Thank you for standing by and welcome to the MOVE-FA top line results. At this time, all participants are in listen only mode. After the speaker's presentation, there will be a question and answer session. To ask a question during this session, you'll need to press star one one on your telephone. To remove yourself from the queue, simply press star one one again. As a reminder, today's program is being recorded. Now I'd like to introduce your host for today's program, Dr. Matthew Klein , Chief Executive Officer. Please go ahead, sir.
Thank you all for joining this afternoon's call. We had a number of updates today, and we wanted to take this time to discuss the top line results of the MOVE-FA study and the announced portfolio prioritization decisions. Before I begin, I refer you to our forward-looking statements on this slide, which are also posted on our website, as well as our risk factor section in our most recent Form 10-K. The MOVE-FA study was a 72-week placebo-controlled trial of vatiquinone for the treatment of Friedreich's ataxia patients. As we have previously discussed, the trial was designed to focus on pediatric patients, given the strong safety profile of vatiquinone established in children. The natural history data demonstrating that younger FA patients tend to have more rapid disease progression and the fact that there were no approved therapies or other therapies in development at the time for children with FA.
Accordingly, the primary analysis population included Friedreich's ataxia patients 7-21 years of age. In addition, we enrolled a small cohort of subjects over the age of 21. The study enrolled ambulatory patients only who had a baseline Modified Friedreich Ataxia Rating Scale, or mFARS score of 20-70. The study's primary endpoint was changed from baseline to week 72 in the total mFARS score. Other secondary and exploratory endpoints included the FA-ADL scale, one-minute walk test, the upright stability subscale of the mFARS, given its correlation with future loss of ambulation, and the modified fatigue scale, given that fatigue has been described as the most burdensome symptom of patients with FA. The mFARS is a composite scale used to assess neurological signs and symptoms of the disease.
The mFARS includes four domains that assess different aspects of disease, including bulbar function, upright stability, lower limb coordination, and upper limb coordination. The scale has been used to longitudinally assess disease progression over time. The FA community has established a robust longitudinal natural history database that includes a large volume of mFARS scores over time in both adult and pediatric patients. Based on this natural history database, mFARS scores worsened on average by two to three points per year in pediatric patients. The total enrollment in the primary analysis population of the study was 123 patients, and an additional 20 patients over the age of 21 were included in the overall analysis population.
I'll note that we over-enrolled the study due to both patient and physician interest, as well as the fact that the study was conducted during the COVID-19 pandemic and we anticipated potential pandemic impact on the study. The average age at enrollment in the primary analysis population was 14.6 years, and in the overall study population it was 18.7 years. Other key characteristics of the treatment and placebo groups were well balanced, including baseline mFARS and geographic origin. Looking at the results, let me first point out that higher scores on the total mFARS and subscales reflect higher disease severity and are therefore worse and lower scores are better. Unfortunately, the study did not reach statistical significance in the primary analysis population for the primary endpoint of total mFARS score change from baseline to week 72.
Strong vatiquinone treatment benefit was recorded in two key disease subscales bulbar function and upright stability in the primary analysis population with nominal P values of 0.044 and 0.021. Similar magnitudes of treatment benefit were recorded in the overall study population. On this fourth spot, we demonstrate that a consistent favorable vatiquinone treatment benefit was recorded across the mFARS and several other endpoints, confirming that vatiquinone impacts several different aspects of disease. There are significant nominal P values on several endpoints and a trend towards treatment benefit in the primary analysis population and overall study population on others.
I want to highlight the benefit recorded on the modified fatigue scale, given that fatigue is one of the most burdensome symptoms of Friedreich's ataxia and that the FDA external patient focused drug development day for FA patients, fatigue was identified as the number one symptom patients want a therapy to target. As I mentioned earlier, this study was enrolled and conducted in the midst of the COVID-19 pandemic. Given this reality and the 72 week duration of the study, we pre-specified a sensitivity analysis to include subjects who completed the study protocol on their assigned treatment without dose disruption. Indeed, there were a number of patients not included in the completers analysis who discontinued for COVID related issues, non-compliance, dose disruption or other reasons.
For the completers sensitivity analysis, there were 96 patients from the primary analysis population and 110 from the overall study population who met the pre-specified completer analysis criteria. The baseline characteristics of the completer analysis populations were similar to those in the primary analysis and overall enrolled populations that I showed earlier. The number of impacted patients from the vatiquinone and placebo groups were similar, so that the treatment and placebo cohorts were balanced for the completers analysis. Here are the results of the pre-specified completers analysis. When looking at the results of the mFARS score, we see that there is a 2.31 point placebo-corrected difference in the score over 72 weeks, which is on par with the changes recorded in the Reata MOXIe trial over 48 weeks.
This vatiquinone treatment effect translates to a 75% slowing of progression at 72 weeks. As in the primary analysis, we see nominal significant changes in the bulbar and upright stability subscales and the fatigue scale. In the completers from the overall population, we see a slightly smaller treatment effect on the overall mFARS score, which reached a nominal P value of less than 0.05 and consistent benefit across disease subscales and secondary and other endpoints. This graph demonstrates the changes in mean mFARS score over time in the placebo and vatiquinone treatment groups in the completers analysis. Given the understood natural history of disease in pediatric patients, the 2.31 placebo-corrected point difference at week 72 signifies about one year of slowing of disease progression after one and one-half years of treatment, which is clearly clinically meaningful.
We also see that the placebo and vatiquinone curves appear to be spreading further apart from 60 to 72 weeks, suggesting a potential disease-modifying effect. In terms of safety, the vatiquinone and placebo patients in MOVE-FA had similar adverse event profiles. The most common adverse events in the study were falls and COVID-19. The most common treatment-related adverse events for vatiquinone were GI symptoms, including nausea, diarrhea, and abdominal pain, the majority of which were low-grade. Overall, the favorable safety profile of vatiquinone in MOVE-FA was consistent with that seen in other pediatric studies of vatiquinone. Here we present an AE table which details the MOVE-FA safety data. As you can see, adverse event frequency for vatiquinone was generally similar to placebo, as were the study discontinuation numbers.
The one death in the placebo group was due to suicide, and the one death in the vatiquinone group was due to cardiac failure deemed to be disease-related. These results demonstrate evidence of meaningful benefit on key aspects of Friedreich's ataxia, particularly in pediatric patients for whom there remains a large unmet medical need. While the study did not achieve its primary endpoint, there are a number of important signs of benefit recorded on overall mFARS score, confirming slowing of progression by 2.31 points in the completers analysis. On the upright stability subscale, which has been established as a key predictor of future loss of ambulation. On the bulbar subscale, which captures highly morbid functional symptoms such as loss of speech and swallowing.
On the fatigue scale, which was identified in the external FDA patient-focused drug development day as the most burdensome disease symptom and the number one symptom patients want a drug to impact. Given the data demonstrating the vatiquinone treatment benefit, the well-established safety profile of vatiquinone in pediatric patients and the remaining unmet medical need for pediatric FA patients, given that SKYCLARYS is approved for patients aged 15 and older, we plan to share these study results with the FDA and EMA and discuss if there's a potential path to approval. In addition today, we also announced that as planned, we have made some strategic portfolio prioritization decisions, including the decision to discontinue our pre-clinical gene therapy programs and to suspend development for our IND and CTA stage gene therapy programs in Friedreich's ataxia and Angelman syndrome.
These decisions, along with associated reductions in headcount, will result in an estimated 15% reduction in residual 2023 OpEx. We will plan to provide updated 2023 annual OpEx guidance at the Q2 earnings release. As we build the PTC of the future, we will continue to review strategic priorities so that we can ensure we are focusing our resources on programs that leverage the many unique strengths of PTC in R&D and product commercialization and can deliver meaningful return on investment and value to all of our stakeholders. I will now turn the call over to the operator for Q&A. Operator?
Certainly. As a reminder, ladies and gentlemen, if you have a question at this time, please press star one one on your telephone. One moment for our first question. Our first question comes from the line of Robyn Karnauskas from Truist Securities. Your question please.
Hi, guys. Thanks for taking my question. I guess I have three. I appreciate the benefit that you have in the younger patients that we haven't seen before. I guess the question there is, you know, you talked about the completers analysis being pre-specified. You know, what kind of points can you make that the FDA said would give you confidence in this approval? The second question is really taking a step back and we've had many sort of confusing data sets or like not super clean data sets. Maybe give us some color around the departure of Emily Hill when I think, you know, she's very well respected at the company and investors use her a lot to sort of navigate these types of data sets.
When someone like that leaves, it sort of, you know, begs into question if something else is going on. Just like to get your point of view on that, on those two things, and I have a follow-up. Thanks.
Sure, Robyn. Thank you. Thank you for the question. The first question regarding the data. Look, you know, there obviously was COVID impact, and we anticipate those types of things in these studies, and there's been FDA guidance, which we obviously follow. You know, we acknowledge that we failed the primary endpoint in the study. We also acknowledge that there's many pieces of evidence on things that really matter in the disease, including the bulbar scale and upright stability subscales, both of which is regarded as really the key functional aspects in terms of clinical meaning in the overall mFARS. In particular, the upright stability being predictive of long-term loss of ventilation. We see signs of effects on the fatigue scale as well. That was true in both the non-completers and the completers analysis.
Look, we acknowledge we failed the primary endpoint. We also think there's many important signs of benefit, a strong safety profile of the drug and a very strong unmet medical need for kids with FA. We look forward to discussing with the agency what they think the potential path could be. We'll obviously follow up once we have those conversations with everyone, with the agency on that. Regarding your second point, look, this is rare disease drug development. Data sets are usually messy. It's incredibly unique to be in a situation as we were last week with PKU, where in a rare disease we have a primary endpoint, which is a blood test, and we can provide clear and unambiguous transformative treatment benefit for a still large unmet medical rare need.
Rare disease drug sets, drug data sets tend to look more like we have today, where when you're developing drugs for populations that don't have them, such as pediatric FA patients, there's always this task of sort of building the bicycle and riding at the same time. That's why we're incredibly pleased to be able to have the pieces of clinical benefit in this study, both because it's the first time a dedicated pediatric FA Phase 3 study has been done and second, because there was a COVID impact, and we still had evidence of benefit shining through. In terms of your question regarding the departure of Emily, first, as you did, I want to acknowledge the great work that Emily has done for PTC over the many years she's been with the company.
After taking over as CEO, one of my jobs is to look very carefully at the composition and the roles and responsibilities of the executive team and any decisions we make, such as this decision regarding Emily, is done to ensure that we have the executive team in the best position to build PTC forward for its future. We're incredibly excited of all of the valuable assets we have in our people and our programs, and also I'm incredibly confident in my leadership team who's here today and our many team members across the organization to effectively develop drugs for rare disorders and navigate the challenging regulatory landscape that we know exists globally for rare disorders.
Be able to understand and clearly communicate the valuable pieces of data we get from studies like MOVE-FA and others to ensure that we can do the best we can to as best as possible deliver these therapies to patients around the world who need them.
Great. That's, that's helpful. Then, you know, I guess I'm gonna ask the big picture question because I know investors are gonna go nitty-gritty on all the data. What is your thoughts, given that you are very well in, you know, knowledgeable about the mechanism of action here on the read to MDS, if there is any, for the data coming in June? That's my last thing.
Robyn, as we said, we previously shared that we expect to share data from the mitochondrial disease-associated seizures as well as the PIVOT-HD study in June. I think as we talked about before, we have these data sets, we felt it'd be probably very little read-through from one to the other. They're very different diseases. They're very the patients are quite different. It's very different disease state. I think what these data do show us is that by targeting 15-lipoxygenase, we are able to affect important symptoms, CNS symptoms of disease such as bulbar function, which relates to swallowing and speech, which obviously is important in mitochondrial disease-associated seizures, where we're relying on the drug to reach the brain and affect brain pathology and mitochondrial disease.
I would say we stick to what we said before, that we would see very little read-through from one study to the other. Obviously this study provides encouraging data about the ability to target in a meaningful pathway and provide benefit on important CNS pathology.
Okay, great. Thank you.
Thank you. One moment for our next question. Our next question comes from the line of Kristen Kluska from Cantor Fitzgerald. Your question please.
Hi, good afternoon. Thanks for taking my questions. When I look at slide 11, and this is also in your prepared remarks, it looks like the benefit from week 60 to 72 is perhaps where you're seeing the most robust trends. I'm curious if you can comment on the open label extension study enrollment to understand if you're looking at the effects between the two arms longer term beyond week 72. If that is the case, how much data could you potentially have to bring to the FDA and the EMA when you intend to meet?
Yeah, Kristin, that's a great question. Clearly, while we see in weeks 36, 48 out to 60, we're seeing separation in those curves and clearly differential treatment response. We're really seeing, obviously that greatest point difference over time. You know, obviously, we'll look to the open label data when they're available to understand to what extent we're seeing continuations of these trends. Obviously, that'll be an important piece of data to discuss with the regulatory authorities. I will point out also, one important point of this data set that's shown nicely on curve 11. You know, when we said when we enrolled this study, we were focusing on pediatric patients who tend to have a more rapid and uniform disease progression, and we're certainly seeing that over time.
They're losing a little more than three points over the 72-week duration of study, which is very much in line with natural history. I think what we're really getting a very good demonstration of is the drug effect in the context of a placebo group that is moving a lot like the natural history of the disease. To see less than one point worsening over the same 72 weeks in the treatment group, I think, is a very important piece of data that speaks to the potential for the drug to really modify disease progression.
Great. Thank you for that. Last question is just on that note. When you look at the different subscales in the primary endpoint analysis, like bulbar function and upper limb benefits, where you saw, you know, some clear benefits, I'm curious over time if that tends to happen with these patients. I know we don't have a lot of, like, treatment experience, but just even, like, from a natural history, like, if typically these patients would benefit on All At Once or is there really kind of like a natural progression that, you know, perhaps some of these endpoints become more clear with intervention over time or even just slowing down when you're not on any treatment? Thanks again.
Kristen, that's a great question. There was actually a paper published in Neurology in October 2022 by Christian Rummey, who's a well-established FA researcher, and others who very nicely looked at the robust Friedreich's ataxia natural history data to say, "Okay, which of these subscales are most relevant to the disease at which time?" It is good to know that in the patients in this trial, mostly those 7- to 21-year-olds, the subscale that seems to move the most in that period is the upright stability scale. That's part of the reason, and there's been a separate paper by Dr. Rummey that was published, I believe in 2020, that clearly correlates changes during these age groups in the upright stability over time with risk of loss of ambulation.
That's why this is now being that particular portion of the subscale is particularly relevant in these patients. It moves a lot in this period, and the rate at which it moves can predict risk of loss of ambulation, which of course is a common morbid point in disease for all FA, virtually all FA patients. Seeing the changes that we're seeing in upright stability in this population, it's the right subscale to look at. I'll also point out that bulbar seems to move throughout the course of the disease, so it's relevant in these age groups. Inversely, upper limb coordination tends to be something that's seen more later in disease, particularly in adult populations.
It's understood that on upper limb in younger patients, you might have just some improvement over time just because of their maturation and gain of strength and coordination that occurs from childhood into adolescence. It's a very important question in understanding the effects on all the different subscales. Again, I think that's what's encouraging to see that the one that's most relevant in this age group and the one that may be most predictive of future loss of ambulation is one we're seeing a very clear and strong treatment benefit.
Thank you.
Thank you. One moment for our next question. Our next question comes from the line of Eric Joseph from JPMorgan. Your question please.
Hi. Thanks for taking the questions. Matt, you mentioned, you know, how you wanna seek a meeting with the FDA about a potential NDA filing path forward. I guess if that doesn't materialize, I guess should we think about a potential follow-on Phase 3 program, given that it seems like, you know, MOVE-FA perhaps, you know, failed... It was a design that failed the drug, not so much vatiquinone not being clinically active. If that is the case, can... I guess could a Phase 3 study perhaps be run more efficiently or along a more efficient timeline? I have a follow-up.
Yeah. Thanks, Eric. It's a good question because I think, despite not hitting the primary endpoint, I think we clearly see an active drug here. You see that on the four spots with activity across a number of the different endpoints, and obviously on some of the key subscales we're seeing pretty meaningful effects. Look, I think the key right now is let's take one step at a time. We'll meet with the regulatory agencies, gain their viewpoints and obviously the content of that discussion, including their views towards the viability of a NDA submission at this point, will play into our decision-making process. I'd say right now we're gonna focus on the task at hand. Let's get the analyses completed.
Let's meet with the agency, see what those discussions are, and then, make a decision about future development pending those discussions.
Okay. Got it. And just with the pipeline prioritization, I guess it, you know, it makes sense as part of, you know, a portfolio and evaluation process now with you at the helm, Matt. We'll get updated OpEx guidance next quarter. I'm just wondering whether, you know, with respect to the revenue outlook, is there anything new, any changes there that might be driving some streamlining of the R&D spend? I guess, should we expect a reiteration of revenue guidance near term? Thank you.
Yeah. Let me say absolutely not. This is not based at all about any by any changes to revenue. As we discussed at Q1 earnings, we had a very strong, a record first quarter that positions us very well to meet our targeted guidance of $940 million to $1 billion. It's very important, and it's an important question. This had nothing to do with any changes in expectations of future prospects. In fact, it's really with the strength of our revenue base, the strength of the PKU data, the clear large market opportunity that we discussed, both the U.S. and ex-U.S. for PKU, that it's really became the important time to undertake this exercise. Look, we understand that we took an approach where we said, "Look, we're gonna invest heavily in R&D.
We're gonna take a lot of shots on goal. Once we had turned some cards over in clinical trials and had some results, it would be time to now focus in. Part of that focus exercise is saying we need to look to reduce OpEx and carefully focus our spending on R&D programs that deliver meaningful return on investment. Obviously, any time that you make a decision about your portfolio, it's always very difficult. We're incredibly proud of all of our programs. We're incredibly proud of what we've accomplished in gene therapy, particularly with Upstaza. I think you can look very clearly at our annual report to see the OpEx dedicated to our pre-clinical gene therapy programs over the past three years. I think it's on the order of $570 million, which is a lot of spending.
When we take a step back and we look at what we now understand to be the likely timelines for potential approval, the likely investment that's gonna require to get these programs there, and the uncertain commercial landscape that will occur many years later at those times, it became a decision that, for us, was one of deprioritizing these programs and focusing our efforts and focusing our resources on the many other highly valuable R&D programs and opportunities that we have. This is not anything coming from a position of reduced revenue or weakness. This is actually a decision made from a position of strength and how we can continue to strengthen our balance sheet to position us well to enjoy all the future successes we believe that are ahead of us.
Okay, great. Thanks. Appreciate the color. Thanks. Taking my questions now.
Thank you. One moment for our next question. Our next question comes from the line of Brian Abrahams from RBC. Your question please.
Hi. Thanks so much for taking my questions. Two for me. First off, on the on the secondary endpoints, it looks like you reported, you reported fatigue, as well as ADL. There were two other secondaries that were listed in the clinical trials listing 1one minute walk and falls. I was wondering if you could give us any sense of what you saw there and maybe just how many secondary endpoints you looked at overall in the study and what the trends looked like. Did most of them trend in the favorable direction or not? Then I had a follow-up. Thanks.
Yeah. Brian, thanks for the question. I think what we saw in the primary and all endpoints, secondary, and then exploratory as well, we saw a trend towards benefit, I think, across all of them, except for, I believe, falls, which was not much of a difference between active and placebo. We were seeing a trend towards particular benefit. A lot of those endpoints are highlighted in on the fourth spot on slide seven. Fatigue scale was an exploratory endpoint that gives a simple reason it hasn't really been used as an endpoint in FA trials, but obviously it's an incredibly meaningful endpoint to FA patients.
So we were, you know, actually very happy to see, one, that it worked very well in capturing treatment benefit in an FA trial, and also that we clearly recorded a magnitude of benefit for patients with an overall reduction in fatigue burden over the course of the trial, where there was clearly a worsening in the placebo group. If you look at publications from there's a recent publication a few years back from Lynch and Lynch that looked at fatigue scale over time. What we're seeing is that the placebo group behaved a lot like the natural history in terms of that worsening. Again, we're recording an important treatment benefit with regards to a symptom that really matters. That's a clear departure from natural history.
Got it. That's super helpful. Then just, as a follow-up, you know, it looks like you, the sensitivity analysis that was pre-specified for the completers, you showed that data on the, in the slide deck. Can you talk about just, I guess, how many overall pre-specified analyses you guys conducted? Are the P values that you're showing here, for the completers analysis, adjusted for multiplicity? I'll hop back in the queue. Thanks.
Yeah, absolutely. Let me answer the second question first. Given that we failed the primary analysis, we didn't do any adjustment for multiplicity there. That's why we're basically framing them as nominal P value. As typical, you have a number of different analyses. Obviously, we had the primary analysis population, we had the full analysis set, and we had a safety population, and then, again, had this sensitivity analysis as one of the type of protocol analyses we conducted.
This was the one that we really wanted, to ensure that we did, really based on FDA's guidance, regarding how you handle COVID impact on clinical trials, where they say that you should clearly in your analysis plan, have a pre-specified approach to how you would handle, the impact of the pandemic on a trial.
Makes sense. Thanks so much, Matt.
Thank you. One moment for our next question. Our next question comes from the line of Peyton Bohnsack from TD Cowen. Your question please.
Hi, guys. Sorry to hear about the results. I guess my question kind of is more on how the people that were part of the pre-specified analysis, if you could give us any more color on which patients actually dropped out, why they dropped out, and if there were any geographical differences between the study sites, in terms of just baseline or, you know, other characteristics? Thank you.
Yeah. Thanks for the question, Peyton. We didn't see much difference across study sites in terms of the impact. You know, just to give you an example of some of the dropouts we had. You know, we had patients who dropped out for travel concerns. Obviously, during the pandemic, traveling was an issue. We had a dropout for patient and family that didn't wanna have to wear a mask at a study site. We also had others that dropped out for other reasons, including fatigue or refusal to comply with study procedures. That was sort of the nature of the types of dropouts that we saw during the procedure. That was in the primary analysis population.
The overall population, which had more adults, we saw a few more instances where there was refusal to come to the study site because of concerns about travel and refusal to comply with study procedures. Those were the types of things that we saw in terms of the non-completers.
Great. Thank you.
Thank you. One moment for our next question. Our next question comes from the line of Kelly Shi from Jefferies. Your question please.
Hi, this is Shawn Tan on the call for Kelly. Thanks for taking our questions. Just wondering, in the prior conversations with the regulators, have you discussed the cases where the trial misses on primary endpoint, but shows treatment benefit? I also have a second question. In light of the planned OpEx re-reduction, is there a better clarity on the timing of breakeven? Thank you.
Thank you for the questions. On the first one, we have not, with regards to this trial, had any discussion with the agency on different scenarios. you know, I think historically the FDA has shared their view with us and others regarding the mFARS score. I think this came up a lot in the discussion around the path for SKYCLARYS to approval, as traditionally the FDA had concerns that as a composite score, the mFARS is a conglomerate of signs and symptoms, and it's somewhat sometimes difficult to interpret what specific changes in the overall score mean.
They've commented, previously that of the two of the four subscales, the two that they believe are most interpretable in terms of meaningful benefit are, upright stability because of what I discussed, its ability to capture things like gait and balance, and also the potential predictive value in terms of time to loss of ambulation, as well as bulbar, because it's measuring speech and swallowing, which, you know, I think are quite clearly measurements of clinical effect, over the course of the trial.
I would say that we've not had a discussion of our specific scenario, but rather have, based on our discussions and their general feedback, them wanting to understand more than the overall score, what's going on within those subscales, particularly the ones that may have more meaning with regard to direct benefit in how a patient feels or functions in everyday life. In terms of a view towards breakeven, you know, as we talked about on our CEO transition call back in March, you know, that's something that our teams are committed to looking at. Obviously, one of the first steps in that process that we talked about on that call was doing a portfolio review and starting to look at where we can focus our resources.
We said that we would undertake that exercise once we started turning over cards in those clinical trials, which we've done. The next step is to continue, obviously, to look at the overall OpEx impact of the decisions we made today, which we said we'll provide more detail on at the Q2 earnings. Also look to future revenues. Over the course of the next period of time, we can begin to clarify what a path towards breakeven could look like. We look forward to continuing to undertake the process that we started and said we'd start a couple of months ago and continue to provide you all updates as we move forward and have more clarity on the timing and what assumptions will underlie achieving that breakeven.
Okay. Thanks for the color.
Thank you. One moment for our next question. Our next question comes from the line of Brooke Schuster from William Blair. Your question please.
Hi. Thanks for taking my question. This is Brooke on for Sami Corwin. Our question was could you provide more details on how the compliance was determined or what the exact cutoff was?
Yes. The compliance typically in these studies are based on drug logs and drug dosing diaries and returned drug. For the completers analysis, we eliminated folks who were off drug for a period of time that would not have been that were not consistent with the definition of compliance in the study, which is 80% of drug taken over any interval of time. That would be if you didn't meet that, you wouldn't meet the study definition of compliance in the study. That's a fairly standard definition of compliance.
All right, thank you.
Thank you. One moment for our next question. Our next question comes from the line of Tazeen Ahmad from Bank of America. Your question, please.
Hi, good afternoon, and thank you for taking my questions. Can I ask one on the financials? When you talk about residual OpEx, how should we be thinking about that for the rest of the year as it relates to the discontinuation of some of these earlier stage programs for your R&D line items? How should we think about, you know, the trends in OpEx on a go-forward basis? I know you're not providing longer-term guidance year by year, but just trends-wise, should we be expecting to still see uptick in expenses because you do like to have several programs in the clinic at any given time? I just wanna get a better sense for that.
Yeah, Tazeen, thank you for the questions. On the first one, when we talk, you know, we've obviously started this exercise and made the decision to discontinue the preclinical gene therapy programs. Those in and of themselves bring about savings in terms of OpEx or OpEx reduction. Obviously, there's headcount reductions also associated with those programmatic decisions which we outlined in the slides as well as in the press release today and as well as in our Form 8-K today. We've estimated that that's gonna result in a lowering of approximately 15% of residual 2023 OpEx. We haven't closed out the second quarter in terms of what OpEx, what expenditures look like so far in the second quarter, then what that means in terms of residual OpEx over the year.
We're comfortable saying that it will be at least 15% reduction in the, our previous, reported OpEx. In terms of long-term OpEx, look, I think what you're seeing here is an obvious commitment, to look very carefully at how we deploy our resources. Look, I think we're in a great situation that we have so many programs with promise, across our research and development portfolio. I think what it's incumbent on us to do is to look carefully at how we deploy our resources and ensure that we're doing so in a way that we're funding programs that of course are innovative, of course are pioneering. That's what we do. There's many things that we can do and develop from a scientific standpoint, including things in splicing and bioenergy that others can't do.
Of course, we have to invest in that. I think we also have to be very careful in strategically deploying our capital so that we are putting ourselves on a path to one day break even as we just talked about. I, obviously we're not gonna give long-term OpEx guidance here, but I hope you're understanding from my words that this is something we're taking seriously. We undertook this exercise, as we said we would move away from sort of a broad shots on goal approach to a much more focused deployment of resources, again, on a number of different programs that have a high degree of promise and are things that PTC can uniquely do.
Okay. Thanks for that color. Just maybe one question regarding the FA program. It's very hard to do an apples to apples comparison to other people's products and programs, but is there anything from the way that FDA handled the Reata application that you think will be beneficial to you as you now have your data in front of you? Thanks.
Yeah. Tazeen, as you said, it's always, it's hard to know what goes on inside a company's ongoing discussions with the agency. I think obviously we can look to what's been put out and made public regarding the NDA and the comments in the NDA. I think we can gain an understanding that the agency, in the case of Reata, I think we all agree in a very good way, used the regulatory flexibility that's afforded to them to look for important, meaningful signs of clinical benefit in a clinical study to help get a therapy to patients who desperately need one.
It's in that context where we again are having a trial where we do see several pieces of meaningful impact on things that matter to patients with FA over a very long study in a relatively large population of patients, and again, in a population now in kids with Friedreich's ataxia, for whom there will be no approved therapy given the label for SKYCLARYS. It's in that sense, we believe that it's appropriate to have a discussion with the agency, as there is a large unmet medical need here, a drug that has a demonstrated strong safety profile and signs of meaningfulness on a study despite it not succeeding in hitting the primary endpoint.
Okay. Thanks, Matt.
Thank you. One moment for our next question. Our next question comes from the line of Danielle Brill from Raymond James. Your question, please.
Hey, guys. This is Alex on for Danielle. I just wanna circle back on the pipeline. Sorry if I missed this. Just curious what your current plan is to replace those assets. Is your thinking that these will primarily come from internal R&D, or are you at all considering external assets? For any of the internal projects that you mentioned, how far away are these from potential IND or IND-enabling studies? Thanks.
Thanks for the question, Alex. To be clear, this exercise was undertaken to say, "Look, we've got a lot going on in our R&D pipeline." We obviously have a number of ongoing trials in the clinic. We obviously are reading out data from some. We've got the PIVOT-HD study. We're gonna have interim 12-week data report coming up in June. That study is gonna go for a while. We have our CardinALS study, we have our SUNRISELMS study, as well as a number of non-disclosed preclinical programs that are at varying stages of preclinical development, including nearing IND ready stage. Those won't be touched. We're basically just continuing deprioritizing a number of preclinical programs in the gene therapy space, and that's resulting in, as you said, about a 15% reduction in residual OpEx.
We still have a robust R&D pipeline of products that we continue to advance forward in using from all of our different platforms, obviously excluding gene therapy, targeting rare disorders in a way that we think we can uniquely do. This is not about taking things away and replacing it. It's about saying, "Okay, let's focus. Let's say, where should we focus our resources on the not several R&D programs that we have that we believe to be highly important for patients and for which there'd be, you know, a reasonable probability of success as much as possible in rare disease drug development, and can provide a meaningful return on investment over the long term.
Great. Thanks so much for the color.
Thank you. One moment for our next question. Our next question comes from the line of Joseph Schwartz from SVBS. Your question please.
Hi, thanks very much. Given Reata Pharmaceuticals supported their NDA for SKYCLARYS with a delayed start analysis and the curves in MOVE-FA seem to be separating at the end of the randomized period, I was wondering if this is something that you may be able to do in the not so distant future. If you could give us an update on progress through the open label extension, if there is one. I was wondering if you've performed any subgroup analyses for patients under 16, given there's still nothing approved for FA patients in this age group. Thank you.
Good questions, Joe. Obviously, you know, one major difference between the two studies is we do have 25% longer, right, placebo-controlled data, which I think are really important and robust. Obviously, we will have the ability to look at a delayed start, given the fact that we'll cross over the patients who are on placebo onto active. That's happened already. We'll certainly look at those data to come in. Again, to contextualize longer term results, of course, we have the very robust FA-COMS database, which has a large volume of natural history, FA data. I think what we plan to do is meet with the agency with the data we have in-hand.
Obviously, it's gonna be some time before we have the open label data, just given that where we are today and the 24 weeks of open label, which are still gonna be ongoing and gain their feedback. Obviously we'll provide any data we can to support a potential regulatory path forward. With regards to the under 16, we did look at that group. We did see on the mFARS, the total mFARS score, a slightly larger magnitude of effect, I believe, was on the order of 2.38, favoring treatment. Not surprising on those younger patients, there was a greater decline in the placebo group.
I think one of the themes here is one that we talked about from the beginning, is that the younger the patients are, the more rapid their progression tends to be, over the course of the clinical trial. Obviously as we go younger over the course of the 72 weeks, we are not surprisingly seeing a more rapid progression of disease. Again, we're seeing a strong treatment effect as well on those patients, which is obviously very important.
Thanks very much. If I could just ask one follow-up on that point, with the 2.38 point change in the younger patients, how should we interpret that given it's kind of in the ballpark of what omaveloxolone showed. I think you expected the placebo group to decline much more on the order of 4.7 or so. You know, what does that 2.38 imply for the value proposition of vatiquinone now, relative to omaveloxolone?
Yeah. I think the way we have to think about this is you've got a progressive disease, right? We have a uniform progressive disease that over time there's worsening on this disease rating scale, that also comes along with it several morbid transition points of the disease, including loss of ambulation for some patients, worsening speech for some patients, debilitating cardiomyopathy and many other symptoms.
I think the way you really have to think about it is if you're seeing a disease that progresses, let's say, you know, 2.5-3 points a year, or over the course of 72 weeks you're seeing worsening of, you know, 3.5-4 points, and you can have a two, you know, 2.37 or almost 2.4 point improvement, you're really slowing the disease progression in the case of our completers analysis by 75%.
You're basically saying over the course of 72 weeks or almost a year and a half of study, you're providing patients, you're sparing them a year of progression. I think that's the way to think about it, less perhaps in terms of what's the number in one study mean to the number in the other, but really looking at in the context of a placebo-controlled study, you really have the luxury of saying, which is why we do placebo-controlled studies, what would happen if a similar group of patients didn't get the drug? What you're seeing is much greater, much more significant rate of decline in a unilaterally progressive disease that you're sparing with treatment.
I think that's where we really begin to understand the importance of that magnitude of effect, really in the time saved for these patients, the years you're saving them in progression.
Thanks for the call.
Thank you. One moment for our next question. As a reminder, if you have a question, please press star one one on your telephone. Our next question comes from the line of Colin Bristow from UBS. Your question please.
Hi, this is Yihan, also calling. Thanks for taking our question. Just a follow-up question on the pipeline. Given the exit of the early stage gene therapy program, so how should we think about the business development priorities as well as the areas of interest going forward? Also a follow-up one on the other PTC518 HD program. Could you please provide any updates on the U.S. clinical hold? Like what specifically like FDA saying, like what is required to lift it? Thank you so much.
Yeah. Regarding the first question. Look, as we've said, we have a very robust R&D portfolio, and we're incredibly excited to be able to focus on things such as our splicing platform, where, you know, we've talked a lot about pioneering there with Evrysdi and now having our 518 PIVOT-HD program and as well as we have pre-clinical programs there where, you know, again, we view our ability to do splicing and what we've built over 20 years to be unparalleled in the industry. We're incredibly proud and excited to be able to continue to devote our efforts to using splicing to develop important and innovative therapies for patients. Obviously, we have the success of the PKU trial, which is something we're obviously incredibly excited to move forward and get to patients around the world.
We have other pre-clinical metabolic programs that we're incredibly excited to bring forward for patients as well. Obviously, with vatiquinone as the first compound for our Bio-e platform, we've had many other compounds that have come forward and leveraged the learnings we've made over time. Again, we're in a really strong situation and we can't be able to continue to develop potentially differentiated therapies with unique mechanisms that can be incredibly meaningful and impactful to patients. I think again, we're in a situation where we have an abundance of valuable programs that we really look forward to thoughtfully resource and also continue to bring forward, again, through our prisms of return on investment. I think we're also in an opportunity to look at how we can leverage our programs that we have as sources of external BD.
I mean, we have mechanisms that could be incredibly valuable for developing blockbuster drugs that maybe PTC itself may not develop, but could be very valuable to others. We also have the opportunity to leverage BD to complement what the things we are doing and the strengths that we do have internally, whether those be in earlier stage programs or to complement our existing global commercial infrastructure, which has obviously demonstrated itself to execute quite well in regions all over the world, including those where others are more challenged to have commercial success. We're incredibly excited on all those fronts. In terms of HD, obviously we said we'll be giving an HD data update in June, and we'll look forward to providing an update on the program and data from that interim cut at that time.
Thank you.
Thank you. One moment for our next question. Our next question comes from the line of Roderick Ma from Goldman Sachs. Your question please.
This is Roderick for Paul. Thanks for taking all our questions. We have two questions. Based on the data you have and the, I guess maybe the benefit on the upright stability, do you expect maybe a multi-year natural history propensity match study will be needed just to further demonstrate vatiquinone's effectiveness as a whole and for potential registration? Sorry.
Yeah, Roderick, thanks for the question. It's unclear what we'll be at. Look, we've done that natural history comparator in the past in the Phase 2 study, which provided us the important data that we had a treatment effect over a longer period of time. I think one of the things we're seeing in MOVE-FA, which is important, is that the placebo group is moving already very much like the natural history of disease does, which I don't believe has been seen in the course of the placebo-controlled phase of an FA trial before. One of our thoughts going into this is that the kids would progress more rapidly and maybe behave much more like a natural history population than they did.
Obviously, we'd be more than happy to buttress these findings, these placebo-controlled findings with natural history data, whether it's to further contextualize the important impact we've observed over the course of this clinical trial. Again, I think we would see that we're seeing a benefit that's quite consistent, and would be equally meaningful for placebo and natural history, but also to potentially buttress some of the longer term open label studies, in order to contextualize those results once placebo is removed.
Yeah, thanks for that. Just one additional question. Are there any biomarker analysis to in the study? I don't know if you can provide any details.
Yes. We did not collect any blood-based biomarkers or any radiographic biomarkers. Obviously, there's always questions to what extent are some of these scales, biomarkers themselves versus direct measurements of clinical benefit. Are they predictors of future benefit? Are they intermediate endpoints? You know, those are all obviously subtleties in terms of how you look at these endpoints, but we did not specifically collect any blood-based or radiographic biomarkers.
Thank you.
Thank you. One moment for our next question. Our next question comes from the line of Jeffrey Hung from Morgan Stanley. Your question please.
Hi, this is Michael Riad on for Jeff Hung. Thank you for taking our question. Yeah, we know that vatiquinone is well tolerated, and you're seeing a clear benefit on FA at week 60 onwards. Have the results from MOVE-FA changed how you're thinking about MIGHTy, which is a 24-week study? Maybe does it increase the importance of the 40-week open label for contextualizing those results? Thanks so much.
Hey, Michael. It's a good question. I think as we've talked about a bit before, that they're really different indications. What we have in FA is we're targeting the disease itself, which we know progresses over time and typically progresses at two to three points a year. We also know that historically in FA trials, there's been a placebo effect that's quite prominent even out to 24 weeks in many cases. We've seen that. I think that you can see that also some residual placebo effect in the Reata mFARS trial. That really tells you that a longer period of time is needed, not only for the placebo effect to subside, but to better appreciate the impact on a disease-modifying therapy or a therapy that slows progression.
That's where having that longer observation window is really, really important when what you're trying to do in a study is demonstrate that you're impacting the progression of the disease. Looking over now to mitochondrial disease-associated seizures, what we're doing in that study is focusing on a specific symptom that isn't progressive. It doesn't tend to regress, but it's there, it's measurable, it's quantifiable. Typically pediatric seizure studies are such as we're doing with vatiquinone mitochondrial disease-associated seizures tend to be three months because of that reason. We went to six months, which again is twice as long than what is standard in these types of diseases.
We can ensure that we capture treatment effect in the event that there is some placebo effect and also to allow us to potentially capture impact on other aspects of disease. I think in terms of the nature of the study, we believe that the 48 weeks or almost one year for the parallel arm portion. I'm sorry, the 24 weeks in the parallel arm portion of the study is important and should allow us to ascertain an important drug effect. As you say, of course, the additional open label period will, as always is the case in these longer open label periods, allow us to appreciate the benefits of drug over a longer term, which could be again, also important to understanding the ultimate impact to patients with who have a chronic disease.
That's very helpful. Thanks so much.
Thank you. One moment for our next question. Our next question, our final question for today comes from the line of Gena Wang from Barclays. Your question please.
Thank you. I have three data questions. The first one is on slide five. When we look at the patient baseline characteristics, you share with the age at the onset, you know, less than 14, that was 93.5% for placebo. I think higher than the drug arm. That's 86.9%. What is the percentage of patient that at the enrollment that was less than 16 years old?
I'm sorry. You're asking who was. We're showing it 14 because that was the strata. You'd like to know.
That's the age at onset, right? That's different-
Yes, yes.
When you enroll at the age. This is the age at onset. you do have
Yes.
More patient at the younger onset for the placebo arm compared to the drug arm.
Yes.
Wanted to know the enrollment baseline age, what is the breakdown percentage that patient was younger than 16? I think 16 was mentioned earlier, you know, younger than 16.
Yes.
In the placebo arm compared to the vatiquinone arm.
Yeah. There were 79 patients total, Gena, who were enrolled in the study, who were in that age group of under 16 years old, which is the number we quoted. Those include 43 placebo and 36 active. We can do the math of basically, you know, 43 of the 62 placebos is roughly, I know 69%. If we look to 36 in the active group, again, we're in the realm of about, you know, there almost about 60% or so.
Okay, good. The second question is, if we look at the slide six, you did show the subgroup, I mean, sorry, not subgroup, the sub analysis, the bulbar and the upright stability, show better trend. Wanted to know what is the baseline also again between the placebo arm and the drug arm for these two measurements? Any major differences there or how close they were at the baseline?
Yeah. I don't have We'd have to get you the exact baseline numbers, but I can tell you that if we looked over the balance in the groups, those numbers tended to be quite similar. We can pull them up quickly for you and or actually can follow up with you and let you know. On the whole, they were quite similar for both bulbar and upright stability.
Okay. My last question is regarding the pre-specified sensitivity analysis. Can you share what methodology you were using?
This, the analysis was done with a mixed effects model, an MMRM.
Mm-hmm.
In terms of the variance, covariance matrix, I have to get those details from the stats, but it was from our stats group, but that's basically a mixed effects model. We obviously had data points for the vast majority of those patients.
Okay.
I'm not sure what specific detail you want on the model, but we are happy to get that for you.
Okay. No follow-up. Thanks.
Okay. Thank you, Gena.
This does conclude the question and answer session of today's program. I'd now like to hand the program back to Dr. Matthew Klein for any further remarks.
Okay. Well, thank you all again for joining the call today. Obviously, as I stated, we had a number of announcements today, both in terms of the MOVE-FA and the portfolio prioritization, which again, we believe positions us quite strongly for the future growth that we desire. We look forward to sharing with you all the updates as we move forward with our interactions with the FDA. Of course, we have, as we said, results to report in June from both our MIGHTy study and PIVOT-HD interim analysis, Phase 2 study in PTC518 and Huntington's disease . Thank you all again for joining the call, and have a great evening.