmed that PTC518 not only crosses the blood brain barrier, but is not e-flux. -- an incredibly important requisite for treating a whole brain disease like HD. In HD patients, we are then getting excellent CSF exposure with greater levels of unbound drug in the CSF than in plasma. The ratio of CSF to plasma appears to be nonlinear with a ratio of 1.11 at 5 milligrams and 1.5:1 at the higher 10-milligram dose level. With the 30% reduction in HTT protein recorded in peripheral blood cells at the 10-milligram dose level and the approximate 50% higher drug exposure levels in CNS, brain cell HTT protein reductions could be as high as 45% at the 10-milligram dose level, again, meeting our target brain cell protein reduction level of between 30% and 50%. In addition to the important pharmacodynamic effects and drug biodistribution observed in the interim analysis, PTC518 was also demonstrated to be well tolerated. There were no treatment-related serious adverse events no adverse events leading to subject discontinuation and no reports of peripheral neuropathy. Overall, the 5-milligram and 10-milligram treatment groups and placebo group had similar adverse event profiles. The most common adverse events across each treatment group were upper respiratory tract infection and headache with all treatment-related adverse events in Grade 1 or Grade 2. Here is the adverse event table, showing in more detail the similar adverse event profiles across each treatment group. Importantly, when looking at the specific numbers of adverse events, there was only one Grade 2 adverse events at each dose level reported to be possibly treatment-related. The single reported Grade 3 adverse event with a musculoskeletal issue deemed not related to study drop and resolved without impact on study treatment. When we initiated PIVOT-HD, we included change in CSF neurofilament light chain [loans] as a 12-month biomarker endpoint of treatment efficacy. Given the understood association between disease severity, disease progression and increases in NfL levels. However, NfL has recently been used as a marker of drug safety in clinical trials, as treatment-related NfL spikes may reflect neuronal cell injury resulting from either on-target or off-target drug effects. Importantly, as you can see in the graph on the left side of the slide, there were no market treatment-related CSF NfL increases recorded at week 12. Similarly, for reference, in the plasma, there were no NfL spikes recorded over the course of the first 12 weeks in the study. When looking at the overall mean changes in CSF NfL levels from baseline to week 12 in the graph on the right side of the slide, we observed a trend towards NfL lowering in both PTC518 treatment groups. This is an interesting and potentially meaningful treatment benefit find that, of course, will be followed over the longer course of the study. In summary, all key objectives of this interim data analysis were met. PTC518 treatment resulted in dose-dependent lowering of blood cell Huntington protein with mean lowering of 30% in the 10-milligram dose cohort. PTC518 treatment resulted in a targeted level of CNS exposure with a ratio of CSF to plasma exposure of 1.5:1 at the 10-milligram dose level, suggesting that greater lowering of HTT protein above 30% and possibly up to 45% and to be occurring in brain cells. Importantly, PTC518 was well tolerated with no treatment-related serious adverse events, reports of peripheral neuropathy and no treatment-related CSF NfL spikes, with an overall trend towards lower NfL levels in PTC518 team. With these encouraging interim data, we will continue to enroll Stage 2 in early [Stage 3] patients into the PIVOT-HD study. And of course, look forward to the 12-month data readout of these initial subjects, at which time we can know more about the longer-term effects of PTC518 treatment in [key] disease biomarkers. We also plan to share the data from the current readout, including safety data with the FDA to support enrollment of U.S. patients in PIVOT-HD. Finally, I also want to highlight that we are particularly excited that these promising results are in addition to our 2023 commercial revenue guidance of between $940 million to $1 billion as well as the recently announced impressive registration directed affinity trial results, which we anticipate will support another potential $1 billion-plus revenue opportunity. I will now turn the call over to the operator for questions on the PTC518 HD program. Operator?

[Operator Instructions] And our first question comes from Kristen Kluska with Cantor Fitzgerald.

Congratulations on these data. So based off your preclinical and early clinical work and expertise around the splicing platform, do you have a sense of when you could expect to see the peak effects mutant HTT lowering? And then while I recognize it is just 12 weeks data at this stage, can you comment on your expectations for durability in light of these previous findings?

Yes, Kristen, thank you very much for the question. What we're seeing in the 12-week data is what we believe is steady state reductions in blood cell levels of HCT protein. So we believe we are at steady state in the blood. As we've talked about, we believe to achieve steady case in terms of CNS or brain cell lowering, that may take a little bit more time, which is also in part why we said the CSF protein changes would be a 12-month endpoint. In terms of durability of effect, again, this is 1 of the advantages of having an orally administrated therapy where we can actually continue dosing and ensure that we're maintaining all the lowering that we're seeing once we achieve steady state.

Okay. And then my last question is just on the CSF NfL lowering. Are you surprised to see these effects so early in the trial? And then is there anything you may take away highlighting that it seems to appear that those with the higher levels at baseline saw some of the more obvious declines at this stage?

Yes, Kristen. So I think when we -- as we mentioned, when we started the study, we really focused on NfL as a longer-term endpoint thinking that it's going to be closer to 12 months before we can appreciate what will be ultimate steady-state impact on NfL levels because, of course, that's a marker over time an HD of neurodegeneration. So to be able to record over the long-term evidence stability or even lowering, obviously, being incredibly important for representing a potential important therapeutic benefit. Being able to see early signs of decrease at the 12-week point is obviously very encouraging and suggest that we're potentially starting to have an important impact. We'll, of course, follow this over time but needless to say, we're quite pleased to be able to see that signal or potential benefit so early in the study.

Our next question comes from Eric Joseph with JPMorgan.

This is Hannah on for Eric. So just saying that you had an intended goal of about 30 patients per dosing arm. So just wondering if you intend to further enroll up to those 30 patients as part of Stage 2? And otherwise, what enrollment would you be focused on at each particular dose level? And then secondly, just wondering about the expected regulatory or IMD outlook in the U.S. now with clinical data? How soon do you expect to go back to the FDA to seek listing as a whole?

Thank you very much for the question, Hannah. So to your first question, those are -- does remain the target enrollment goal. Obviously, this is an interim analysis to provide an important first glimpse of drug safety and evidence of pharmacodynamic effect and biodistribution. We intend to complete enrollment of those 36 patients plus or minus in the 5 and 10 dosing groups in both the Stage II cohorts as well as the Stage III cohorts. And obviously, these data strongly support continuing to move forward and enrolling patients in those dosing groups. And to answer your second question regarding discussions with the FDA. Obviously, we've talked a lot about the partial hold being due to clinical toxicology data from the non primates and our discussions with the agency that included the fact that we could bring clinical data to support dosing the dose levels and the duration we would like to conduct the study in the United States. Obviously, we now have these data -- new safety data in hand, which obviously are demonstrating that the drug is and safe and well tolerated over the first course of the study, and we plan to submit these results to the FDA as part of a complete response to the partial homes in the near future.

Great. And just as a follow-up, so you do have regulatory clearance to move up to the 20 mg dose and all sites where you're conducting the trial, but just wondering what would determine that decision to move up? Or has that decision already been made?

Yes, it's a great question, Hannah. So that decision to go to 20 milligrams is based on 2 factors. One is our independent data safety monitoring board who oversees the trial and were charged with answering that specific question in your most recent review, which is do you support going to 20 milligrams. And the second part, of course, is our decision of whether we think we need to go there to reach a desired 30% to 50% long in brand cells. So in Part 1, the DSMB recently met and supported going up to that 20-milligram dose level, which has been -- received regulatory clearance in the countries in which we're doing the study. However, as we look at the data, we're seeing that at the 10-milligram dose group, we may very well be in that desired range of 40% to 50% lowering, with 30% lowering blood and the 1:1.5 relationship between blood and CNS exposure, we very well may be where we need to be with the doses currently being studied. So obviously, we'll discuss more that you've got timing, the timing of and if we decide to go to 20 milligrams, obviously, right now, we want to continue enrollment by the tenet and begin to fully understand what the long-term benefits of that lowering we're observing in these current dose groups could be.

Okay. Perfect. And then maybe just one more. Just wondering if you're able to take forward 2 doses in the Stage II and early stage III patients? Or it would be one go-forward dose for all patients?

So I'm not entirely clear on the question, Hannah. Obviously, right now, we're studying the 2 dose levels for both cohorts, stage 2 and stage 3, 5 milligrams and 10 milligrams. And that's what we're going to move forward with at this time.

Our next question comes from Brian Abrams with RBC Capital Markets.

I guess I'm curious if you could maybe talk a little bit about any -- I guess, the patient-to-patient consistency versus variability that you saw in the plasma HTT mRNA and protein reductions, just given that it does look like you did see an increase in the placebo arm and then there's some other data out there today suggesting potential for variability in those measures. So I know there are arrow bars are on the chart, but I wonder if you can maybe speak a little bit more to some of the consistency that you saw on those measures and just the overall validity of those as a biomarker?

Yes. Thanks for the question, Brian. A couple of important points here. First, with regards to variability, they were quite consistent. I think you see that on the arrow bars on the graph that we showed. And also, when we look at the median reduction, they're actually on par with a mean reductions, which gives you, again, a little -- a sense of some degree of consistency there. I think one of the clear benefits of being able to sample the blood compartment is that we get quite reliable and quite consistent, quite accurate assessments of the time RNA and protein lowering. To your other point regarding the placebo change, it's a very interesting question, and we've actually thought a bit about this. Obviously, no one has done studies on changes in Huntington protein levels in blood cells or, quite frankly, brain cells longitudinally over time. And there is a question of whether or not there could be some gradual increase in Huntington protein reduction, whether that be through somatic instability or any other particulars of the -- related to the genetics of this time. So obviously, this is something we'll watch as we go forward because, obviously, there is an increase in protein level, particularly in Huntington protein level over time and we're reporting these level of reductions in the face of that increase, that's obviously speaking to potentially even greater potential treatment benefit.

Got it. That's really helpful. And then maybe just as a follow-up. Can you talk a little bit more about sort of the next steps from here, just given that you're seeing this higher exposure. So you may be at doses that will get you to your target protein knockdown in the I guess, how do you sort of balance moving forward with higher doses, 20 or even maybe somewhere between 10 and 20 with the potential need to sort of go back to the FDA and wait for them to process some of this new data? How should we think about next steps?

Yes. I think there's a few different next steps here. So clearly, we're going to move forward with the 5 and 10 dosing cohorts. I think even as you say that we are we believe we are very well in target range of what we want to see for Huntington protein lowering. We clearly want to complete enrollment at these dose levels and also look at the longer-term data so we can begin to better appreciate some of the meaningful biomarker impact that we're having at these dose levels. in parallel to continuing enrollment moving forward with these dosing cohorts. As I mentioned, we will, of course, submit these data to the agency in an effort to now be able to enroll patients at U.S. study sites. Obviously, there's a balance here, as you pointed out, Brian, the whole goal of this program is to take advantage of the fact that we're in this unique setting in an early gen needs where we, one, understand the putative cause of disease, the classic mutant Huntington protein. And two, we have the ability to act on that cause of the disease with a drug like PTC518. Obviously, there's a balance between the level of mutant Huntington protein reduction as needed to deliver treatment benefits that has be balanced with doing so safely within the fact that we're also lowering wild-type Huntington protein. I think that's why to be able to look at these 12-week data and see both that we're exceeding target levels of Huntington protein lowering and we're seeing the signals of safety and tolerability. It's really encouraging that we may very well be in that for a sweet spot, if you will, right now, which is why we're really keen to continue moving forward at these dose levels and fully appreciating the impact they can have on the disease over a longer term.

Our next question comes from Robyn Karnauskas with Truist Securities.

Congratulations on the data. I just had one and then just some points of clarification on that. So regarding like the NfL reduction you saw, it seems like not all patients had a decline but there were a bunch that did. Have you looked more carefully at the characteristics of these patients? Were they Stage 2 or Stage 3? Or do they have any characteristics? And when I asked the question, just thinking about especially given other data that come up today, thoughts on like trying eventually to reduce variability. So in these clinical trials, we don't have a failed trial ultimately in Phase III because it's -- there's a lot of variability, but there's a subset of patients that benefit. That's my first question for you.

Sure. So Robyn, thanks for the question. And so what we're seeing, again, in the decline in some patients early on, we think is really strong. We quite frankly didn't expect to be seeing that impact early. So I think what we're -- you're seeing the fact that some patients may be getting some benefit early while as we'll see that benefit over time as we fully expect we didn't see any particular relationship between patient characteristics and those changes. All the patients in this study were Stage II patients. And again, I think the NfL story will, of course, be better told over time, but again, seeing these changes early on, some patients is obviously very encouraging. And of course, stability is also really important given the fact that indices a disease where anatomies over time. Certainly, we would be point that understanding patient characteristics and getting the right patient population is important to ensuring that you are capturing potential treatment benefit in this. And that was the same thing behind a lot of the work we did in the inclusion criteria for this trial to make sure that we are getting a patient population that we can best capture in the potential treatment benefit.

Great. And then just one point of clarification, sorry if I didn't catch everything. So first, just to be clear, so you're going to the 5 and 10 mg dosing attention roll up to the 30 patients in those dose groups and just continue that along, when would you explore the 20 milligrams, that was a little confusing to me because it sounds like you were saying we may already be hitting that at 10%? Just from a time line perspective, when might you make that decision? And when you think about the next dose or going higher with dose, what might you project that you could be in the range of? How are you thinking about like from a modeling perspective, if you're getting the 30% now, would that get you to 50% with the 20%?

All really good questions. Look, we -- one of the strengths of this program is that we have an oral molecule that we can titrate. It's an incredible luxury to be able to have the ability to titrate the dose level. And also the other luxury we uniquely have in the HD space right now is with a systemically administered therapy, we can monitor PK/PD with blood test. So we can actually really get an understanding of how we want to titrate the dose. So these are really some incredible advantages that we have. When we started this program, we said, look, we believe the optimal level of Huntington protein lowering in brain cells is probably between 30% and 50%, and that's based on a number of different studies as well as some epidemiology studies showing that individuals and contingencies that have nuclear polymorphisms in the promoter region of Huntington gene can have reductions of 50% of Huntington protein level and they have a market delaying onset of disease and disease progression. So there was a lot of literature supporting that 30% to 50% range. In terms of understanding what we are getting in terms of brain cell protein reduction, a little trickier, of course, because we -- while we can take blood tests frequently and understand what's going on in blood cells, we, of course, can't take brain biopsies and get a real-time look into what's going on in brain cells. So then how do we figure out what's going on in the brain cells? Well, it's a function of 2 things. One, it's a function of understanding the relationship between drug levels and lowering in blood cells, right, and understanding the relationship between exposure in the blood and exposure in the brain. So these were 2 important data points that we got from this study because we're seeing that at a 10-milligram dose level, we're getting 30% reduction in blood cells, and we're seeing a 1 to 1.5 relationship between plasma and CSF drug levels, telling us that we may very well be having potentially up to 45% lowering with in brain cells. Again, this is the best we can do is calculate that because we can't think brain biopsies. So for right now, knowing that we were seeing the target plan, our goal is to continue to get more data on more patients and get longer-term data on these patients because if we are where we need to be, let's focus on answering what the biomarker effects could be in these patients, knowing that if need be, we could always titrate up to 20 milligrams, we can tie that up to 15 milligrams but we want to make that now a little bit more of a data-driven decision what we see including the longer-term data at the 5- and 10-milligram dose cohorts.

So when is the next data set for investors Like, I guess, that's the ultimate question from a time line. If you're going to continue on with the 5% to 10% would be so at the back end of this year? Have you thought about when that would be yet?

Clearly, we will have the next data -- we'll have the 12-month data from this better patients, obviously, about 9 months from now, right, once they're done with the 12-month portion. And obviously, we will have some point of data from the 12-week data from the new patients coming in that are filling out the Stage 2 and Stage 3 cohort. We haven't given specific time on when those will be. But obviously, we look forward to sharing those data as soon as they're available.

Our next question comes from Peyton Bohnsack with Cowen.

Congratulations on hitting all the objectives of the study. I guess the first one for us is when you look -- you've got this NfL data in the CSF, and I know you guys weren't planning on releasing many mutant Huntington in the CSF. But do you have the ability to use the samples that you use for the NfL to measure the mutant Huntington's protein levels there? And if so, would you plan on releasing that before you say, releasing follow-up data at 9 months?

Yes. Good question. So obviously, Peyton, we are collecting CSF samples and that we will be looking at protein in those samples. We said that the story of mutant Huntington protein, we believe, is going to be better told at the 12-month time point. The reason for that is that CSF Huntington protein is not the same as blood Huntington protein, right? In the blood, we're able to look at what cells and measure changes in Huntington protein, but there are no cells within the CSF. So how does the Huntington protein get there? Well, it gets there from leakage of brain cells. And if you measure Huntington protein levels in Huntington's disease patients over time in early-stage patients, you actually have no detectable Huntington protein. It's only over the course of neurodegeneration, but you start seeing progressive increases in mutant Huntington protein over time. So in many ways, those levels of hunting and CSF protein are actually a marker of neurodegeneration. With more neurodegeneration, you see more spilling from more injured cells of Huntington protein into the CSF. Therefore, when we think about it that way, our drug effect of mutant Huntington protein is likely a neuroprotective effect in that we are decreasing the level of brand cell injury and therefore stabilizing or potentially decreasing the amount of protein that is now leaking because there's fewer in cells and therefore, that's translating again into this reflected lower mutant Huntington protein. So if we think about it that way, it's logical that we wouldn't expect to see steady state in Huntington protein to around 12 months. And the fact, if you look at other share changes in Huntington protein, you see that it actually takes several months longer than 3 months to begin to see steady state. Now obviously, I will share that we have Huntington protein level changes at this time that we're seeing. We're seeing lowering that we think is very encouraging, and we look forward to getting to steady state and being able to share those data when they're clear and interpretable and can clearly represent what we're seeing in terms of impact on the mutant Huntington protein level.

Great. That's super helpful. And I guess just as a follow-up, as you move into the 9-month data, is that going to be the kind of the most important biomarker is this protein level in the CSF? Or are you also going to look at like certain functional changes of brain volume changes similar to other programs. And what would really drive like the most important, I guess, marker, in your opinion, would be function?

Yes. So look, I think the reason we're really looking carefully at these biomarkers as a 12-month data point is it's pretty difficult even in over 12 months to see meaningful changes in the clinical measurements of disease whether those be the UHDRS scale, the single-digit modalities test, total motor scale. We know that in early degenerative diseases, it takes a little bit of more time to get a clear signal of drug effect. So as we look to those biomarkers in 12 months, again, we're in a good position that we have several different biomarkers that we can look at. Obviously, we're seeing from ALS and other neurogenerative disorders being able to record an impact on NfL extremely important and could not only be supportive of longer-term treatment benefit, but also could avail ourselves of regulatory pathways around the NfL biomarkers. So we'll be looking carefully not only at the NfL changes, mutant Huntington protein changes and the volumetric changes as you say, and using each of them as a source of information to confirm that we're seeing important benefits on biomarkers of disease from the levels of Huntington lowering that were achieved.

Congratulations on the data set.

Our next question comes from Kelly Shi with Jefferies.

Congrats on the progress. So I'm curious to see that level tenders pretty interesting, but it seems like it's lower -- it's even lower at the 5 milligram. Do you think the trend will change over time?

Kelly, thanks for the question. I think we can easily say that these levels are not near steady state at only 12 weeks. So I think what we'll see over time as we reach steady state is likely a more dose-dependent trend. Obviously, we'll follow that over time. But I think that variability you're seeing is probably more of a function of just being pretty early to be looking at these markers and seeing the clear dose-dependent signal.

Okay. And I also have a follow-up here. So based on the drug PK in CSF, do you have a model to predict the HTT reduction in CSF? Or more specifically, I want to ask, so at the 10 milligrams, there is a proportionately higher drug exposure in CSF versus plasma. So curious, do you expect to see the HTT reduction in CSF if you compare a 5-milligram versus 10-milligram, this difference could be bigger in CSF than in plasma?

That's a great question, Kelly, because as we -- as I mentioned earlier, the level of reduction we're getting in brain cells is obviously going to be a function of exposure. And if we're getting that higher exposure in the CNS at the 10-milligram dose level, yes, one would then expect a steady state that we're getting greater level of Huntington protein reduction in the brain cells, which should translate to greater reductions at steady state in the CSF.

And our next question comes from Brooke Schuster with William Blair.

This is Brooke on for Sammy Corwin. We were wondering if you could provide more color on what the in Huntington's protein to the whole Huntington protein ratio is in the blood, the reduction ratio?

Yes. Absolutely, Brooke. So that ratio is approximately 1:1. So not surprisingly, you're seeing changes in total Huntington and mutant Huntington given the non-allele-selective nature in the market.

Our next question comes from Jeffrey Hung with Morgan Stanley.

This is Michael Riad on for Jeff Hung. Congrats on the data. First, were you able to see any early signs or trends hinting at improved efficacy with increased CAG copy number either on HTT or NfL?

Yes, Michael, thanks for the question. So at this point, we didn't see any relationships between patient characteristics and those changes. Obviously, the changes have been fairly consistent across all of the subjects.

Awesome. And then as a follow-up, what are your expectations for the 9-month data in terms of Huntington and NfL? I guess what I'm asking is should we expect NfL change to remain stable in placebo? Or would you expect like a meaningful increase by month 9? And then same question for Huntington. Would you expect like placebo to be meaningfully above the 12-week 12% increase at week 12?

Good question. So just to clarify, the next date of the 12-month time point, which is obviously not months from now, and we believe that, that 12-month time point we should be getting closer, if not at steady state reductions in both the NfL and Huntington protein. We would expect there to be probably a gradual increase in NfL levels in the placebo group, given the fact that over time, NfL levels do increase in Huntington's stations as neurodegeneration progresses. In terms of the changes in Huntington protein in blood over time, I think we're pretty much at steady state right now. So I wouldn't expect to see changes there, but obviously, we'll continue to collect those data and perform the analysis and see what they show us.

That's super helpful and congrats again.

Our next question comes from Colin Bristow with UBS.

Congrats on the data. I think first point of clarification going about the NfL level, in the patients that you saw an increase, do you think there was nothing mendable in terms of exposure or any other characteristics? Is that correct?

In the patients whom we saw decreases in their health, we saw no particular -- there's no patient characteristic differences. Yes, that's correct.

Okay. I just -- is it from one of the plots that there was a few patients who actually saw sort of a modest increase. And then on -- just on the clinical hold, is there any more detail you can provide around what was the specific NHP kind of observations that drove FDA to obviously take this action and add/or what FDA specifically needed to see to feel good about lifting it?

Yes. So Colin, I just want to go back to the NfL for a second. I think overall, for the most part, we're seeing stability or lowering an NfL level. But if you look at other studies where you've seen market changes in NfL related to on-target or off-target effects, you're seeing spikes on the order of 4, 5, 6, 7x increases in the levels. So I think that when you look at the -- what we're seeing in those line graphs, you're seeing overall stable to lowering. You're not seeing the kinds of increases that are recorded in other studies, which has been their own neuron toxicity and again, multiple fold increases in NfL levels. Regarding the FDA and the nonhuman primate data, look, as we said, it is nonhuman primate data issue. We tend not to get into details of findings in nonhuman primates for a number of reasons, not the least of which is particularly in the splicing experience, the lack of friendly the ability of what nonhuman primates into humans, for example. In the SMA program, we're still talking about foundlings and non-primates that have never been served in units. With regards to what we hope to achieve with these data. That's based on the conversation we've had with the agency where they said that clinical data could be used to address the concerns they had over dosing and duration. What we've talked about before is that this may have been a decision that was influenced by what was being observed in some other studies are Huntington to lower agents. There could have been a any painting of all splicing molecules with sort of the same block for brush stroke. And obviously, what we're seeing here again is importance of selectivity and specificity at those important learnings from the SMA program, which are allowing us to achieve the targeted levels of reduction with obviously, to date, a favorable patient tolerability profile. So we plan to submit the data, all the safety data that we have from the study as well as obviously the DSMB reviews of the data -- agency, and it's obviously our hope that, that should address their concerns that we're bringing them, obviously, on the most relevant to humans, which is data that we've collected in patients in the trial.

That's great. And maybe just one last one as you alluded to competitor data sets. This obviously run out this morning and I was wondering did you have any comments specifically in relation to NfL levels and/or the sort of relationship seen between the mutant Huntington levels and, I guess, early sort of functional endpoint improvement?

Yes. So we did see the data come out this morning and haven't had a chance to fully digest it. I think they do seem to suggest that there again, maybe an optimal dose range where you're going to see the most favorable biomarker and potentially the most favorable clinical changes. We did observe the mutant Huntington protein lowering that was occurring in the longer term in the low-dose cohort and the data that we reported, and obviously, we opened up carefully and as I mentioned earlier that we were not providing the specifics at this time on Huntington protein lowering in the CSF, but we're seeing levels of reduction at this growing time point that are even greater than what's been reported in the longer term and as well from that lower dose cohort than the other companies center. So that's obviously very encouraging for us and of course, we look forward to seeing with those Huntington protein changes look like over the longer term as we achieve steady state lowering.

This is very helpful. Congrats again.

Our next question comes from Gena Wang with Barclays.

I have 2 questions. more like a scientific question. The first one is, when I look at Slide 9, I'm just wondering what was the reason the blood Huntington -- sorry, Huntington protein in placebo group could go up 12%? And then my second question is on Slide 10, Matt, could you explain the reason or rationale why the higher dose, it will have a higher brain exposure there? And then lastly, my third question, I think I kind of apple everyone's watching around the higher dose 20-milligram. So any thoughts there for 20 milligrams a day, you can provide wider therapeutic window to provide a 30% to 50% or around 50% not done in the brain, given the variability of the measurement that we can see from the data?

Okay. Thank you for those questions, Gena. So let me take the first -- I'll take the first one first. In terms of the increase observed in protein in the placebo group, as I mentioned earlier, we're interested in what that represents. Obviously, no one before has taken serial measurements of blood protein -- Huntington protein levels in Huntington's disease patients. And equally as obvious, no one has taken serial measurements of brain cell Huntington protein changes because it's just not feasible. There is a possibility that there is a gradual increase over time in Huntington protein production, which could result from some sematic instability in the triplet repeat zone of the [indiscernible]. That's one possibility. I think this is something we're going to look at over time to see if this is variability or is this is a true finding. Obviously, it is a gradual increase in Huntington protein over time and we're seeing 30% lowering beyond what an increase in that could be occurring in the absence of treatment, that's suggesting that we're actually getting much higher levels in fact of protein reduction. Your second question was around biodistribution. And what we're seeing is a nonlinear relationship between CNS exposure and dose. This could be a result, as we mentioned, that to be more by design, crossing the blood brain barrier plus that it might be over time that we're getting greater accumulation of drug at the higher dose level in the CNS, which wouldn't be surprising that sometimes is a reality of pharmacology, particularly when you have a nonlinear relationship around exposure. Your third question was around the 20-milligram dose group and our thinking about that. When we set up the study, we did 5-milligram and 10-milligram to start with, and that was based on the findings in healthy volunteers, where we had the 15-milligram dose group in healthy volunteers, roughly 40% lowering. And at the 30-milligram dose level, we had approximately 60% lowering. We also had a relationship of about 1 to 2.5 in terms of plasma to CSF exposure, which again may be reflective of -- and that was at 30 milligrams, which again may be reflective of this nonlinearity in terms of dose and CSF exposure. So we were developing the dose levels for Phase II, we said, "Look, if that ratio of plasma CSF exposure holds, we may very well be in the range of the 30% to 50% target lowering at the 5-milligram and 10-milligram dose. If that relationship didn't hold and it was more 1:1 then 20 milligrams should put us right around 50%. Well, obviously, we have data, what we're seeing is one at -- first at 10 milligrams, we're getting approximately 30% production in protein levels in the blood. And that appears to be fairly consistent. Those results are fairly consistent. And at 10 milligrams, we're seeing a roughly 1 to 1.5 lesion blood-to-brain exposure, which does it could be as high as 45%. Now if you think about extrapolating these data to the 20-milligram dose group, Obviously, we're twice as high a dose level with the nonlinearity, we could be looking at lowering at much beyond 50%, which is why I think at this point, the fact that we're in the target range, likely with the doses we have now, we want to plug additional data to fully appreciate what is the relationship between the lowering we're able to achieve and some of these key biomarkers of disease, before making a final decision about going to a higher dose. So that's 20 milligrams or getting leverage to titrate $1 billion on the drug, maybe we plot it to 15. But obviously, for right now, we're incredibly encouraged by the results we're seeing, both in terms of lower biodistribution as well as reporting safety to be able to be at the potential target levels of lower and seeing the casing tolerability profile so far, again, is very encouraging for us.

Our next question comes from Paul Choi with Goldman Sachs.

Just had a question on Slide 9 regarding just the sensitivity of the Huntington measurement here. Can you maybe just comment on the sensitivity, particularly given the placebo change 12% over 12 weeks. Just your thoughts on that and the sensitivity of the mRNA approach? And then my second question is, can you maybe comment -- you didn't share any data on the slides with regard to any MRI or volumetric changes even if it's anecdotal at this point? And just anything you're observing there with regard to clinical assessment on MRI?

Yes, absolutely, Paul. Thank you for the question. So these are pretty sensitive assays, the mutant Huntington protein and total Huntington protein assays are both MSD-electric chemiluminescence assays, which are highly sensitive and highly specific. The RNA protein is an RT-PCR assay, again, which is highly specific. So those results we're finding are true. They're not due to lack of robust on some of the assays. And as we say, that change in the placebo group is very interesting. And again, this study is the first time that we're able to record, serially record cell levels of Huntington mRNA and protein in Huntington's disease patients. Obviously, as we enroll more patients in the study and collect longer-term data, we'll see if that 14% remain the average change in the Huntington's Disease patients.

Great. Any color on the MRI volume changes?

So obviously, we don't expect to see impact, favorable impact of treatment on brain volume until longer time periods, probably closer to 12 months and perhaps even beyond. I can share that obviously, all these MRIs get led by radiologists who report out that they are no abnormality detected. And I think they just looking to date to bring volume across all treatment of placebo groups, the whole mainline has remained unchanged. So -- but in terms of understanding impact on volumetric MRI treatment benefit, that's a story again, that's going to be better to closer to the 12-month time point and beyond.

Our next question comes from David Lebowitz with Citi.

Hi. This is [ Debanjana ] on for David. We just wanted to ask that given the past like history of several failures in Huntington's disease with [ Ionis ] or antisense technology, how do you think this approach will be different in the long run with PTC518?

Yes. Thank you very much for the question. Obviously, there's a number of differentiating features of PTC518 that make it a very attractive therapeutic for the treatment of HD. First, just going back to the entire HTT lowering hypothesis. Again, we're in this very unique situation in neurodegenerative disorder to have a clear understanding of the etiology of disease, that being the production of mutant Huntington protein and being able to directly target that through a number of different therapeutic approaches. That's why the HTT hypothesis remains so strong and so well supported in the physician and patient communities despite the setbacks of trials. Now if you think about the way you go about achieving Huntington lowering, obviously, to be able to have a drug like PTC518, which is orally bioavailable and tradable gets to broad brand biodistribution and the ability to use peripheral blood cells to help gauge PK/PD and dose selection puts us in a very strong position. Other approaches that are intrathecally administrative or even the ultimate local administration through stereotactic diode neurosurgical procedure, which obviously PTC does a great deal about from their tiered efforts in [indiscernible] you're really hampered by distribution. So even if you're able to achieve Huntington lowering in a limited lesion of the brain, you're still ignoring a larger portion of the brain that are contributing to ongoing disease pathogenesis given that Huntington's disease is a whole bad disease. Furthermore, obviously, other approaches, including ASO, are known to have maybe inflammatory impact, so you're getting high levels of ASOs, you actually are potentially providing inflammatory insult into the CNS or patients with Huntington disease that has already a high degree of [indiscernible] stress and inflammation. So again, just coming full circle being able to have an oral therapy that broadly biodistributes the brain that we can titrate up and titrate down as needed as we see data on both treatment effect and safety really put us in a very strong position to realize the potential of the Huntington protein lowering hypothesis.

There are no further questions. I'd like to turn the call back over to Dr. Matthew Klein for closing remarks.

Well, thank you all for joining the call today. Obviously, we're incredibly enthusiastic about these interim data from the PIVOT-HD study, again being able to seize the level of HTT protein lowering steady state in the blood at the achieving the level of biodistribution we need to have. And then obviously, the safety data are all incredibly encouraging, and we're looking forward to sharing additional data from this program as they become available. Thank you all again for joining the call.

Thank you. This does conclude the program. You may now disconnect. Everyone, have a great day.