Good morning, and welcome to the Sarepta Therapeutics conference call to discuss the two-year results from the EMBARK study. As a reminder, today's program is being recorded. At this time, I'll turn the call over to Doug Ingram, President and Chief Executive Officer. Please go ahead.
Thank you, Shannon. Mary, next slide, if you will. Good morning, everyone, and thank you for joining us today. To remind you, we'll be making some forward-looking statements today. I would appreciate it if you would refer to our public filings for the various risks and uncertainties associated with making predictions about the future. Next slide, Mary. So thank you for joining us for an update on our two-year follow-up data for our pivotal trial for Elevidys known as EMBARK. As many of you know, we have all been looking forward to these important results for a host of reasons. First, in a smaller cohort of patients, we have previously observed a very strong and widening therapeutic benefit over years as treated patients are protected by shock-absorbing Elevidys dystrophin, while untreated natural history shows functional decline following irreversible muscle wasting.
If successful, EMBARK would confirm these positive results in a larger controlled study over two years. This would further add to the deep body of evidence compelling early intervention of a Elevidys in Duchenne children to protect muscle and arrest or slow decline. Second, these results provide, for the first time, a very interesting, well-controlled, and blinded trajectory analysis as blinded patients who have been on placebo for a year and then are treated can be compared under identical circumstances against blinded patients who were treated previously and only received placebo at crossover. And finally, EMBARK provides a larger set of muscle MRI data that allows us to look objectively at muscle health following treatment with a Elevidys versus non-treatment. Again, if successful, this would be a further compelling reason to treat as soon as possible to protect muscle from irreversible damage from non-treatment.
With that, let me turn the call over to Dr. Louise Rodino-Klapac, our Head of R&D and our Chief Scientific Officer. Louise.
Thank you, Doug. It's a pleasure to be here today to share our EMBARK part two results. Next slide, please. EMBARK is a double-blind placebo-controlled trial with a primary readout at one year. At the end of year one, the placebo patients crossed over and received Elevidys. Patients already treated received a sham infusion, and all patients received the per protocol increase in corticosteroids around the time of dosing. Participants, investigators, and the study team remain blinded for the second year. Today, we will be sharing the crossover results from participants who received Elevidys in part two, as well as the two-year results of the participants treated in part one compared to external control. As you will note, following the crossover, all participants have been treated. Thus, an external control is required for comparison.
However, as you will see, one can also compare the trajectory of patients newly dosed in part two versus those who have been stably on therapy for a year from part one. Next slide, please. Before looking to the external control, here are the NSAA results for all patients treated throughout the study. Dark purple shows the patients who received active treatment in the first part of the trial. The gold line is placebo in part one that becomes the light purple when they cross over and receive active treatment. Note the trajectory shifts and improves from gold to light purple after 9001 treatment in part two in patients that are one year older at the time of treatment.
It's important to remember that the mean age of these crossover patients at the time of treatment is approximately seven years old, an age that we know from natural history are extremely unlikely to be gaining function, and in fact, the large majority are losing functional ability. As said, both part one and crossover patients received a second period of increased steroid dosing at this time. It's also striking to note both the higher peak NSAA achieved by the treated patients in part one and then the retention of this gain out to two years in contrast to the expected decline. In the next slide, let's take a closer look at year two. Here we are seeing the raw NSAA changes from week 52 to week 104 for both the crossover patients and the participants treated during part one.
You will note that NSAA increases in crossover treated patients following an Elevidys dosing. As a reminder, both of these groups received steroids at week 52. So this change in trajectory, something we've seen consistently across all of our many studies, is exclusively a result of an Elevidys treatment and the production of protective 9001 dystrophin. This provides strong evidence that the functional gains we have observed in the crossover patients are not related to the increase in the steroid regimen since the part one patients do not have any measurable change in their NSAA score when they cross over. Next slide, please. Muscle MRI provides an objective approach to assessing underlying muscle pathology. Measuring the level of fatty infiltration and T2 signal are known to correlate strongly and predict future physical function. Lower levels of both fat fraction and T2 indicate healthier muscle.
In the absence of an external control, here we are showing the two-year data in two representative muscles versus the one-year placebo data. We see modest to no increase in fat fraction from baseline to two years, and levels at two years are well below what is seen at one year in the placebo patients. This is consistent across muscle groups. Even though you see the improvement in NSAA on the previous slide, you see the impact of treatment being delayed even one year. The damage in the muscle continues, and you never achieve the same level of fat fraction as patients treated a year earlier. This highlights the importance of treating as soon as possible to preserve muscle. Next slide, please. Here we are looking at T2, a marker of muscle inflammation. We see the same pattern of disease stability.
There is little to no increase in inflammation from baseline to two years and levels at two years well below what is seen at one year in the placebo patients. This is consistent across muscle groups. We are pleased with this treatment effect in a blinded study and reconfirmed with MRI imaging. Again, this highlights the importance of treating as soon as possible to preserve muscle. Next slide, please. Now we can look to the external control data. Next slide. In the absence of a placebo control for year two of EMBARK, a pre-specified external control statistical analysis plan was created in advance of the unblinding of these results. External control comparisons are limited to the NSAA, time to rise, and 10-meter walk/run by the availability of these measures and appropriate external control data sets.
These three measures, known to be clinically relevant and highly predictive of future disease progression, are called out as the three co-primary outcomes in this pre-specified analysis plan. The external control data set is made up of a high-quality contemporary natural history studies and placebo-arm patients from other Duchenne trials. All studies were prospectively selected and represent contemporary standards of care, including the use of chronic corticosteroid therapy. The same propensity-weighting approach as previously presented was employed to optimize the baseline matching of the external control cohort to EMBARK trial patients on the key prognostic parameters of subsequent disease progression. Next slide, please. As shown here, the propensity-weighting technique produced an extremely well-matched comparative group to the crossover patients treated in EMBARK. Next slide, please.
A forest plot of the results at one year following crossover showed consistent, highly statistically significant benefits for Elevidys in comparison to the well-matched external control across all three primary endpoints. Please note that time to rise and 10-meter walk/run results are provided as both times and velocity. For orientation, everything to the right of the red line favors treatment, while anything to the left of the red line, of which there are none, would have favored the untreated cohort. Now let's look at each of these endpoints individually. Next slide, please. First is NSAA. The purple line here represents the crossover treated patients. The gold line, the external control. A 2.34-point benefit over external control is seen with a p-value of less than 0.0001. Next slide, please.
Next, for time to rise from floor, a 2.7-second benefit is seen over external control in time to rise, with a p-value of less than 0.0001. Note here that an increase on the y-axis indicates increasing time and, as such, disease progression. Also, as you will recall from prior presentations and the literature, slowing time to rise and time to rise velocity are among the strongest predictors of earlier loss of ambulation. So this is a particularly important signal. Next slide, please. Finally, a 1.07-second benefit is seen in a 10-meter walk/run, also with a p-value of less than 0.0001. As before, an increase on the y-axis represents increasing time and worsening disease. Next slide, please. Now we're turning to year two expression and functional outcomes in part one treated patients. Next slide, please. Patients in the biopsy sub-study underwent biopsy at week 12 and week 64.
Here we see the results of patients treated in part one of the study who showed consistent and sustained expression at week 64. This is important context for when we look at the functional results. 9001 dystrophin is the biological basis for the long-term functional results you will see. Next slide, please. The patients treated in part one and the external control were well-matched across baseline characteristics. Next slide. Two years following treatment, highly statistically significant and clinically meaningful differences are seen across the three co-primary endpoints. Again, the timed function tests are shown as times and velocity. Next slide, please. At two years, the NSAA benefit for Elevidys treated patients was 2.88 points with a p-value of less than 0.0001. You will note that at year two, we are seeing a widening divergence from natural history. Next slide, please.
The benefit at two years and time to rise was 2.06 seconds and showed a widening divergence from the natural history group who are beginning to show the expected decline in function. Next slide, please. The benefit in 10-meter walk/run was 1.36 seconds, again showing clear divergence from a declining external control group. Next slide, please. Now turning to safety. Next slide. No new safety signals were identified. The frequency of AEs and SAEs was similar for crossover patients to that seen in year one for patients treated in the first year of the trial. For those patients treated in part one, the overwhelming majority of AEs and SAEs occurred in year one, and there were no treatment-emergent SAEs in year two. Next slide, please.
Unsurprisingly for their age, there were no cardiac abnormalities seen at baseline for the patients enrolled in EMBARK, and then there is no subsequent signal of decline or harm. Values remain in the normal range for both groups throughout the study. As a reminder, we would not expect to be able to detect an efficacy signal yet over two years in the DMD patient cohort, but look forward to detecting such a signal method in longer-term follow-ups of these patients and studies of older patients. Next slide, please. Now to summarize and remind you of our longer-term durability data from our 101 study. Next slide. At the World Muscle Society meeting this past October, we disclosed our five-year results from our first study with the Elevidys study 101.
We saw a sustained increase in NSAA score over five years with a statistically significant and clinically meaningful difference at year five compared with the EC cohort of 9.8 points. Taken all together and looking at the totality of evidence for Elevidys, we continue to see a consistent clinically meaningful response across all of our studies with increasing divergence from natural history over a time that is durable. Next slide, please. To summarize, treatment with the Elevidys corresponded with increases on the NSAA at one year in crossover patients while the study remained blinded. We saw statistically significant increases on NSAA, time to rise, and 10-meter walk/run when compared to a pre-specified well-matched external controls for crossover treated patients one year after treatment. Results in part one treated patients demonstrate sustained disease stabilization two years after treatment.
Across NSAA, time to rise and 10 meters were statistically significant two years post-dosing compared to a pre-specified propensity-weighted external control group. Expression is consistent with data from other Elevidys clinical trials and sustained week 12 to week 64 after treatment. MRI continues to show minimal progression in underlying muscle pathology and remains consistent with the functional benefits shown. Benefit-risk profile remains favorable. No new safety signals were identified. EMBARK part two results add meaningfully to the totality of evidence supporting treatment with the Elevidys and support the conclusion that Elevidys modifies the trajectory of Duchenne. Long-term follow-up of patients will continue, and we will work to publish and present data in scientific form. In closing, I'd like to thank the individuals and their families who participated in our studies, our investigators and site teams, and my Sarepta R&D colleagues for their tremendous contributions to this study. Next slide.
Thank you for your attention. I'll now pass the call back to Doug.
Thank you, Dr. Rodino-Klapac. Shannon, let's open the call 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. We ask that you please limit yourself to one question. Our first question comes from the line of Gina Wang with Barclays. Your line is now open.
Thank you. Congrats on the update. Okay, I will stick with one question. So with these data sets, how would you envision this impact the commercial uptake and also incorporation into the label?
Yeah, I'll take this one. First of all, this won't have an immediate impact on commercial uptake for the simple reason there is already an overwhelming amount of demand.
As you know, we provided guidance for the year, which is very robust. We're presuming that we're going to do over 160% growth in the Elevidys year over year. That cadence of that growth relates to broadly three things. It relates to the cadence at sites, which is a three- to really more like four-month process from start form to infusion. It relates to manufacturing, and it relates, of course, to the access and reimbursement cadence. So we feel very confident. I think this is really powerful additional evidence, and it should really be a significant additional call to action both for physicians and for patients, but we already have an enormous amount of demand, so I wouldn't see this as dramatically changing the uptake this year.
And then as it relates to the label, it's certainly something we can look at, but I'm not sure on the face of it. Louise, you correct me if you disagree. I don't see this as a compelling need. This is consistent with everything we've seen before, but compelling because it's two years. It's a larger data set. We have this really fascinating new trajectory analysis that we weren't capable of doing previous to a crossover like this and this really impressive MRI data that shows that even in a short period of time, we get a significant change in muscle health, which I would remind everyone is important because damage that's done to muscle and infiltration of fat and fibrotic tissue is not reversible. That is an irreversible damage. So the goal of getting treated and avoiding that is, of course, paramount.
Louise, tell me if I've missed anything on the labeling issues.
No, you've captured it. Thanks.
Thank you. Our next question comes from the line of Tazeen Ahmad with Bank of America. Your line is now open.
Hi, good morning. Thanks for taking my question. Doug, you've talked about your thoughts about the competitive landscape for gene therapy going forward with potential next-gen therapies from other companies. How do you think today's data presents itself vis-à-vis the barrier to entry for future gene therapies going forward? Thanks.
Thank you very much for that question. First things first, there are no next-generation therapies around today. That's a misuse of a marketing term from my perspective. Our goal, we really aren't looking over our shoulders at other people that are working on other therapies, although we wish them all well.
Our goal is to treat the patients in front of us today who are, but for therapeutic intervention, being damaged every single day, and while we have this enormous amount of data, I would remind everybody how much data we had even before today. We've dosed over 600 patients. We've dosed children as young as two years old. We've dosed young men in their mid-20s. We've dosed very light children, 26 pounds. We've dosed literally men that are almost 300 pounds. We've dosed a significant number of non-ambulatory patients, so we've got this enormous amount of wealth of data showing the safety and efficacy of this therapy and the importance of getting this therapy to families as fast as we can, subject to the cadence we talked about before, and this data simply adds to the weight of that compelling point.
It is confirmatory of a lot of stuff we've already seen, but confirmatory in a much larger data set. As an example, just to remind you of what Louise said, we've seen what happens to children who've been dosed with this therapy versus natural history over five years, and it's dramatic. This is a much larger data set. Now this is two years, but you're seeing the same thing over two years. We see the muscle MRI, which is powerful. We see the trajectory analysis, which is powerful. So I think that while there certainly should have always been a call to action for families, I think this is just continuing compelling evidence that the treatment with this therapy can be potentially profound for patients. But with that said, we're really focused on the work in front of us right now and serving the patients that we have today.
Hopefully, that answers your question.
Thank you. Doug, I just want to reiterate one point. Doug, you already said it, but just further on the data that the MRI shows where delaying treatment results in damage to the muscle that you can never restore, and so I do think it's a really important takeaway from this data set that people see that and waiting for therapies means that you'll end up getting damage that you'll never be able to recover.
Thank you. Our next question comes from the line of Brian Abrahams with RBC Capital Markets. Your line is now open.
Hey, good morning. Thanks for taking my question.
For patients receiving ELEVIDYS at the one-year time point in the crossover, I'm curious, how did the changes versus natural history on NSAA and the time tests compare for the younger portion of patients there versus the older portion of patients? I guess it would be six to, yeah, five to six versus seven to eight.
Shall we all turn this question over to Louise?
Yes, a couple of points there. So in general, we saw consistent results between patients treated in part two versus part one. It is an important point to consider that the patients treated in part two are now at an average age of seven. So this is at a point where they're expected to decline from natural history, and we didn't see that. We saw an improvement from baseline. We didn't do any sub-analysis because now patients are a year older.
It doesn't make sense to break things out as previous. So this is done as a group analysis for the part two crossover. But overall, throughout the trial from patients treated in part one as a whole versus part two, we see consistent results on the NSAA, all the time tests. So we're very pleased with the results. And as we've stated before, regardless of what age you are at, there is benefit from an Elevidys treatment in all of our trials. But to Ian's point as well, that treating early is important because patients are accumulating muscle damage over time.
Thank you. Our next question comes from the line of Andrew Tsai with Jefferies. Your line is now open.
Hey, thanks. Good morning. Thanks for taking my questions. Appreciate the update.
So just one quick question is, do you think your partner, Roche, can leverage this data set as part of their ongoing MAA filing in the EU, as well as for their other ex-US submissions? Thanks.
Yeah, thank you for the question, Andrew. Obviously, I'm going to leave it to Roche to comment on their filing strategy and the importance of data, but I would certainly editorialize that this is very helpful additional information. I think very powerful information, very consistent across all of the measures in both time frames, the part one and the part two here. So I think this is going to be very, very important information. How they use it in their regulatory filing is for Roche, but certainly it should be powerful not only for regulatory and filing, but also for the access and reimbursement issues that occur after approval around the world.
So very excited about the data and what it may mean for patients not only in the United States, but around the world.
Thank you. Our next question comes from the line of Eliana Merle with UBS. Your line is now open.
Hi, this is Jasmine on for Ellie. Thank you for taking your question and congratulations on the update. So two from us. First, turning to your longer-term strategy of $30 billion cumulative revenues you expect by 2030, can you walk us through the breakdown of what you think will come from ELEVIDYS U.S. sales, ex-U.S. royalties, and what you would expect from the pipeline? And then just to follow up on an earlier question, so has this data been submitted to European regulatory authorities as part of the ongoing review? Thank you.
Yeah, I'll leave the last question for Louise to discuss.
This data is obviously hot off the press as well as a number. So just let me be very clear. We've provided some broad stroke guidance over the course of this decade through 2030. We've talked about the potential for net product revenue and royalties. We've also talked about operating income, which could be as much as $16 billion over that period in free cash flow, which could be $13 or so billion over that time frame. We haven't broken down the net product revenue in more detail. Obviously, a significant percentage of it comes from Elevidys. In 2025, to remind you, we'll do about $3 billion in net product revenue, and more than two-thirds of that will come from Elevidys. So you can see that Elevidys plays an outsized role even in our revenue for 2025, and our PMOs are continuing to do quite well.
If you look over that period, 2025 through 2030, and those numbers, both net product revenue and royalties and operating income and cash, the one thing I will say in the broadest of strokes is the great majority of that financial performance comes from existing therapies, therapies that are approved today and that we've been doing, in my view, a very good job of executing on. So most of the performance over the rest of this decade will simply require us to continue to execute on our four approved therapies. We will have some modest participation of our Limb-girdle launches as well, but the bulk of that success will come from Elevidys, Amondys 45, Vyondys 53, and Exondys 51. Thank you for your question.
Thank you. Our next question comes from the line of Kostas Biliouris with BMO Capital Markets. Your line is now open.
Good morning, gents.
Congrats on the update. A quick question from us. Can you comment on the ambulatory status of patients in year two? And sorry if you clarified that before. We are wondering whether there was any patient during the entire two-year study who transitioned from ambulatory to non-ambulatory status. Thank you.
Louise.
All patients remained ambulatory in the study. Thank you.
Y ou see how much I identify you with this therapy. I called you Dr. Elevidys. Louise.
Thank you. Our next question comes from the line of Gil Blum with Needham. Your line is now open.
Good morning, and thank you guys for the update. So maybe a question for Louise. As it relates to the treatment kinetics, it looks like even after a year, you got roughly similar delta of benefit, maybe a little smaller than before.
At the end, at NSAA, it looks like pretty much both patient groups reached a similar level. I'd appreciate your comments there, especially as it relates to the differences in NMR. Thank you. Louise?
Sure. Yeah, certainly. So we're pleased. We see a similar response in both years. So regardless of what age the patients were treated at, we saw that particular response after treatment. Just a couple of things to remind you of is that we've seen significant responses in the time function tests in both part one and part two. In particular, here, we're anchoring to a crossover that is to an external control cohort because we don't have the placebo comparison like we did in part one. But if you look at both part one and part two, we saw similar effects.
We saw a significant improvement in the time function tests in both cohorts as well. The MRI data is particularly interesting because that shows what's happening on a cellular level, and you see that you're seeing an improvement following treatment, but the loss of that muscle that patients had early on, they'll never recover compared to that. So in general, we're seeing similar magnitudes of effect regardless of the treatments. We're pleased with the sustained NSAA that, as you referred to, in the part one treated patients, they sustained that benefit over time. And that's indicative of what we saw in part one in Study 101. So over five years, we also saw that sustained benefit. So we're pleased with the magnitude of effect in both part one and part two.
Thank you. Our next question comes from the line of Salveen Richter with Goldman Sachs. Your line is now open.
Thanks for taking our question. This is Tommy on for Salveen, and congratulations on these results. If we could just ask on manufacturing, maybe could you provide an update on where you stand for any comparability study for the suspension manufacturing process? Thank you.
Yeah, thank you for your question, Tommy. We are continuing to work on it. Our goal is to commence a bridging study this year with the goal if we show comparability to be able to launch suspension manufacturing starting in about 2027.
Thank you. Our next question comes from the line of Ritu Baral with TD Cowen. Your line is now open.
Good morning, guys. Thanks for taking the question. One question and one quick follow-up. Can you talk about the steroid dose given at week 52?
Was it equal between both patient groups, and how did it compare to the initial steroid dose given at study start? And just a quick follow-up. Doug, do you anticipate that today's data will be used in any payer discussions? Have any Medicaid plans asked for the two-year data in evaluation for continuing coverage or current coverage just to make things easier for patients?
Yeah, Ritu, thank you. I'll answer the second question first, but the first question, let's clear, is an absolutely important question, and I want to turn that over to Louise. Look, we use all of the data that's available to us that's good evidence to work with payers.
We've had very good discussions with payers, and you see that reflected in our performance over the last year and a half with ELEVIDYS, but we will take this data and certainly use this as part of the broader armamentarium of evidence that supports getting these kids on this therapy as rapidly and efficiently as possible. But with that, I will turn the call to Louise, who can talk a bit about the steroid protocols.
Sure. Both in part one and, importantly, to your question in part two, both patient groups, so both the longer-term treated and the newly treated patients, received the same dose of steroids. That same steroid pulse over the first several weeks was given to those patients.
So what we've seen in terms of the response, when you compare those two groups, if you're thinking back to that slide, that was all from a Elevidys because both treatment groups received the same level of steroids in the study.
Thank you. Our next question comes from the line of Joseph Schwartz with Leerink Partners. Your line is now open.
Hi all. This is Will on for Joe. Thanks for taking our question today. Congrats on the data. So one for us, in some of our payor checks, we've heard that longer-term data could be helpful in the physician's use of a ELEVIDYS. And so it seems like these results are something that the community could be very receptive to. Is this something that tracks with what you've been hearing from those in the field, and how do you think these data today could impact prescribing patterns? Thank you.
Look, I think that we've already had long-term data. We've had data out to five years, although it was a smaller cohort of five patients. I think physicians reasonably would love to have more and more information about the long-term impact of this therapy. And so I do think that while there is an enormous amount of data already supporting the safe and efficacious use of ELEVIDYS across a very broad patient population of Duchenne muscular dystrophy, this data is going to be extraordinarily important as well going forward. It's important not only because it's a larger data set, not only because we get to see it over two years, but there are things in this data that we have not yet been able to look at. For instance, the muscle MRI. We had a very, very small subset of some muscle MRI historically.
Now we have a much larger database of muscle MRI, which I want to say is unbelievably important to be able to see the impact on muscle health over this relatively short period of time, is compelling. And likewise, I think this trajectory analysis that Louise just talked about is really important. Given the way the studies and protocols worked, we didn't have this before now, this opportunity to essentially keep a group of patients blinded on therapy for a year so we get them stable on the therapy. And good news, they were all stable on the therapy over that year, and then give them an increase in steroids and give them a placebo versus take the naive group of patients, give them steroids, again, on a blinded basis, give them therapy and see the differences.
Of course, you see the significant difference between those two groups because of the installation of the shock-absorbing ELEVIDYS dystrophin. So I do think this is going to be very compelling for physicians. I think it's going to be compelling for payers, and I'm certain that it will be continuing to be compelling for patient groups that are looking to find ways to bring a better life to their children.
Thank you. Our next question comes from the line of Kristen Kluska with Cantor Fitzgerald. Your line is now open.
Hi, good morning, everybody.
Since the field has really moved to understand that markers, endpoints, excuse me, like NSAA are going to require a lot longer than a year's worth of data, now that you have two years' data from a good number of cohorts, are you seeing that the patients that perhaps didn't have as robust of an effect at year one are starting to catch up and benefit more through months 12- 24?
I'm going to turn this question over to Louise. I do want to be clear. I don't think that it is the case that in the original EMBARK, that the patients weren't having as robust an effect. I think the issue in part one of the EMBARK, the primary, was the following.
We saw that all of these kids on all of the key secondary endpoints, all of the more sensitive time tests showed a significant difference where kids on the therapy were benefiting and kids that didn't get treated were declining. The issue with NSAA in the first part was that given that the coarseness of that measure, which is a sort of coarse one, two, three measure, and giving the short period of time and giving the fact that the placebo arm wasn't that large, you couldn't see the decline that was occurring in those patients in a short period of time. The nice thing about going out now is you get two things. One, you've got two years to see the difference in those patients, and we would have predicted you'd see a significant difference, and of course, we did.
And then even as kids that crossed over, you got to take this natural history cohort where you could really not only properly match it to the active arm, but increase the size of that. I think we almost quintupled the size of the natural history cohort versus what you would have had in the normal placebo, which again should create more sensitivity even with a coarse measure like NSAA. But with that, Louise, do you have some insight into the questions that were posed?
Yeah. You hit most of the points that I would have hit. I'll just add and point back to the expression as well. I think that's an important point to consider in terms of the durability of the response.
This is the first time in a blinded way we've been able to look at the same patients at 12 and 64 weeks, and you saw that the expression was completely sustained. So patients are continuing to make 9001 dystrophin, benefiting their muscle, and then leading to the functional changes that we saw. And to Doug's point, it was shown by both NSAA and time function tests. We knew from the one-year data that time function tests were highly statistically significant, and then we continued to see this improvement in benefit. And really, the decline in the natural history cohort is what we would have expected over this period of time versus year one in NSAA, where it just wasn't enough time for that placebo to decline on NSAA. But the time function tests have been highly significant throughout the study. So we're pleased with these results.
Thank you.
Our next question comes from the line of Michael Ulz with Morgan Stanley. Your line is now open.
Hi, this is Rohit On for Mike. Thanks for taking our questions. Can you share if there were any surprises from this data? And then would you expect any read-throughs to the ENVISION study? Thanks.
Louise?
I can clearly say I was extremely pleased with this data. It's extremely clean, powerful, just giving you an honest impression of seeing the data. Extremely excited when we saw this data. It just adds to the value of evidence. This is a highly controlled, blinded study. The data is just exceptional. And so that's my honest opinion of this data.
Thank you. Our next question comes from the line of Sami Corwin with William Blair. Your line is now open.
Hi there. Congrats on the data, and thank you for taking my question.
Some of your earlier gene therapy competitors have communicated that they think that percent dystrophin positive fibers could be a better early surrogate marker of long-term benefit as opposed to micro-dystrophin expression as measured by Western blot. So I guess I just wanted to get your thoughts there and if it would be possible for you to retrospectively analyze percent dystrophin positive fibers in this study. Thank you.
Louise, go ahead.
Yeah. Yeah. I mean, Western blot is our primary expression outcome for the study. This is the top line. We've seen consistent results with PDPF with Western blot. So certainly, in the future, as we release the whole data set, we're going to provide an expanded analysis at the MDA. That data will be shared as well, but it's been consistent throughout our studies.
I will also note that at least historically, the FDA, starting in the neuro division for some years and then moving over to CBER, has really preferred Western blot, generally speaking, over intensity and PDPF, I think, because of the view that done properly, Western blot is more quantitative than PDPF and intensity. So we look at all of those issues. But if you're wondering why we've leaned towards Western blot, it's been guidance from the FDA for now, really going on about a decade that's kind of driven us in that direction.
Thank you. Our next question comes from the line of Anupam Rama with JP Morgan. Your line is now open.
Hi guys. This is Priyanka on for Anupam. Congrats on the updated data.
Considering the strength of the continuing data, especially the muscle MRI, if added to the label, could you walk us through the timelines to update the label and getting the message to the patients, physician community, especially via the publication or medical meeting strategy?
I would just say we haven't, Louise, you'll correct me if I'm wrong about this, we just got this data. We haven't reflected on the process for or even the value in attempting to get additional data like this in the label itself. It's something we can look at, but generally speaking, you should know that you are permitted to provide information, additional evidence, as long as it doesn't run contrary to your label. So we'd have to really think about whether there's value in that, something we have to reflect upon. Louise, am I misstating anything?
No.
The only thing I'll add is there is the intent to publish this data both at a scientific meeting as well as in a publication. So it will be in the public domain that can be used.
Thank you. Our next question comes from the line of Daniel Smith with H.C. Wainwright. Your line is now open.
Good morning. This is Dan On for Mitch. Thank you for taking our questions and congratulations on the data. So we now have one-year follow-up for cohort two. And at the same one-year follow-up mark for cohort one, the NSAA wasn't statistically significant and was only increased 0.65, which was much less than cohort two at 2.34. So what do you think is driving the considerable differences between cohort one and cohort two?
Separately, how might unique side effects to the AAV capsid immunologically have affected the integrity of the crossover cohort's functional finding? Thank you.
Louise?
Yeah. So to the question around the NSAA specifically, why we didn't reach that SIG at year one, but we did in year two, a couple of points. So we saw an improvement in both cohorts. The difference is that in the placebo cohort in part one, as we've talked about before, we didn't see a significant decline on NSAA. NSAA is a coarse measure. We talked about it one year. It's very difficult to see those changes, but they were reflected in the timed function test where we saw a significant decline. In part two, we are using an external control because there's no longer a placebo arm to use for comparison.
And then the external control group is then matched to the baseline of those treated patients at year two. In addition, using external control, the N is much larger in terms of, you can see on the slides several hundred patients. And so you get to see, you can see differences easier as well. So the answer is, in both cases, we saw significant results as reflected by the time test in the year one on NSAA. We didn't see it because the placebo arm didn't decline quite as much as expected, but we did see it with the crossover group in comparison to the external control.
Thank you. Our next question comes from the line of Gavin Clark-Gartner with Evercore ISI. Your line is now open.
Good morning. I'm just wondering what you saw on biomarkers such as creatine kinase. Thank you.
Louise?
We certainly are. We actually still have a ton of data to dig into. We certainly looked at creatine kinase and continue to see a sustained effect. We will give a more fulsome data update at MDA with more of the data from this trial, but we continue to see an effect on markers like CK as well.
Thank you. Our next question comes from the line of Uy Ear with Mizuho. Your line is now open.
Hey guys. Yeah. Congrats on the data. Just curious. Wondering if you also saw other benefits other than time function tests, such as the ability, better improvement in breathing or cardiovascular problems, whether you've seen any improvement in those functions. Thanks. Louise?
So the outcomes that we've shared today, the NSAA and then the time function tests, which are the 10-meter walk, run, and the rise from floor, these are where we have fulsome external control data sets that are well-controlled that we can use in comparison, so there are additional endpoints like the wearable devices and the 100-meter—one example that will be included in a full data release, but the ones that we shared today are part of our top line because we have the very extensive natural history data for comparison.
Thank you, and this concludes the Q&A session. I will now turn the call back over to Doug Ingram for closing remarks.
Thank you very much, Shannon. Thank you, Dr. Rodino-Klapac. Thanks, everyone, for your questions this morning. Obviously, reiterating what Louise said earlier, we are delighted with this data.
While it's confirmatory of all of the things we have had an enormous amount of conviction for, it's extremely satisfying to see the consistencies of these results across over two years with muscle MRI and the like, and I do think this is additional compelling evidence and a call to action for this therapy, which I think already existed, and this is just more profound, so we look forward to presenting this data in more depth at MDA later this year, and then we look forward to keeping you all updated as we execute our enormous number of important objectives and milestones across 2025. With that, I hope everyone has a wonderful day. Thank you.
This concludes today's conference call. Thank you for your participation. You may now disconnect.