Ladies and gentlemen, thank you for standing by. Welcome to PTC Therapeutics' PIVOT-HD Long-term Extension Study Top-Line Results call. All participants are in a listen-only mode. After the presentation, there will be a question-and-answer session. Today's conference is being recorded. I would now like to turn the conference over to Dr. Matthew Klein, Chief Executive Officer. Please go ahead.
Thank you all for joining the call today. We are excited to share the positive and promising top-line results from the 24-month interim analysis of the PIVOT-HD long-term extension study. The findings of safety and treatment effect I will share today give us confidence that Votoplam has the potential to provide long-term meaningful effect in slowing the progression of Huntington's disease. Before I begin, I refer you to our SEC filings for a full description of risks and uncertainties. As a reminder, the phase II PIVOT-HD trial was a 12-month placebo-controlled study of Votoplam at two different dose levels in individuals with Stage 2 and Stage 3 disease. Following the 12-month placebo-controlled phase, all participants were eligible to enroll in a long-term extension study in which those initially randomized to receive placebo would be re-randomized to receive either high or low dose of Votoplam.
Importantly, all study participants and investigators remain blinded to treatment assignments. As we shared last year, PIVOT-HD achieved the primary endpoint of blood HTT protein reduction at week 12, with evidence of durable dose-dependent lowering of HTT protein at 12 months. At that 12-month readout, there was early evidence of dose-dependent benefit on the cUHDRS rating scale for the Stage 2 participants, along with evidence of safety and tolerability without any treatment-related NfL spikes. Today, we will share results from the 24-month interim analysis of the long-term extension study. The long-term extension study was designed to assess safety, clinical, and biomarker effects of Votoplam over time. This interim analysis assessed the long-term effects of Votoplam treatment on disease progression, as assessed by the cUHDRS and its subscales, as well as long-term safety and biomarker effects following 24 months of Votoplam treatment.
Given there was no placebo group after month 12, the long-term extension protocol specified that a well-matched natural history cohort from the Enroll-HD Disease Registry would be used to contextualize Votoplam treatment effect at month 24. This table summarizes the baseline characteristics of the Stage 2 and Stage 3 study participants included in the 24-month analysis. I want to point out that these are the participants who were initially randomized to receive Votoplam at 5 or 10 milligrams at the start of the placebo-controlled phase of PIVOT-HD, for whom we now have data following 24 months of Votoplam treatment. The key points to highlight on this table are that, as expected, the Stage 3 participants tended to be older, with evidence of decline on the total functional capacity for TFC scale, which is a hallmark of Stage 3 disease in Huntington's disease.
As I mentioned, in order to contextualize the Votoplam treatment effect following 24 months of treatment, a natural history cohort from the Enroll-HD registry was developed. Enroll-HD is the largest HD disease registry with over 30,000 patient records and includes data for all the key inclusion criteria of PIVOT-HD. Here are the key matching variables used to identify the natural history cohort, the key factors that influence disease progression. This slide summarizes the key baseline characteristics of the Votoplam-treated subjects and the natural history cohort. As you can see, the natural history cohort is well-matched with regards to the key variables that may influence disease progression, with no relevant differences across the groups. Here are the results, first for the Stage 2 participants.
I am pleased to report that at 24 months, Votoplam demonstrated dose-dependent slowing of disease progression relative to natural history on the cUHDRS scale, with a mean of 52% slowing versus natural history at the 10-milligram dose and 28% at the 5-milligram dose level. Notably, from month 12 to 24, we see the curves continue to diverge from natural history, supporting an increased treatment effect over time. While the differences did not reach statistical significance, there is a trend with the P value less than 0.10 for the 10-milligram treatment effect. Next, in looking at Votoplam treatment effect on the four individual cUHDRS subscales, we see evidence of benefit for both dose groups on several of the subscales.
Importantly at 24 months, we continue to see no evidence of NfL spikes, and for both the 5 and 10-milligram groups, NfL levels are below baseline, which is a departure from the understood natural history of progressive NfL increase over time. Moving to the Stage III participants. As we have discussed, when we initiated PIVOT-HD, we understood that individuals with Stage 2 and 3 disease may progress at different rates. Anticipated that the Stage 2 subjects may be the population in whom disease progression could be better captured over the 12-month course of PIVOT-HD. At 24 months, in the Stage 3 participants, we are beginning to see signals of potential favorable treatment effect.
Looking first at the TFC scale, which is a particularly relevant cUHDRS subscale for stage three patients, where by definition of a Stage, a functional decline, we see benefit relative to natural history at both dose levels. The cUHDRS as a whole, we observe a trend of benefit for the 5-milligram dose level at month 24, with what may be an early signal of slowing of progression from month 12 to 24 for the 10-milligram dose level. For NfL, not shown here, there were no treatment-related spikes in the Stage 3 participants, with median levels below baseline for both 5 and 10 milligrams at month 24. I am also pleased to report that the safety profile of Votoplam remains favorable after 24 months of treatment.
There are no new adverse event signals identified, and the overall profile is consistent across both dose levels and both stages at month 24, as well as consistent with what was observed in the placebo group. On this adverse event table, we show the adverse events from the first 12 months of PIVOT-HD here on the left side of the slide, with the events for months 12 to 24 in the open-label extension on the right side of the slide. As you can see, the AE profile is quite consistent over time and across dose levels. In the long-term extension, all Stage 3 and 4 AEs and SAEs were deemed not treatment related. These safety and efficacy data, particularly those in the earlier stage participants, provide us increasing confidence in the design of the phase III INVEST-HD global trial, which Novartis shared earlier today is now enrolling.
This study will directly assess the long-term efficacy of Votoplam in earlier symptomatic individuals with a normal TFC score of 13. Participants will be randomized three to two to receive 10 milligrams of Votoplam or placebo. Target enrollment is approximately 770, the primary endpoint will be changed from baseline up to 36 months on a cUHDRS rating scale. This study will also include interim analyses for both efficacy and futility. As we have shared previously, this registration study could serve as a confirmatory study in the context of potential accelerated approval. In conclusion, in PIVOT-HD, Votoplam demonstrated statistically significant dose-dependent reductions in blood HTT levels. Now at 24 months, Votoplam has demonstrated dose-dependent slowing of disease progression relative to natural history in Stage 2 participants, with an average slowing of over 50% at the 10-milligram dose level.
At 24 months, there remains no evidence of NfL spikes, with NfL levels below baseline. The safety profile continues to be favorable across both dose levels and disease stages. These clinical findings support that the effect on HTT lowering demonstrated in the placebo-controlled PIVOT-HD study is manifesting in early signs of clinical benefit that will be assessed in the now enrolling phase III INVEST-HD study. In terms of next steps, the Novartis and PTC teams will continue to review the data from the interim analysis and then will align on plans for potential regulatory interactions to discuss the results. Thank you, and I will now turn the call over to the operator for questions. Operator?
Thank you. Ladies and gentlemen, if you have a question or comment at this time, please press star one one on your telephone keypad. If your question has been answered or you wish to remove yourself from the queue, simply press star one one again. Again, to ask a question, please press star one one on your telephone keypad. Please stand by while we compile the Q&A roster. Our first question or comment comes from the line of Kristen Kluska from Cantor. Miss Kluska, your line is open.
Everybody, congrats on the strong data today. Two questions for me. Just thinking about the primary endpoint on the phase III, the language is up to month 36. Even if there isn't a potential for accelerated approval on these data set, is there a potential for this phase III to do either an interim analysis or wait until a certain number of patients potentially reach that 36-month endpoint?
Hi Kristen. Thanks for the question. I'll say that I wanna compliment our partners at Novartis, as well as the joint development committee. The protocol is very well thought out, very well designed. The results we shared today really support that design, which is obviously very encouraging. The study does have an interim analysis for efficacy, which you know, has the potential then to take an early look and potentially depending on what those data show, could accelerate a timeline for approval.
Okay, have you guided what that specific analysis is, or it's confidential at this stage?
Yeah, the details of that haven't been shared yet. As you can imagine, as you think about an interim analysis, it would clearly be at a point that would be allow for an early look, understanding that the primary efficacy analysis is up to 36 months.
Okay thanks. My second question is just understanding how you did this comparison. You know obviously, FDA has been pretty outspoken that they're supportive of natural history comparators, they need to be done in a thoughtful and appropriate manner. If you could just help us understand your confidence in why the natural history group that you used is indeed a good comparison and why it holds to the strong integrity the FDA is looking for. Thank you again.
Yeah, absolutely. It's a very good question. Clearly there's been a lot of discussions about natural history and natural history comparator groups. Look, first it started with the fact that in the long-term extension protocol, we had pre-specified that we would be leveraging the robust natural history registry, specifically Enroll-HD, to generate a natural history comparator group. That's one thing that FDA really likes you to do is specify that ahead of time and to as well as have an analysis plan that would pre-specify the matching criteria that would be used. That was done for this study.
I think in terms of registries, the Enroll-HD has a large number of records as we shared, and a very thoughtful approach was taken to ensure that we have a registry that includes all of the key inclusion criteria for the PIVOT-HD and open and long-term extension study, as well as ensure that we matched, or we generated a matching group that had similarities or in terms of the key factors that drive disease progression. As you can see from the slide we shared today, the cohorts are well-matched for those key variables, really with no meaningful differences between treatment cohorts and natural history cohort.
Thank you. Our next question or comment comes from the line of Ms. Ellie Merle from Barclays. Ms. Merle, your line is now open.
Hey guys. Thank you for taking the question. Just a couple for me. Maybe first, on NfL, I guess how do you interpret the data on NfL and why do you think it wasn't dose-dependent? Your perspective on how to interpret what was seen at year one versus year two for NfL. I have a follow-up question after that. Thank you.
Yeah Hi, Ellie. Look, NfL, the exact relationship between specific NfL levels and disease progression, I don't think is that well understood for HD. What's generally appreciated is that over time, NfL should be increasing. I think we referenced the recent study that was done, published in 2024 saying that that could be anywhere being around 13% a year increase. I think for us, what's most encouraging is that we see in both dose groups that there is a reduction relative to baseline, which supports that we are having an effect, particularly on potentially on neuronal biology and neuronal sparing. I think it's really supportive evidence that there could be an overall favorable treatment effect on disease pathology, despite not being dose-dependent. I think again, the key thing is that we're below baseline.
Got it. Just in terms of the next steps with the FDA, if you could give us any more granularity on when you plan to meet with the FDA, and I guess how we should think about the timelines for when on our side we could hear more about the potential filing strategy. Lastly, just a housekeeping question. I know for the phase III, you said early HD. Can you clarify if that includes both Stage 2 and Stage 3? Thanks.
Yeah, absolutely. Let me take the second question first. It's early symptomatic individuals with HD. It would be Stage 2 and also very early Stage 3. Those individuals would have to have a normal TFC score of 13, which I think is an important factor to consideration. As you could imagine, the decision for the enrollment criteria, the design of the study, all took into consideration the things that we were observing in PIVOT-HD. Looking at the data today, I think that's what's so encouraging to see that the data we're presenting support the plan, the design, and all the thinking that went into the design of that INVEST-HD study.
In terms of next steps, as I mentioned, and I think Vas mentioned on the Novartis earnings call this morning, the key next step now is for the teams to go through all the data, understand what data we have, and then align on what would be an appropriate next step, including potential regulatory interactions. I think right now we wanna go through these data. Of course, the team working on phase III is full speed ahead, on getting that trial going. Then we will, as partners, discuss what the appropriate next steps would be.
Great. Thanks so much.
Thank you. Our next question or comment comes from the line of Tazeen Ahmad from Bank of America. Mr. Ahmad, your line is open.
Hi, guys. This is Jeremiah on for Tazeen. Thanks for taking our question, congrats on the update. We were wondering if you could just help us contextualize the benefits associated with some of the changes on the cUHDRS subscales, maybe specifically as it relates to impacts on patients' quality of life. Just given since this therapy will be dosed chronically, just wondering what you guys' expectations are on, like, real-world adherence. Thanks.
Yeah. absolutely, Jeremiah. Look, I think the reason that the cUHDRS is really favored as an endpoint in Huntington's disease is because it assesses many different components of the disease, including motor function, cognitive function, and then ultimate functional decline of functional capacity. It, it really is able to capture a number of different relevant signs and symptoms of a disease, including those that would be particularly relevant to how individuals can feel or function in everyday life. Obviously, as you go deeper into each of these scales, there are different items that can capture different things. For example, the cognitive functions on the Symbol Digit Modalities Test can get into really elements of cognition that are particularly important to individuals with HD.
As you look at the TFC scale and start looking at things that relate very closely, to activities of daily living. All of those things should translate quite well into quality of life. In terms of your second question regarding, long-term adherence in the real world, look, I think one of the clear advantages of Votoplam is that it's a single, once a day, small molecule, that so far is demonstrating to be safe and quite well-tolerated. So the ease of administration, the ease of use, especially if we're able to continue to demonstrate, efficacy, I think it would be certainly something that should have a very high adherence given its tolerability, safety profile, and ease of use.
Appreciate that, color. Thanks again.
Thank you. Our next question or comment comes from the line of Judah Frommer from Morgan Stanley. Frommer, your line is open.
Yeah. Hi, thanks for taking the questions. A couple for us. You mentioned, Matt, on the kind of the slope of those lines widening or the difference between the lines in cUHDRS widening as you got to 24 months. Now, the error bars are, you know, wide, but it does look like part of that is that the Votoplam 10 mid line is flattening out. Is there anything to read into potential improved effect over time there?
Judah, it's a good question. I think we're all starting. You know, we're still in the process of learning what can happen over time. Clearly, it's encouraging. As you say, when we look at the difference in the slope from zero to 12 months and 12 to 24 months, we certainly see some, at the 10-milligram dose level, we certainly are seeing some flattening there. You could also say a similar thing is being observed on the TFC subscale. In fact, it could be that flattening on TFC that, you know, could be driving the flattening we're seeing on cUHDRS. I think the encouraging thing for us is that as we are, you know, taking, observing these individuals for more times, we're seeing continued benefit that seems to be increasing in magnitude.
I think we understood all along in complex neurodegenerative diseases that are heterogeneous, it takes a longer period of time to clearly understand treatment effect. I think that's why we're encouraged now looking at 24 months, we're seeing what we believe are stronger signals than we saw at 12 months, which is exactly what you want to see and, quite frankly, expect to see if you have a therapy that could ultimately provide disease modification.
Okay, great. Just on the crossover patients, those patients that crossover from placebo in the first 12-month period, are they included anywhere in these data or anything you can tell us kinda directionally about those patients as they reach 12 months?
Yeah, absolutely. The readout here that we're sharing is focused on those who have had 24 months of treatment, again, to help get us, give us an idea of is what we observed at 12 months in PIVOT-HD here in terms of HTT lowering. Are we starting to see greater signals or stronger signals over time of efficacy? I would say on first look at those crossover patients, it appears that a delay in getting the drug could have an impact, but the teams are still working through to understand those data 'cause they're also very small numbers.
Makes sense. Thanks.
Thank you. Our next question or comment comes from the line of Brian Cheng from JP Morgan. Mr. Cheng, your line is now open.
Hey, guys. Thanks for taking our question this afternoon. Can you walk us through how we should view the changes that you are seeing at the subscale level? 'Cause it seems that the symbol digit modality, the SDMT subscale, seems to be the one driving most of the impact that we're seeing on the cUHDRS score and also the dose response we're seeing here too. How should we view the response in the individual subscales and also the reliability of the SDMT subscale when it comes to the phase III and the Stage 3 trial? Thank you.
Brian, thank you for the question. Again, as I mentioned, HD is a heterogeneous disease. Individuals with HD may have different manifestations, they progress at different rates, may progress on different aspects of the disease at different times. One of the strengths of the cUHDRS is its ability to assay different aspects of disease progression and thus also simultaneously assay drug treatment effect on these different aspects of disease. I would think as we look at the cUHDRS subscales, what we're seeing at the 10-milligram dose level is contributions, you know, from several of them, which tells us that we are impacting for individuals what may be what is important aspects of the disease to them.
I would say we're not reading too much in depth to what one individual scale is saying here, particularly in these Stage 2 individuals, where I think getting an understanding that we're seeing contributions from different scales is really good. The fact that we're seeing it across several scales also supports that we're seeing a real treatment effect at the 10-milligram level.
Thank you, Matt.
Thank you. Our next question or comment comes from the line of Mr. Ben Burnett from Wells Fargo. Mr. Burnett, your line is now open.
Hey, thanks very much. I wanna just clarify and come back to one other point just around the regulatory path. I guess, understanding that you will align with Novartis about plans to sort of have interactions with the FDA. I guess, is accelerated approval still on the table with these data?
Yeah. Ben, I think as we've talked about and both companies have talked about, you know, there's a strong desire to get this drug to individuals with HD as quickly as possible. There's a clear appreciation of the unmet need. I think both companies believe that all options remain on the table. It's just that we want to look through the data, have a very thoughtful plan about when and how we would engage regulators in discussing the data. I think it's more a matter of it's not a matter of saying something's off the table or on the table. It's really a matter of saying, "Let's. We have data to go through. Let's be very thoughtful about how we want to approach things.
Let's leverage learnings from our own study, leverage learnings from other things going on in the environment. Then as we, you know, we're just analyzing the top line now. As we get deeper into the data, then I think we'll be able to, as partners, align on those best next steps, the best timing, and how those interactions could be most successful for getting the program forward.
I gotcha. Okay. That's very helpful. If I could just ask one follow-up, just about the efficacy you're seeing, and if you're seeing any correlation with any of your sort of natural history variables. Like, do you see any efficacy correlation with like, the number of CAG repeats or TFC at baseline or anything else?
Yeah, it's a good question. I'm not aware that that's really been looked into quite yet. I think the focus thus far was to ensure that we had those variables, and we were trying to get as close to apples and apples comparison as one could be. I think one of the things that was encouraging to us is that looking at the trajectory of the natural history in the first 12 months in placebo and the first 12 months that they are, you know, they're fairly close. They're directionally in the same way and numerically quite similar and consistent, which is a really good sign.
Again, as we looked at the variables, it was more about making sure that we had an apples to apples comparison and haven't really looked at any of the individual factors being a correlate or predictor of response.
Okay. Understood. Thanks so much.
Thank you. Our next question or comment comes from the line of Mr. Geoff Meacham from Citigroup. Mr. Meacham, your line is now open.
Hey, guys. Good afternoon. This is [uncertain] for Geoff. Two questions from us. Maybe first, could you remind us why you guys chose the TFC subscale as the enrollment criteria in phase III? You know, I totally understand that that is a good predictor of disease progress in cUHDRS, but it does seem like perhaps some of the other ones could portend perhaps efficacy as well. Then the second question is, do you guys have any emerging correlation data between the degree of HTT suppression and maybe magnitude of benefit on cUHDRS? Thanks.
[uncertain], thank you. Thanks for the questions. Let me start with the first one. I wouldn't say that TFC was the criteria. That wasn't the driving criteria of the enrollment for the trial. The idea was to go into early symptomatic individuals with HD that consists of Stage 2, those with Stage 2 disease and early Stage 3 with a TFC score that's normal. That was more of a way of having a cutoff of severity, again, to account for the population in whom we think we're likely to have the greatest chance of impacting disease progression. I think it was really learning from the data that we had. There were a number of important criteria.
The TFC score I mentioned, an independence score greater than 90, total motor scores between 7 and 25, CAP-100 of greater than 70. There were a number of criteria that were developed, and they were really well thought out, again, based on the team's understanding of the disease progression, what's understood based on natural history, and obviously what we've observed thus far in PIVOT-HD and the long-term extension. Again, I think that's why when we look at the data we shared today, we feel that they really support the design of the phase III trial because, again, we're seeing a lot of the thinking and assumptions that went to design that trial get, you know, verified in a way when we see the treatment effect we're observing thus far.
In terms of correlations between HTT lowering, I will say at a larger level, I mean, we're dealing with small, still relatively small, subject group numbers. I think it is encouraging to see that the treatment difference at 24 months on cUHDRS at 10 milligrams was 52% and at 28% as observed at the 5-milligram dose level. We're seeing that about half the dose level is getting us about half of the slowing of progression. Again, these are small numbers. I think for us, that dose dependency is an encouraging sign that the differences in HTT lowering could manifest in a differential impact on disease progression. We've not dug yet into doing any deeper associations.
Okay. Makes sense. Thanks, guys.
Thank you. Our next question or comment comes from the line of Brian Abrahams from RBC Capital Markets. Mr. Abrahams, your line is open.
Hi. Thanks so much for taking our questions. I guess, have you looked at caudate volume changes out to 24 months and any trends emerging there? Secondly, the Enroll-HD derived natural history, control parameters look. Just subtly different here versus, in the prior 24 months, interim cuts. Just wondering how the criteria for, I guess propensity matching may have changed between then and now. Thanks.
Yeah. On the first question, Brian in terms of the MRI data, the teams are still in the process of analyzing those, so we don't have those data yet. In terms of the natural history look, I think there's many different ways to approach how you do the specific natural history analyses. In this particular case, as we shared, there was a desire to ensure that we were matching on the key variables. There was then a new assay of the Enroll-HD database that yielded the comparator group that we used here.
Thanks so much.
Thank you. Our next question or comment comes from the line of Faisal Khurshid from Jefferies. Mr. Khurshid, your line is now open.
Hey, guys. Thanks for taking the question. wanted to ask, did you have a chance to look at the reduction HTT levels out to month 24? Was there any meaningful difference of what you saw at the earlier time points?
Here we're just looking at, Faisal, at the clinical data at the 24-month time point. As we reported in PIVOT-HD, the focus really there was in the primary endpoint was the reduction in blood HTT levels. We saw the dose dependence that hit the primary endpoint at 12 weeks. We saw that we were at the steady state at around nine months, and then at 12 months we saw that continued dose dependence. In here is basically looking at did those changes we observe in 12 months, are they starting to manifest over time in clinical benefit.
Got it. Thank you.
Thank you. Our next question or comment comes from the line of Mr. Joseph Thome from TD Cowen. Your line is now open.
Hey there. Good afternoon, and thank you for taking my questions. Just curious, how many sites were patients identified at for this study? Maybe how many sites are planned for the phase III? I guess related to the question, I guess, how much site-to-site variability is there in the assessment of some of these measures, if at all? Obviously, I know you're focused on MSH3 as well internally earlier in the pipeline. I guess mechanistically, how might that target be differentiated? Any thoughts on that versus the data you're presenting today? Thank you.
Yeah, absolutely Joe. You know, this PIVOT-HD was obviously a smaller study than INVEST-HD, with target enrollment of approximately 770 individuals in 30 different countries. I'll say that one thing, I think there'll be probably approximately 200 sites or so for phase III. You know, I'll say first I think the Novartis team has done an outstanding job in moving quickly to get this phase III study started from what was in discussion with the FDA in the fourth quarter on a study design to getting this study up, getting it running, getting enrolling.
It's been really incredible to see, and we're very grateful to have them as a partner, and this is exactly the type of muscle they bring to this necessary large and complex study that we think heightens its probability of success there. Again, the key will be to work with centers that are expert in these assessments that, you know, most of them will enroll and participate in Enroll-HD and contribute to the Natural History Registry. You can be sure that there will be great efforts to ensure the quality of assessors so that we have the greatest consistency as possible across sites.
In terms of your second question, the MSH3 program, we have shared that we have, we're moving towards drug development candidate in our internal MSH3 program. That's another aspect of that can impact disease progression. We've always thought that targeting MSH3 could be complementary with huntingtin lowering. It's really tackling two different aspects of the disease. One, the pathogenic, mutant, huntingtin protein, as we're doing with Votoplam, and the somatic expansion, which is another aspect of disease progression. We've also shared that we thought it's possible that the MSH3 molecule could also be particularly suited for juvenile HD, where there's more rapid somatic expansion.
We're excited to be able to apply our splicing capabilities to really attacking the disease in two different what we believe to be meaningful ways.
Great. Thank you very much.
Thank you. Our next question or comment comes from the line of Luke Herrmann from R.W. Baird. Mr. Herrmann, your line is open.
Hey, thanks for the question, team. Just following up on the flattening of the functional curves in the Stage 3 group at 10 mgs, can you just clarify the statistical modeling for dropouts and whether that 24-month time point was maybe just less affected by patients who were in steeper decline at the 12-month cut?
Yeah. I would say, Luke, that these are as observed data, so there's no modeling here. We've not had, you know there's been very few dropouts. There's been actually quite very high adherence and individuals sticking in the trial high compliance. This is really those who came in and observing them over time.
Great. Thanks. On the MRI data, is there any idea of when we should expect to see those?
Yeah, I can't guide to that. I know we're sharing the top-line data today. I, the plan will be to share a more full data set, obviously once analyses are completed at a academic meeting, a scientific meeting. You know, obviously, I think the Novartis team will determine when the right time and the appropriate meeting to share those data would be.
Okay, sounds good. Thank you.
Thank you. Our next question or comment comes from the line of Paul Choi from Goldman Sachs. Mr. Choi, your line is now open. Mr. Choi, you may need to unmute your phone.
Hi. Thank you for taking our questions. My first question is with regard to the phase III INVEST-HD trial design. Matt, can you clarify if the study is based on the natural history decline on the unified Huntington's disease rating scale? The reason I ask is since we don't have a multiyear placebo-controlled data, your slide 10 shows about a 0.6 decline at one year for the natural history cohort, but I think in your prior update you showed a smaller decline for your placebo-controlled arm at the time. Any clarity there would be helpful. My second question is, does the phase III initiation trigger any sort of milestones from a financial or modeling perspective? Thank you.
Thanks, Paul. Let me take the second question first. Yes, there's a $50 million milestone tied to the initiation of phase III. In terms of your question look, I think the trajectory of what we've seen when we look at 12 months with placebo relative to natural history are actually quite close. There's a very clear trajectory. I think that's one point. You know, there may be numerical differences, but I think importantly, they're both declining and appear to be relatively consistent in that regard.
In terms of the design of the phase III study, this was more not about tracking progression, but zooming out and understanding what we think would be the key variables and the key stage of disease where we think progression is occurring at a rate that we'd be best suited to capture treatment effect over the course of the trial. It's also influenced by what we've seen not only in the preparatory work going into PIVOT-HD, but what we have seen thus far in the data. Obviously, we're gonna continue to analyze the data from this interim analysis, and we'll continue to learn, and we'll continue to enhance our understanding of these different factors and in patient populations.
Okay. Thank you very much.
Thank you. I'm showing no additional questions in the queue. At this time, I would like to turn the conference back over to Dr. Klein for any closing remarks.
Thank you all again for joining the call today. We are, you know, clearly very excited about these data. I mean, the PIVOT-HD study showed us that we have a drug that's doing what it's supposed to do in terms of splicing and reducing toxic huntingtin protein levels. It's getting where it's supposed to get in the CNS with better CSF levels or higher CSF levels than plasma. We're now seeing that those changes in HTT or lowering of HTT is manifesting at 24 months with dose-dependent benefit on cUHDRS. Taken together, these data not only support the promise of Votoplam to be a meaningful therapy, but are also clearly supportive of the study that's the phase III study that's been designed and now initiated by Novartis.
We're looking forward to continuing to review the data and working with our partners on determining the next next steps, including any regulatory interactions. We thank you all again for joining the call this evening.
Ladies and gentlemen, thank you for participating in today's conference. This concludes the program. You may now disconnect. Everyone, have a wonderful day. Speakers stand by.