Good morning and thank you for standing by. Welcome to the PIVOT HD Topline Results conference call. At this time, all participants are in the listen-only mode. After the presentation, there will be a question-and-answer session. 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 today. We are excited to share the most recent data from the PIVOT HD study of PTC518 in Huntington's disease patients. Before I begin, I refer you to our forward-looking statements on this slide, which are also posted on our website, as well as the risk factor section in our most recent 10-K. As a reminder, PIVOT HD was designed as a 12-month placebo-controlled trial to assess PTC518 pharmacodynamic effect and safety at two dose levels, 5 mg and 10 mg, relative to placebo. Initially, the study included only stage 2 patients. A stage 3 cohort of similar size was subsequently added to help identify the best study population for future studies. The primary endpoints of PIVOT HD were total blood huntingtin protein lowering at 12 weeks and safety events.
Secondary endpoints included 12-month blood huntingtin protein levels and other blood and CNS biomarkers, as well as changes in cUHDRS. Following 12 months, subjects were eligible to enroll in a long-term extension study in which all subjects received PTC518. Those subjects originally randomized to 5 mg and 10 mg continue at that dose level. Those initially randomized to placebo were randomized one-to-one to 5 mg or 10 mg. All subjects and investigators remain blinded to initial treatment assignment. Today, I will share the 12-month topline results of all subjects enrolled in PIVOT HD, as well as results from the first set of subjects completing 24 months of treatment with PTC518. I'm excited to report that the study met its primary endpoint of blood HTT lowering and safety, and that the 12-month results are consistent with what was observed in the interim readout last summer.
PTC518 safely lowered HTT protein levels in a dose-dependent manner, with early signals of dose-dependent clinical effect at month 12 in stage 2 patients. In addition, for the subjects completing 24 months of treatment, we observed dose-dependent favorable effect on the cUHDRS and the TFC and SDMT subscales, which was significant relative to a propensity-matched natural history cohort. At 24 months, we also observed dose-dependent decreases from baseline on NfL levels, which is in contrast to the expected increase by natural history. Finally, and importantly, we continue to see a favorable safety and tolerability profile without treatment-related NfL spikes. I will begin by first reviewing the 12-month results. This table summarizes the baseline characteristics of the subjects enrolled in PIVOT HD. Overall, 159 subjects entered the study. As you can see, there are notable differences between stage 2 and stage 3 patients.
Stage 3 patients, on average, are several years older and had more severe disease. Now, the results. PIVOT HD met its primary endpoint of blood total huntingtin protein lowering at 12 weeks, and we again observed statistically significant durable dose-dependent reductions in blood HTT protein levels at 12 months. As expected, we see similar levels of HTT lowering for both stage 2 and stage 3 patients, signifying consistent pharmacodynamic effect regardless of disease severity. Looking at CSF mHTT levels, we see lowering at 5 mg consistent with what was observed in blood, and slightly greater lowering at 10 mg. The CSF analysis at 10 mg was influenced by a significant number of outliers, as a number of subjects had baseline levels at the lower end of detection of the assay.
Looking at NfL levels, similar to the interim results last summer, in stage 2 patients, we see trends of decrease in plasma NfL compared to placebo, and in stage 3 subjects, we see NfL lowering for the 5 mg dose group and no difference at 10 mg relative to placebo. As we have stated previously, 12 months may be too early to see clear treatment effects on NFL. Importantly, looking at trajectories of NfL for all treated subjects, including both stage 2 and stage 3 cohorts, we again see no treatment-related NfL spikes, supporting the favorable PTC518 safety profile. On volumetric MRI analyses, as shown here, we see no meaningful differences in changes in caudate volume. Again, as we have discussed, 12 months is likely too soon to understand treatment effect on brain volume changes. Now, let's look at the clinical data.
First, for stage 2 subjects, as observed in the interim readout, we again see early trends of clinical effect on several endpoints. We see dose-dependent effect on the cUHDRS scale, driven by the TMS subscale, as well as the SDMT cognitive subscale for the 10 mg dose group. Notably, the placebo changes for the full cohort are less than what we observed in the initial readout, but we still observe a similar magnitude of treatment effect. For stage 3 patients, we observed a different treatment effect pattern. While a small favorable effect is shown on cUHDRS for 5 mg subjects, this is not the case for the 10 mg cohort. These data support that optimal clinical effect at 12 months may be better understood in the less severe stage 2 patients. An important learning as we think about inclusion criteria for the next stage of development.
In terms of safety, as previously reported, PTC518 showed a favorable safety and tolerability profile with no evidence of treatment-related SAEs and similar frequencies of AEs across all three treatment groups: placebo, 5 mg, and 10 mg. The most common adverse events are similar to those reported previously: nasopharyngitis, influenza, headache, and falls. As shown on the AE table, there were similar patterns of AE frequencies and severities across dose groups for both stage 2 and stage 3 cohorts. Of the reported treatment-related serious adverse events, none were deemed related to PTC518. In summary, the results for the entire enrolled study population at 12 months are consistent with the interim results reported last year. PTC518 treatment resulted in dose-dependent and durable blood Huntingtin protein lowering, and in stage 2 patients, dose-dependent trends of favorable clinical effect across clinical scales.
It appears that in the short term of 12 months, clinical benefit may be better captured in stage 2 patients. Finally, and importantly, PTC518 continues to show a favorable safety and tolerability profile. Now, I'd like to share the results from the initial subjects to complete 24 months of treatment. This slide summarizes the patient characteristics of the 21 subjects initially randomized to receive PTC518 at 5 mg or 10 mg included in the 24-month analysis. These subjects are all stage 2, as the study enrollment was initially limited to only stage 2 patients. Since the trial was only placebo-controlled for 12 months, we utilized the large Enroll-HD registry to identify a matched natural history cohort to contextualize the 24-month treatment effect. We identified a propensity-matched natural history cohort based on several key disease factors.
The natural history matching exercise yielded a cohort of 1,045 matched subjects to whom we can compare PTC518 treatment effect over 24 months. At month 24 on the cUHDRS, there continued to be dose-dependent differences between 5 mg and 10 mg dosing groups. When compared to the matched natural history cohort, the treated subjects showed less decline relative to natural history, with nominal p-values that reached significance for both dose levels. We see similar dose-dependent favorable effect relative to matched natural history on the TFC and SDMT subscales, again with nominal p-values reaching significance. Of note, the positive trends on the TMS observed at month 12 were not maintained at month 24 due to two subjects that had an over 18-point worsening from month 12 to 24. In addition, we also have NfL results at 24 months, as NfL was collected as a safety endpoint.
As shown here, there is dose-dependent lowering from baseline to 24 months in plasma NfL for the 5 mg and 10 mg dose groups, and the change from baseline reached significance for the 10 mg dose group. For reference, in untreated patients, NfL should increase over time. In the most recent published natural history analysis of stage 2 patients, NfL increased by 12.5% per year. This signal of dose-dependent PTC518 treatment effect suggests a potential longer-term neuroprotective effect of mHTT lowering. In terms of safety, again, importantly, we continue to see a favorable safety and tolerability profile. In summary, over a longer treatment period of 24 months, we see continued signals of dose-dependent favorable clinical effect on cUHDRS and the TFC and SDMT subscales that reach significance when compared to a well-matched natural history cohort.
In addition, at month 24, there is a dose-dependent lowering of NfL levels, suggesting a potential PTC518 neuroprotective effect. In conclusion, PIVOT HD met its primary endpoint, and the month 12 results in the entire enrolled population are consistent with the previously reported evidence of HTT lowering, favorable safety profile, and signals of early clinical effect in stage 2 patients. At month 24, there are continued trends of dose-dependent clinical effect relative to natural history, as well as dose-dependent NfL lowering, supporting that over a longer treatment period, we are seeing effects of HTT lowering on multiple aspects of disease. We plan to complete some additional analyses and look forward to discussing next development and regulatory steps, including the potential for accelerated approval based on these data. 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 Huntington's disease who may benefit. I will now turn the call over to the operator for questions.
Thank you. To ask a question, please press star 11 on your telephone and wait for your name to be announced. To withdraw your question, please press star 11 again. The first question comes from Kristen Kluska with Cantor Fitzgerald. Your line is open.
Hi, good morning, everyone. Thanks for taking the questions. First, on the 24-month data, do you have any HTT lowering data there? Then, because it is a small subgroup, I'm wondering if you can comment on any of the inter-patient variability from 12 months to 24 months, just given that the data looks so clean at this stage. Do you suspect that it was just the disease severity getting worse over time where the effects could perhaps shine a little bit better at this time point?
Thanks for the questions, Kristen. First, in terms of HTT levels at 24 months, we have not run those samples yet. We basically focused on getting the 12-month analyses done, and then were able to access the clinical data from the database, and NfL is being followed as a safety variable. Of course, we are very happy to see no NfL spikes after 24 months, and now being able to see that dose-dependent NfL lowering at 24 months, which we think, to your question, is a further indication that it takes some time for the drug to start manifesting clear effects across many aspects of the disease. By targeting HTT levels, we are targeting really the early, the etiology of the pathogenesis of this disease, and one could naturally expect that it will take a little bit longer time to see the benefits of that HTT lowering.
Furthermore, given the disease progression being heterogeneous and slowly progressive, again, this longer treatment period is really allowing us to see some cleaner signals of effect, not only on the clinical scales that are dose-dependent and much better than natural history, but then, again, also seeing the trend on NFL.
Okay, thanks. Based on the interactions that you had with the FDA late last year, what is the next step for you now that you have this data on hand?
Yep, so we got a lot of questions coming into this readout about the need to show associations, which was the words that FDA used for understanding the relationship between mHTT lowering and associations with other measures of disease. As we've talked about, it's great to see these data with dose-dependent effects. That's a great association because what that's telling you is that if you tend to lower Huntingtin protein more, you're tending to see better clinical effect, and now at 24 months, an effect on NfL that's greater than both at the lower dose of 5 mg and better than natural history. We feel that we now have a number of these associations both in the short term and in the longer term between mHTT lowering and clinical effect.
We'll clearly need to finish up some additional analyses, review the data with our partner, Novartis, and then chart the next steps, including next clinical steps and next regulatory interactions.
Thank you.
Our next question comes from Eric Joseph with JP Morgan. Your line is open.
Hi, this is Billy on for Eric. Thanks for taking our questions. Quick one from us. We're looking at the stage 2 patients. Is there any color into patient analyses on the decline with TMS or with kind of cUHDRS scores?
Billy, thanks for the question. The cUHDRS is the composite, right, that is driven by or composed of the four scales of TMS, TFC, SDMT, and Stroop test. In stage 2, we know that certain scores are driven a lot by either TMS or SDMT based on whether patients have symptoms that are more cognitive or more motor, and of course, those could also evolve over time. When we look at those data, what we're seeing at 12 months is improvements in cUHDRS that are driven by, in some cases, SDMT, in some cases, TMS, and in some cases, both. I think that having those multiple subscales is really a way of capturing the heterogeneity of disease and how treatment effect may manifest differently.
Importantly, in the overall score, what we're seeing are these dose-dependent trends both at 12 months and then significance relative to natural history out at 24 months.
Thanks. Following on, I think, from the prior questions, with these data now in hand, do you mind just recapping for us a little bit as to what kind of the next steps are with the regulators?
Yeah, so the next step is we got to we're new with the data, so we'll go through all the data internally, run some additional analyses. We'll obviously discuss the data in detail with our partner, Novartis, and then chart all the next steps in regulatory interactions, clinical development, and so on.
All right, thank you very much. Thanks for taking the question.
Our next question comes from Brian Abrahams with RBC Capital. Your line is open.
Hey, guys, good morning. Thanks for taking our questions. Maybe two from me. I guess looking at the mHTT reductions, any sense as to why, I guess, in this newer cohort, you did not necessarily see the same sort of relationship between the blood plasma mHTT and CSF? Is that something that might prompt you to consider looking at higher doses, just given the clean safety? Secondly, can you elaborate a little bit more on why you think the stage 3 patients are less responsive and why the data is less interpretable for those patients, despite the fact that they had similar CAG repeat numbers? I noticed that they looked a fair amount older. Could that be a reason that could their disease be much more progressed?
That might be why, and maybe just help quantify the size of the stage 2 market overall relative to the overall Huntington's population. Thank you.
Yeah, thanks for the questions, Brian. The first question regarding mHTT in blood and CSF. At the 10, one thing we know is that Huntingtin protein is in very low quantities in the CSF, and measuring it has always been a challenge as for many patients, their levels are at the lower limit of quantification. What we saw at the 10 mg level is a significant amount of variability and outliers with things ranging from minus 50 or 60 in terms of reduction and some up to 150 or 200. Just a lot of variability that I think really confounded that measurement. Not surprising, at 5 mg lined up very well blood and CSF, it's entirely possible at 10 mg when you're further reducing the Huntingtin protein, you're getting more and more variability because you're driving those levels lower and lower.
We do not think that's a sign to go higher. In fact, it may very well be a sign that we're effectively lowering the CSF protein levels, but we have an assay with very low reliability and accuracy when you're down at those small levels. We've always pointed to the blood as being more meaningful in terms of understanding target engagement and in terms of understanding what's going on in the neurons because that is, blood is a cellular compartment, and we know that the lowering in blood cells mirrors what we saw in brain cells preclinically and that the CSF is really a reflection of things that are going on in the neurons.
Importantly, we're in that range we need to be in the blood lowering to give us confidence that we're in the right place to see the kinds of effects that we're seeing at 12 months and now at 24 months. In terms of the stage 2 versus stage 3, as you know, when we started PIVOT HD, we spent a lot of time trying to understand the right population and whom to demonstrate definitive efficacy. We started with stage 2. We believe that that was the right stage of progression. We subsequently added the stage 3s for a couple of reasons. One, other studies that were ongoing that included stage 3 had been terminated, and so there were a lot of prevalent patients at our study sites who wanted to be in the trial.
The second was it would be a very good way to test our hypothesis of which would be the right age patients and whom we could best capture treatment effect in the course of a clinical trial. If you look at the demographic slide, slide 6, you note differences in age, differences in severity, including lower total functional capacity scores. We also had much worse cUHDRS scores in these folks. Every sign was this was a much more advanced population than the stage 2. Also, what we saw in the placebo group and also in some of the treatment groups is a much more rapid progression. I think this was a very important learning in terms of the optimum population for future studies. Now, it's possible that we could still see treatment effect in stage 3, and it may just take longer.
Again, we're targeting the disease all the way upstream, and it's going to naturally take some time to be able to see effect. The question at stage 3 is whether disease is so advanced that modifying it is very hard. Second, if you're going to modify it, it may very well take longer. Nonetheless, the important learning here was that the stage 2 seems to be a much better population in whom we can capture meaningful dose-dependent treatment effect over the shorter time period that we've observed so far. Again, that'll be an important lesson as we take the next steps in development. In terms of patient market size, about 85% of the population is stage 2 and earlier. About 10-15% of the population tends to be stage 3.
I don't think we're anywhere near answering the question about the potential benefit of the therapy in stage 2 patients. What we know is that in 12 months, it's not a great population in whom we can clearly understand treatment effect. We know we're getting target engagement. We know we're getting HTT lowering, and the drug is working as it's supposed to work. Our exposure data shows the drug's going where it's supposed to go in these patients. The question is, how amenable are they to disease modification at this late stage? If they are modifiable, how much time is it going to take to really see a clear and consistent signal?
Thank you.
The next question comes from Judah Frommer with Morgan Stanley. Your line is now open.
Yeah, hi guys. Thanks for taking the question. Kind of wanted to take the opposite angle of that one. I guess based on what you've seen thus far, could you make the argument that perhaps treatment should start earlier in stage 2? Could that be part of the conversation with your partner, Novartis, and/or FDA? Separately, just as you go back to FDA, how are you thinking about kind of benefit converting the subscales of cUHDRS? Do you think you'd be able to tie Huntingtin lowering to subscales, or would they like to see benefit across the entire scale? Thank you.
Thanks for the questions, Judah. The short answer to your first question is absolutely. I mean, the whole concept of lowering Huntington and the data supporting the appeal of that as a strategy comes from a number of preclinical studies and also an epidemiologic study that shows that in patients who make less protein, who have a single nuclear polymorphism so that they make about 50% less protein, they have a delayed onset of disease and a slower progression. I think there is every reason in the world to believe that going earlier is better so long as you have a therapy that is safe and well tolerated, which our data so far show that we have a favorable safety and tolerability profile. I think this is something that's important.
This is something that I'm sure everyone developing HTT lowering therapies is aware of, that you need to show that this works and then migrate early and earlier. That's absolutely the feedback we've gotten from the KOLs as well as patient community saying that if earlier treatment, slowing the progression sooner is always the ideal in neurodegenerative disorders. In terms of FDA, the feedback we got from FDA as we talked about was their desire to see some associations between HTT lowering and other signs of disease. I think looking at the cUHDRS is helpful in that it has many subscales and therefore can assay many different effects simultaneously.
I think looking specifically at the subscales could also be informative, such as looking at SDMT at 24 months and starting to see a very nice signal in the first group of patients on cognitive function, which is something that is of unequivocal importance in Huntington disease. Being able to have the NfL data, that dose-dependent lowering when NfL should be going up over time is an objective to know that you're having some protection of neurons, neuroprotective effect, which is exactly what you want to do over the long term by lowering the toxicity in Huntingtin protein.
Thanks.
Our next question comes from Eliana Merle with UBS. Your line is open.
Hey guys, thanks for taking the question. Just want to clarify a bit. When you talk about associations between mutant huntingtin lowering and efficacy, what specifically will you look at? Have you seen, in terms of the patients that have had a greater mutant huntingtin lowering, a greater clinical benefit? Just any kind of clarity on maybe some of the variability that you're seeing in the mutant huntingtin lowering and if this has been predictive of, say, greater clinical benefit in the patients that might have seen greater lowering? Thanks.
Yeah, thanks for the questions, Ellie. I think the first thing we've seen that we've talked about is important is this dose dependence. Because the dose dependence tells you that when you go from having no lowering at placebo to some lowering at 5 mg and more lowering at 10 mg, and then you see dose-dependent effects on markers and now NfL at 24 months, that is telling you that there is a relationship in general about how much Huntingtin lowering you're having and the effect that you're having now, both clinically and then on NfL from a biomarker standpoint. That is an association. It is saying that the magnitude of lowering of Huntington tends to be associated with a certain amount of other effect, whether clinical or biomarker. We can go in and look at correlations and outliers. We haven't done that work yet.
That's some of the additional analyses that we'll do. I think on first look, we were encouraged that the dose dependency is certainly representative of associations, particularly in smaller populations as we have.
Got it. Thanks.
Our next question will come from Gina Wang with Barclays. Your line is now open.
Thank you for taking my questions. Maybe follow the previous questions. Also, Matt, you made quite a few comments, right, regarding the lowering association with functional data. When we look at it, there are a few data points. There are some data points. There are some associations there, but there are other data points. There are no associations there. I can give several examples like Huntingtin lowering. We did see the CSF numbers, right? The lack of dose response, 5 mg and 10 mg, we did explain partially. On the other hand, why did we not see this time what we saw last time and why 5 mg showed pretty similar to the blood level, but not the 10 mg. I have another question regarding the neurofilament.
When we look at the numbers, also 5 mg seems to be better, both in the stage 2 and the stage 3. I have a related question on month 24 because you did say further improvement. When we look back, last June 2022, sorry, last June data, neurofilament placebo arm actually had a highest reduction. We would like to know what is the trend there. TMS, now at the 24 months, was not maintained. My question is, do you think at the minimum level, stage 3 is off the table for accelerated approval because the functional trend did not show consistent?
The second, regarding the stage 2, what kind of data point, if you're emphasizing two-year or longer timeline, what data point will be important when you talk to the FDA that will help you emphasizing the accelerated approval path could still be open?
Okay. Do you have a lot of questions there? Let me just zoom out for a minute and say the concept here is that we did conduct a study at 5 and 10 and placebo and showed exactly what we wanted to see in the phase II study, which is the dose-dependent target engagement, safety, and early signals of effect. I think we just have to be clear. We didn't power this to see significant effect in the clinical endpoints, but what we did, in fact, see are the trends that we've talked about. In terms of I'll try to get to all your questions. I think I've got them all. First, on CSF at the 10 mg, we did not see the same dose dependence.
A lot of that, as I said, I believe was driven by the variability and outliers due to the assay sensitivity at 10 mg. On the NfL, one of the things we said last year in the June readout is there's a lot of variability over short term in NfL and that we thought that 12 months would be too short to see the signal, which is why we're encouraged now at going from 12 to 24 months. We're seeing a clear trend towards lowering in the treatment group, including that dose dependency, which when you look at natural history, increases over time, certainly over 24 months. Now, the exact magnitude of that increase can vary in report to report.
We cited in the presentation the most recent natural history study done by Parkin and colleagues, which showed that in the stage 2 patients, they were observing roughly 12.5% increase per year, and that others have reported up to 13%. Some have reported 9%. In that general ballpark, it is understood over 24 months there should be an increase in NfL when we are observing the decrease. In terms of the TMS from 12 to 24, again, we noted that there were a couple of patients who had a significant increase from 12 to 24 months regarding with an 18-point change, which obviously in a small population with two patients changing 18 points would certainly have an impact. We were very happy to see the now emerging signal of SDMT at 24 months.
In fact, in the overall data set at 12 months, we're starting to see a signal of effect, and that's maintained out at 24 months. I think we could all agree that cognitive benefit is probably something that it's going to take a bit of time to see a clear signal on. We were very encouraged by that at 24 months. In terms of what's on the table and off the table for FDA, we'll sit down and go through the data with our partner in Novartis, and we'll come up with an approach to talk about how we would approach regulatory interactions. I would simply say that I think the stage 2 versus stage 3 for us was really about understanding the optimal population for an efficacy trial.
I think what we're seeing here is that for stage 2 patients, we were better able to see an effect in the short term of 12 months, which is not entirely surprising. The concept that earlier stage patients in neurodegenerative diseases may be more amenable to modification or maybe a population when we can see modification is not new. I think that's a lot of the Alzheimer's story as well, that when you started to look earlier, you were able to see an effect that you couldn't see in later stage patients. I think for us, that was a very important learning as we think about next stages of development. How that will inform FDA discussions is something that is something to come.
Thank you.
The next question comes from Geoff Meacham with Citigroup. Your line is open.
Oh, great. Thanks so much for the question. Yeah, I just have a couple on the regulatory side. I guess the first one is, is there a way to weight some of all the biomarkers that you're looking at in the phase II study just to maybe confer an argument for accelerated approval? I wasn't sure if there's a composite that you could do to kind of maybe separate more signal from noise, and maybe that will tell you some difference between stage 2 and stage 3. The second question, I know it's sort of hard to answer with respect to a full approval and a pivotal, but would you expect to do a separate stage 2 and stage 3? I wasn't sure in a pivotal what the value would be to add both if stage 3 is going to add a lot more variability.
Looking to the stage 3 from a functional standpoint, do you see pretty wide variability in those patients from natural histories versus stage 2? I guess that has some regulatory consideration. Thank you so much.
Thank you for the question. On the first part, I think when we think about accelerated approval, there's generally two potential paths, right? One is the surrogate biomarker where you have a biomarker that is meaningful in terms of both how your drug's working and in terms of impact on the disease. Then there's the concept of intermediate clinical endpoints and supportive biomarkers of that. I think with this data set, we see support on both of those. I think first, the intermediate clinical endpoint, cellular Huntingtin lowering is an endpoint in our discussions with the FDA. They accepted the scientific rationale of that’s ability to potentially predict ultimate clinical benefit.
What we then looked for and what they asked from us was to find some associations or other data that we could turn to from the study that can show that lowering the protein is having an effect. I think the standalone, rather than trying to combine all these things, is actually important and provides very valuable information when you're seeing effects on both clinical scales and the NfL biomarker over 24 months. Keeping those separate, saying on different things, you're seeing some association between the Huntingtin lowering and clinical effect. In terms of stage 3 and variability in future trials, we see a lot of variability on the stage 3 patients. In fact, one potential is that it may be very hard to affect the stage 3 patients in the short term.
What we may, in fact, be seeing is just disease variability playing out. Stage 3 heterogeneous patients tend to progress very rapidly. It is unclear at this early stage of 12 months whether we are seeing an indication of treatment effect or disease progression. I think we need a longer time point when these patients are in the open label extension. There will be data at 24 months that I think can further tell the story about what effect the Huntingtin lowering is having in these patients. Clearly, as one thinks about next steps in terms of development, one important consideration for a phase III trial or a next efficacy trial is who is the optimal population and whom over 24 or 36 months can you see definitive clinical benefit?
That was one of the important objectives of this study, was to help inform the optimal population, the inclusion criteria, the endpoints, all those important things when we get to phase II. That is why while on the one hand, we would have liked to see better treatment effect in stage 3, we are very happy to have seen it in stage 2. Maybe the very, very important learning for the development of the molecule and the future of the program is that the earlier stage 2 patients are likely a better population in whom we can establish definitive efficacy in a well-designed, well-powered efficacy trial.
Awesome. Thank you so much.
Our next question will come from Joseph Thome with TD Cowen. Your line is open.
Hi there. Good morning. Thank you for taking my questions. Just a couple on the TMS measure because this does look to be the one that is driving the dose-dependent benefit in the phase II patients, but also saw a little bit of a dose-dependent worsening in the stage 3s. Can you talk a little bit about the overall variability of TMS as a measure? Maybe in the 24-month data, if you exclude those two TMS patients that had the large increases, I guess, what did TMS look like for the remaining patients? Is there anything to explain those large jumps on TMS for the patients that did see that large worsening? Thank you.
Yeah. Thanks for the questions, Joe. In stage 2, the parts of the cUHDRS that are thought to move the most or be most reflective of progression are the TMS and the SDMT, the cognitive scale. As I mentioned in one of the earlier questions, they assay different aspects of the disease. One point is motor function, and the other is cognitive function. Of course, when those progress to a certain point, you start seeing the impact of progression on the TFC score. It is not surprising to see the cUHDRS driven by TMS and SDMT. When we look to the longer term, we are seeing the SDMT certainly driving a lot of that treatment effect. Certainly, if you took those two patients out, we would see a much better outcome on the TMS.
We do know that, and this is something we're going to look into to try to understand what led to those significant swings over the 12 months. We know we've started looking at ConMeds. We know one patient started a medication and has a side effect, some motor symptoms that could have confounded things. We are going to look deeper into that to better understand what could be impacting those scores because that'll be an important learning for the next development steps.
Great. Maybe one quick housekeeping question. I know you have fast track for this agent. Have you discussed breakthrough therapy designation with the agency, or do you anticipate requesting that after this data set? Thanks.
Yeah. We have not discussed breakthrough. We got the fast track. We turn these data over, and then as we discuss with Novartis the next steps, I mean, all those things are going to be on the table in terms of what we want to do in terms of regulatory and development next steps.
Perfect. Thank you.
The next question comes from Joe Schwartz with Leerink Partners. Your line is open.
Great. Thanks very much. There are some big changes in caudate volume in the placebo patients, which were not attenuated to that much of a degree in the drug arms. Given the community, and I think FDA views caudate volume as a potentially valuable surrogate biomarker for clinical development in HD, I was wondering if we could get your thoughts on what story that picture is telling.
Yeah. Joe, thanks for the question. I think it's telling the story we all know that in the short term, it's very hard to understand volumetric changes on MRI when you have a disease-modifying therapy. What's been well understood is that you could, in the short term, things like lowering brain edema, lowering swelling, and lowering inflammation, which would be a therapeutic benefit, would result in decreasing volumes. Disease progression could result in decreasing volumes. There is also a lot of variability in fluid shifts in the short term that make the imaging analysis difficult. The feedback we've gotten from KOLs and radiology experts is that in the short term, it's very hard to understand these changes.
Over a longer term, or two to three years, or perhaps even longer, you could begin to start understanding what effects you might be having in terms of brain volume. Again, we could turn to the Alzheimer's experience where pseudoatrophy was a real thing, and it was actually a benefit of therapy because you were decreasing inflammation. I think what we see on the imaging analysis here is they're not telling us anything. We did not expect it to tell us anything in the short term, but it is certainly something as we go out into the longer term, we will want to understand better.
Okay. Thanks. Is this the full extent of statistical analysis you'll be performing on the PIVOT HD data when you bring your case for accelerated approval to the FDA, or will anything else be done to assess associations between Huntingtin lowering and functional benefit in terms of things like R-value, which we usually think of as being typical statistical tools to evaluate and demonstrate an association in a rigorous manner? Thanks.
Yeah, Joe, as I mentioned, we still have additional analyses to do, and we'll sit down with Novartis and look at other additional analyses we could do to better understand the associations. As we said, we believe that dose dependency in small population is a pretty good sign that there's a relationship between the amount of Huntingtin lowering we're achieving and the effect both on clinical scales and NFL.
Great. Thanks again for taking my questions.
The next question comes from Sami Corwin with William Blair. Your line is open.
Thanks for taking my question. I think I was curious if there's any scenario in which FDA might want to see more data at 24 months in order to have a more productive conversation regarding accelerated approval. If they do kind of want to see that additional data at 24 months for accelerated approval, would you kind of think about running a phase III trial still that would not be hinging on that and would be hinged on full approval instead? I was wondering if you could also provide us some more granularity in terms of the milestone payments you still expect from Novartis and how much of them are tied to clinical milestones versus regulatory. Thank you.
Thanks for the question, Sami. Look, I think it's a little early to be saying what FDA may say here or may say there. I think looking at the data, we are pleased with what we have. We believe we've shown in the larger data set some of the associations that were asked for. We confirm the dose-dependent lowering of Huntingtin protein, which is important when one considers effect on a surrogate biomarker. The good thing about this study is it's ongoing, and we have the ability to continue to harvest data. Again, this will be something that we'll sit down and talk with our partner Novartis about the plans, additional data cuts, and regulatory feedback.
I think everyone would agree that we have data here that supports exactly what we wanted to have, which was evidence that we have a Huntingtin lowering therapy that's demonstrated to be safe and well-tolerated. It's doing what it's supposed to do. It's going where it's supposed to go. We're seeing signals in the short term that it could have ultimate long-term efficacy. Those are the goals of phase II, along with having made important learnings about what the next some important considerations for an efficacy study. I think from that standpoint, we'll have to see that we've ticked all those important boxes for phase II as we now look to a next efficacy study. In terms of milestones, we said $1.9 billion in terms of milestones that are kind of balanced between both development, clinical regulatory, as well as commercial.
We haven't gone into any more granularity on that.
Got it. Thank you.
Our next question comes from Joel Beatty with Baird. Your line is open.
Hi. Thanks for taking the call, team. Could you discuss what doses you see planning ahead? Would it be one dose moving ahead or multiple doses? Could it be different doses for different patient populations?
Joel, thanks for the question. I think at this point, what we have with 5 and 10 mg is we have two dose levels that are getting us to the that are both in the range of the desired Huntingtin lowering. Clearly, the decision of one or two doses going forward will be one that our joint development committee with Novartis will take up. That is going to be an important discussion in terms of design of a next study. Again, I think it's good to see that you have two dose levels that are lowering cellular protein in the range that we believe we need to do to be efficacious and are both doing so safely with no treatment-related serious adverse events, NfL spikes, and the like.
I think we're in a very good place to be able to have two to bring forward, and that'll clearly be the subject of further discussion.
Thank you.
Our next question comes from Kelly Shi with Jefferies. Your line is open.
This is Ethan from Jefferies on behalf of Kelly. Also, for stage 3 and stage 2 patients, different efficacy. I'm wondering, do you expect higher depletion of the wild-type HTT protein may have different effect in stage 2 and stage 3 patients, which may lead to different treatment effect? Also, would you pursue both dose levels, 5 mg and 10 mg, in the potential phase III development? Thank you.
Thank you very much for the questions. I think the reason we chose the 5 and 10 mg is we believe that they were two dose levels that could lower HTT protein sufficiently, the mutant protein sufficiently to have an impact or clinical effect, but also be well-tolerated from a safety standpoint. It is very hard to know whether there is any effect on the wild-type lowering and whether that is going to have an effect on efficacy in stage 3. I think we are comfortable we have two doses that are lowering Huntingtin protein, again, in the range that we believe can provide efficacy and also do so safely. I think we are encouraged by the uniform safety we are seeing across both stages of populations.
As I mentioned in the previous question, I think right now both doses are at the discussion in terms of moving forward because both lower HTT protein in that range that we believe is necessary for efficacy and have both been demonstrated to be safe. That will be a question the joint development committee with Novartis that we have with Novartis will take up as we think about design of future study.
Thank you for taking that question.
I show no further questions at this time. I would like now to turn the call back over to Dr. Matthew Klein for closing remarks.
Thank you all for joining the call today. Again, we're excited to be able to confirm that we have in PTC518 a drug that has dose-dependent lowering of HTT protein, has shown to do that in a safe manner. We're seeing the early signs of clinical effect at both at 12 months and now additional signs at 24 months. With this data set, we're very pleased to have achieved all we set out to in phase II and look forward to discussions on the next steps. We also are looking forward to our earnings call that will be held after the close of market tomorrow. Thank you all.
This concludes today's conference call. Thank you for participating. You may now disconnect.