Good morning, and welcome to the Wave Life Sciences interim data from FORWARD-53 clinical trial conference call. At this time, all participants are on listen-only mode. As a reminder, this call is being recorded and webcast. I'll now turn the call over to Kate Rouse, Vice President, Investor Relations and Corporate Affairs. Please go ahead.
Thank you, operator. This morning, we issued a press release announcing positive interim results from our FORWARD-53 clinical trial of WVE-N531 for the treatment of Duchenne muscular dystrophy. This press release and the presentation to accompany this call can be found in the investor relations section of our website, wavelifesciences.com. Before we begin, I would like to remind you that discussions during this conference call will include forward-looking statements. These statements are subject to a number of risks and uncertainties that could cause our actual results to differ materially from those described in these forward-looking statements.
The factors that could cause actual results to differ are discussed in the press release issued today and in our SEC filings, including our annual report on Form 10-K for the year ended December thirty-first, 2023. We undertake no obligation to update or revise any forward-looking statements for any reason. On the call today with prepared remarks are Dr. Paul Bolno, President and Chief Executive Officer, and Anne-Marie Li-Kwai-Cheung, Chief Development Officer. Dr. Chandra Varghese, Chief Technology Officer, and Dr. Erik Ingelsson, Chief Scientific Officer, will be available for questions following the call. I'd now like to turn the call over to Paul.
Good morning, and thank you for joining us today. A decade ago, we recognized an opportunity to apply our novel oligonucleotide platform to advance new therapeutic options for Duchenne muscular dystrophy. Over the years, our culture, our commitment to always follow the science, has been directly shaped by the resiliency of the DMD community. We brought our next generation PN chemistry to the clinic to improve on exon-skipping therapeutics, starting with our WVE-N531 program. Today, I'm proud to share a positive data update on N-531 with the DMD community and with all of you. DMD is a devastating disorder caused by mutations in the dystrophin gene and a lack of dystrophin protein. There are approximately 20,000 new cases worldwide annually, and up to 10% of these patients are amenable to Exon 53 skipping.
There is an urgent, unmet need for new options that safely and consistently restore dystrophin to levels exceeding 5% of normal. We hear frequently from caregivers about the burden of weekly IV dosing, and there is also a need for therapies that can distribute to heart and diaphragm and reach stem cells, which would further enhance functional benefit and ultimately extend survival. The clinical results we are sharing today demonstrate continued translation of our platform, including differentiated pharmacology enabled by our novel and proprietary chemistry. With our PRISM platform, we have unlocked multiple therapeutic modalities to precisely silence, edit, or splice RNA transcripts. Unlike editing and silencing approaches, which harness catalytic enzymes, our exon-skipping oligonucleotides leverage the complex spliceosome machinery. With exon-skipping, we aim to restore the reading frame of the dystrophin transcript to produce a truncated dystrophin protein.
It is known that many dystrophin isoforms exist in muscle tissue, especially among patients with Becker muscular dystrophy, who usually have a much more mild form of the disease. Within Becker, those that have levels of dystrophin of 5% or greater have later loss of ambulation and better functional outcomes, supporting this therapeutic threshold. Boys with exon forty-four amenable DMD further support this threshold, and they have baseline dystrophin of around 7% and a milder disease course. Today, we are seeing our exciting approach to DMD exon skipping translate in boys with data that includes highly consistent mean muscle content-adjusted dystrophin of 9%, evidence of improved muscle health, a PK profile that supports monthly dosing intervals, and importantly, best-in-class safety and tolerability. We have preclinical data supporting four additional exons: fifty-one, forty-four, fifty-two, and forty-five, that demonstrate potential for even greater dystrophin restoration.
In total, these exons would enable us to address up to 40% of the DMD population. Also, recent draft platform guidance issued from the FDA supports the concept of being able to develop multiple exons in parallel in an efficient manner, and we expect to engage regulators on a platform trial that incorporates multiple exons. I will now turn the call over to Anne-Marie to discuss our ongoing study and these exciting results further.
Thank you, Paul. Today, I will be discussing the interim results of our FORWARD-53 study, which support WVE-N531 as a potential best-in-class treatment for Exon 53 skipping-amenable DMD. After 24 weeks of every other week dosing with WVE-N531, we observed a mean 9% muscle content-adjusted dystrophin, or 5.5% unadjusted, which was quantified as two distinct dystrophin protein isoforms. Importantly, the amount of dystrophin expressed across participants was consistently high, with a majority of boys expressing at least 5% dystrophin with treatment. Our industry-leading muscle tissue concentrations and tissue half-life of approximately 2 months support moving to monthly dosing going forward. Once again, we have confirmed that WVE-N531 is accessing stem cells, as we observed improvements in multiple key markers of muscle health, all with markedly safe and well-tolerated profiles.
I'll now walk you through the data in more detail. FORWARD-53 is an ongoing, potentially registrational, open-label, phase 2 study of boys with DMD amenable to Exon 53 skipping. Key endpoints include safety and tolerability, pharmacokinetics and pharmacodynamics, including exon skipping and dystrophin expression, measured after 24 and 48 weeks of treatment. Functional measures are also being assessed at baseline after 24 and 48 weeks of treatment. Since the disease progresses somewhat slowly in this population, six months follow-up would be inadequate to demonstrate a slowing of disease progression. An interim analysis was planned after 24 weeks of treatment, including a pre-specified analysis of dystrophin protein in ambulatory patients. 11 boys were enrolled in the study, ranging from 5 to 11 years of age. All boys were on stable steroid regimens. There were 10 ambulatory and one non-ambulatory boy.
There were 5 different underlying mutations occurring in exon 45-52 regions. Safety and tolerability through 24 weeks of treatment were excellent. All treatment-related events were mild in intensity. There were no serious adverse events, no discontinuations, and no oligonucleotide class effects. This is an extraordinarily clean profile for an exon skipping therapy, which we believe will be important for patients and prescribers alike. Turning to the results, we observed muscle tissue concentrations of 41,000 nanograms per gram, consistent with our prior Part A clinical results, which followed 3 boys for 6 weeks. Tissue half-life of WVE-N531 is now estimated to be 61 days, supportive of moving to a monthly dosing interval. We observed high exon skipping with a mean of 57%, confirming we restored the reading frame for dystrophin. To achieve exon skipping, WVE-N531 needs to access the nuclei.
We confirmed WVE-N531 is present in myofiber nuclei, as shown with red staining on the left of slide 17. Once again, we detected WVE-N531 in myogenic stem cells in the majority of boys, as shown in the image on the right. In this image, PAX7 positive stem cells are brown and WVE-N531 is red. I'll pause briefly to remind you why we are so encouraged to see uptake in these myogenic stem cells, which are the progenitor cells that produce new myoblasts. In DMD, the absence of dystrophin in muscle stem cells impairs both cell division and myogenesis, by diminishing the self-renewal capacity of these important cells. These defects decrease the regenerative capacity of the muscle.
Restoring dystrophin in muscle stem cells is expected to enable their proper function, including their ability to undergo asymmetric division that is needed to both preserve the renewal capacity of the muscle and initiate productive repair of muscle fibers. We're not aware of any other clinical data for exon skippers or gene therapy that have been able to demonstrate myogenic stem cell uptake. We are delighted to report highly consistent dystrophin expression across all Exon 53 boys, with dystrophin levels reaching up to 14% of normal on a muscle content adjusted measurement. One biopsy was found to be of too low quality to be analyzed. There was one non-ambulatory patient excluded from this analysis per our pre-specified analysis plan. All reported levels are MHC-normalized. Mean absolute dystrophin levels were 9% in the muscle content adjusted measurement, and 5.5% without muscle content adjustment.
Our reported dystrophin was quantified from two isoforms, consistent with those observed in Becker muscular dystrophy patients who display milder disease. Importantly, dystrophin expression was also highly consistent, with 89% of ambulant boys having levels exceeding 5% of normal, which was very encouraging and differentiates N531 from other approved exon skipping therapeutics. Based on our preclinical data, we believe the dystrophin levels we are measuring in skeletal muscles may underpredict what N531 delivers in heart and diaphragm. In our double-knockout mouse studies using an N531 surrogate, we saw significantly greater dystrophin expression in heart and diaphragm than in skeletal muscle, coupled with improvements in cardiac and respiratory function and ultimately phenotypic outcomes. In non-human primates, we also detected more N531 in the heart and diaphragm than in skeletal muscles.
Over the course of this study, we observed clinically meaningful decreases of serum biomarkers indicative of muscle health, such as CK and AST. CK significantly decreased from close to 12,000 units per liter to just under 6,000 units per liter. Similarly, AST decreased from almost 300 units per liter to just under 200 units per liter. The reduction in CK was larger than what is typically seen with the introduction of steroids in DMD, and all of these boys were already on stable background steroids. The CK and AST decreases were also highly correlated. It is encouraging to see these changes related to muscle health emerging concomitant with substantial dystrophin expression. In addition to quantifying dystrophin expression, we also evaluated its localization in biopsy tissue. These representative images from one of the boys highlight dystrophin's proper localization in the sarcolemma membrane.
The fact that dystrophin is localized properly in these fibers supports that it is functional. On slide twenty-three, we compared the biopsies from a boy who participated in both our Part A study after six weeks of N531, shown on the left, and FORWARD-53 after twenty-four weeks of treatment, shown on the right. In both the H&E stained sections and those processed for N531 localization, we see evidence for myocyte regeneration by the increased number of internalized nuclei marked by black arrows, as well as improvement in overall muscle health. These results were particularly encouraging to us, as it is understood in the field that changes in muscle tissue like this occur with functional dystrophin. Looking ahead, the FORWARD-53 trial is ongoing, and we are planning to transition boys to a monthly dosing regimen.
We expect to deliver data from the final time point of the study after 48 weeks of treatment in the first quarter of 2025. These data will include additional safety, dystrophin quantification, as well as analysis of functional assessments through a year of treatment. We also plan to engage regulators and expect feedback on a path to accelerated approval in the first quarter of 2025. Before turning the call back to Paul, I would like to express my sincere gratitude to the boys participating in the study, their families, the clinicians involved, and the study site staff working to keep the study advancing.
Thank you, Anne-Marie. With highly consistent dystrophin, a convenient, infrequent dosing regimen, and a very clean safety profile, WVE-N531 is a potential best-in-class treatment option for boys with DMD. These data also de-risk our additional exon skipping programs, as well as our potential to address other muscle diseases. These data mark our second positive clinical update this year, following our HD data that showed significant and selective lowering of mutant Huntingtin protein, as well as a correlation with slowing of caudate atrophy, a first for the field in HD. Looking ahead, we are approaching several important milestones. First, we expect proof of mechanism data for our WVE-006 program in Alpha-1 antitrypsin deficiency in the fourth quarter of twenty twenty-four, which is the first RNA editing program in the clinic for any disease.
We are also working toward initiating our first clinical trial in the first quarter of 2025 for our GalNAc siRNA Inhibin E program, WVE-007, a potentially breakthrough approach for obesity that leverages siRNA to target Inhibin E. At our R&D day this fall, we will highlight the opportunity for WVE-007, how it is differentiated, and a feature of new preclinical weight loss data. We'll also discuss our rapidly advancing PRISM pipeline, including RNA editing programs. It is certainly a very exciting time for Wave.
We are translating our differentiated and robust pipeline in the clinic and have potential to bring multiple life-changing medicines to patients. Exon 53 and other exons represent over a $1 billion market opportunity, and expanding to other muscle diseases across modalities would expand that further. As we approach proof of mechanism data in RNA editing and move Inhibin E to the clinic, we are poised to unlock significant opportunities in AATD and obesity. We look forward to sharing more updates with you very soon. With that, I'll turn the call over to the operator for Q&A. Operator?
Thank you. We will now open up the call for Q&A. If you'd like to ask a question, please press star one one. If your question has been answered and you'd like to remove yourself from the queue, please press star one one again. Our first question comes from Joon Lee with Truist Securities. Your line is open.
Hey, congrats on the impressive data, and thanks for taking our questions. I have three quick questions. First, is the sixth month pretty much when you see plateauing of dystrophin expression, or are you still in the dynamic range, especially given the stem cell exposure? And question number two, appreciate that you have shown dystrophin induction in the diaphragm and the cardiac muscle in preclinical models, but any indirect evidence of that in the DMD boys? And three, Viltepso's 4.81% reported was normalized to myosin heavy chain in the western blot. Would that be comparable to your 9% or your 5.5%? Thank you.
Thank you, June. To start with your first question, we do believe that we have not plateaued, and I say that for a couple reasons. One, we see high levels of muscle concentration sustainably with a sixty-one-day half-life, so a lot of drug in the muscle, with continued increase from the six-week study in exon skipping, so up to 57%. So we're continuing to see the processing of dystrophin protein. Two, what's important, and it's tied to the question around stem cells, given the exposure we're getting into the regenerative cells and muscle, and as Anne-Marie showed, the improvement we're seeing in muscle fibers between six weeks and six months and continuing that, one of the other approaches that we believe is, as you get better muscle health, you're gonna expose those cells to exon skipping and therefore can create more dystrophin.
So we do believe that we're still within that dynamic range. And with the high consistency we see across boys, I think there's ample opportunity to continue to recruit and bring more cells, and therefore continue to drive dystrophin expression. I think what's also important to note is when we go back and look at the Becker phenotype, crossing 5% was a major threshold in changing outcomes. So we've already crossed that threshold, but we continue, again, to believe that we're in that dynamic range. In terms of looking at the boys, at this stage, we are looking and will be measuring, and the 48-week time point will be a good another assessment at respiratory function and other endpoints, where similar to ambulation, where one might be able to see changes at that time point.
We can't obviously biopsy the tissues there to be able to ascertain what's happening from dystrophin. But I think what does give us confidence on the preclinical data was across species, whether we looked at the double knockout mouse or whether we looked at exposure in the non-human primate, it was highly consistent that the exposure of drug concentrations, and including the production of dystrophin, demonstrated that those tissues were much more productive in dystrophin than skeletal muscle. So again, our 9% dystrophin expression is probably higher in those tissues. In terms of Viltepso, it's our belief that that was MHC non-adjusted, so that would be more equivalent to the 5.5 for comparison.
I think it is important that, as you saw, we present it, because I think it is important in DMD, that we should see patient-level data, because it is important to see that high degree of consistency, because obviously, that's what boys need, but when we went in and looked at muscle-adjusted, I think it's a good time to reflect on that. What we see in DMD, and this is not just Wave, but what the community sees, is fat and muscle all within the biopsy,
and so this normalization quotient is really about trying to identify the production of dystrophin in the appropriate compartments of the cell, meaning in the myofibers, and trying to assess how much dystrophin can be produced in those productive areas within the biopsy. So we're excited about the data we delivered to date. We think it's meaningful to the community and our discussions with members of the community as well as with the KOLs. These are exciting data.
Excellent. Thank you so much, and, congrats again on the exceptional data.
Thank you.
Thank you. Our next question comes from Salim Syed with Mizuho. Your line is open.
Great. Good morning, guys, and congrats on the data. I guess three for me as well, if I can. Anne-Marie or Paul, I know you mentioned the functional measures were taken at 24 weeks, so there really wasn't much detail on the slides, and I appreciate that you might need the 40-week data for that. But just curious, if you can maybe speak to perhaps some of the visual changes, anecdotally or early data that you've seen there on the functional side.
Number two, just on the regulatory, do you anticipate needing anything from the 48-week data set, either dystrophin or functional, to file for accelerated approval? And then just lastly, number three, just on the platform trial design, just early thoughts how that could potentially be constructed, just considering some of the exons, I believe, like exon 44 typically present with higher baseline dystrophin. Thank you.
Sure. Anne-Marie, go ahead.
Yeah. Thank you, very much, Salim. So, as you said, in six months, the progression that you would expect in this population is somewhat slow, so you wouldn't be able to detect that you're slowing anything on that basis. And that's true, actually, of all the functional measures, including, 95th percentile stride velocity, the digital measure, which is likely to be the most sensitive of all of them. I think what is really encouraging, actually, is the serum biomarkers. So this reduction, this clinically meaningful reduction that we're seeing in CK and AST, actually, I think, is one of the most encouraging things we're seeing with these data. The CK reduction is greater than what you see when you introduce steroids. And of course, all these boys are already on steroids, so this is over and above whatever benefit they're getting from their steroids.
So, you know, I think we can conclude from this, it's really encouraging, coupled with the dystrophin and what we're seeing in the tissue, and certainly the KOLs who have looked at our tissue have all said, "You know, this looks really healthy muscle." So encouraged. You asked about the 48-week data and the regulatory pathway. So, you know, we'll be engaging regulators on the pathway to the accelerated approval. We'll be finishing the study. You know, all of this is gonna become available in Q1 2025, and we'll be able to speak more to that then. But we're in the right zone with these encouraging data to be having meaningful conversations. And then finally, about the platform study, I think this is a really important point.
So FDA have recently issued draft guidance, signaling their understanding of when you have a platform therapy that can be applied as a platform, which is absolutely the case for DMD, where there are multiple exons, that they are proposing ways in which that development could be made much more efficient, so the sort of things that this would encompass would be clinical trials with shared placebo arm. That's obviously really important in this rare population, where the burden of placebo for patients is considerable,
and so that would make studies much quicker and less expensive to execute and will also benefit the patients from not having as many on placebo. You're absolutely right that exon forty-four is different from the other exons, and so for exon fifty-four, you would need to have exon fifty, forty-four placebo. But they could still be in the same platform. You could adjust for that. So this would be an extremely encouraging approach that would allow us to hasten all of the other exons that we have in scope with 53.
Yeah, I mean, I think it's to Anne-Marie's point, I think it's highly encouraging. As you said, we shared the biopsy data with the images that you saw and, you know, obviously, the clinicians who have been involved in the study. And I think while everything's anecdotal, I think the observations that we're hearing from families, patients, clinicians, that we do recognize they're anecdotal. I think it's important when we actually have hard data. And so it's encouraging, and that's exciting.
As Anne-Marie pointed out on the platform component with regulators, one does remember that in the past, we had engaged regulators around studies where we could use that augmented placebo design. And so we have really put a lot of thought into how to efficiently run a platform design study. And so we're excited to bring that forward as we approach the end of this study. But we will keep people updated in the first quarter.
All right, great. Thank you so much. Congrats again.
Thank you.
Thank you. Our next question comes from Eric Joseph with J.P. Morgan. Your line is open.
Hi, morning, and thanks for taking the questions, and congrats on the data. I guess, just following up on the point of, you know, dosing and being in the dynamic range of expression, is there any benefit, further benefit that you see to dystrophin expression from perhaps dosing higher? It seems from the data, the safety data, you've, you know, perhaps have the margins to explore that. Any plan to do so as you kind of move to monthly dosing? And then, secondly, just in with respect to the one patient, where you didn't get to that 5% threshold, anything notable there, perhaps a reaction to treatment that sort of might undermine the level of expression? Your expectation that might kind of get above the 5% threshold with continued treatment. Thank you.
Yeah. Thank you, Eric. So the dosing is definitely within the dynamic range of continuing to produce dystrophin production. And I think what's important to note is, we're seeing near saturation of muscle. I mean, some of the images you saw with those little red dots on the muscle staining, that's oligonucleotide. So we've got a tremendous amount of drug in the muscle with a 61-day half-life. So I think as we think about how the splicing and spliceosomes works, is we're producing protein, and it will continue to be produced so long as there's oligonucleotide in the muscle.
And so at this point, we feel very confident that this isn't about dose exploration higher, which is why we believe that going to monthly, even with half-life that extends through that, not only we will not lose efficacy, but we continue to preserve in that dynamic range of production of dystrophin. I think the safety profile, you know, continues to be important to us as well. And so I think the idea still of high quantity of dystrophin, so achieving Becker-like dystrophin levels, consistency across patients and across tissues, and potential for higher expression in diaphragm and heart. Monthly dosing, which we know is a necessity for families and boys. We recognize the burden of having to go in for a weekly IV infusion.
The ability to really change families by going in once a month, and couple that with a safe profile where there's not a sacrifice or decision to be made by taking safety for that less frequent administration or dystrophin expression, were always the key components of this program. You know, we're very happy to deliver for the community on that profile. In terms of that one patient, it's always difficult when you take a biopsy to try to see what's happened.
You get a window in time. We're encouraged that the last patient is in the range and very well could have in other samples, higher dystrophin. I think we see that consistently across the range. You know, we'll look at 48 weeks when we'll have other opportunities to evaluate biopsy specimens. But I think if we look at the 9% dystrophin and seeing 89% of the patients above 5%, I think we're highly encouraged.
Can I answer that?
Yeah.
Yeah. So, the non-ambulatory patient had similar concentration and skipping, but I think the most important thing is, the KOL responsible felt, you know, given the benefit, potential benefits in heart and diaphragm, they would absolutely want to keep this patient on the treatment because of the benefits that they could have, later.
And I think that piece, you know, echoes the sentiment that this exposure to heart and diaphragm shouldn't be underappreciated. I mean, we do have to remember that a lot of the discussion in DMD, for very good reasons, is around preservation of ambulation. So we're committed, like others, to make sure that's important. But when we think about two opportunities, given the profile that we shared today, and as Anne-Marie alluded to, the first being that exposure to heart and diaphragm, that's ultimately the driver of mortality in this disease, cardiac, respiratory failure. So the ability to get access to those tissues in a non-ambulatory setting, in addition to in ambulatory boys, is very important.
I think on the other end of the age spectrum, the ability to get access muscle stem cells, if we think about now, the progress that the community has really made in newborn screening and identifying the disease early, so patients don't have to go on multiyear journeys for diagnosis, that opens up an opportunity for treatment much earlier in the disease setting, where you could get the muscle stem cells, the regenerative cells, the muscle, and therefore, potentially delay the progress of losing ambulation or starting to develop disease. I think our opportunity to really reflect on the various stages of the DMD journey. I think we can play an important role there.
Thanks. Maybe a follow-up, if I could. Just as you look to interact with regulators, how much, if any, additional clinical work would be needed to support an initial registration using once-monthly dosing? Or is that a plan? Would you look to register with a once-monthly regimen, or perhaps with the data that you have in hand first and backfill for a longer dosing interval? Thank you.
So we're switching our patients in the FORWARD-53 study to monthly dosing. So at the end of the study, it will include data on monthly dosing.
I see. Thanks. Thanks for clarifying. Appreciate it.
Thank you.
Thank you. Our next question comes from Timur Ivanikov with Raymond James. Your line is open.
Yes, hi, this is Timur Ivanikov on for Steve Seedhouse. So just a couple of questions about your analysis, Western blot analysis. Was it something that you did in-house, or did you have to send it to a third party to analyze? And how do you think this assay compares to NS Pharma's analysis for viltolarsen? Thank you.
Yeah, so we use an outside CRO standardized to run the standard Western blot using the antibodies that have been used with viltolarsen.
Okay, got it. And then can you talk about any correlation that you may have seen for week twenty-four dystrophin expression with respect to the type of exon deletion or baseline dystrophin expression, especially for ambulatory patients who had a lower expression at week twenty-four? Did they have a different type of exon deletion or perhaps lower baseline dystrophin?
There weren't any patterns that would lead us to believe any particular expression responds better or worse. I think, you know, the response was pretty consistent with the majority of patients meeting the 5% or greater threshold.
We do think that's important as we think about being able to treat Exon 53 amenable boys, not to have to. As you saw in the enrollment, we did have a range of deletions. Seeing consistent dystrophin on top of no changes in output tells us that, you know, all deletions should respond similarly.
Okay. And then the final question we have is, so what type of functional measurements are you expecting to report at week 48? And then could you remind us about the primary endpoint, approvable endpoint for full approval, that you will report? Thank you.
It's the usual functional measurements, things like NSAA, four-step climb, time to rise, pull, et cetera. This information is in our clinicaltrials.gov disclosure, if you want to look in more detail. For full approval, so what you're talking about is a confirmatory study. Other sponsors have used things like six-minute walk, NSAA, et cetera. And of course, these are things we'll be discussing with FDA when we engage them to talk about the pathway to accelerated approval.
I think just to echo that, I mean, one of the other things that Anne-Marie's mentioned before is we're also looking at 95% stride velocity. So as we think about that, not just for the U.S. approval, we do know that in Europe, the regulators there are more inclined to look at functional outputs, clinical outputs like stride velocity, even over dystrophin production. So I think the fact that we'll be generating these data will be important as we do think about treatment opportunities for boys, not just in the U.S., but outside the U.S.
I think the challenge to date in DMD has been a lot of therapies moving forward with the FDA for accelerated registration, and then boys outside the U.S. not having access to therapies. As we think about the community globally, our view would make sure that we continue to build a data set that could support this program and others being available to boys in the U.S. and outside the U.S.
Okay, thank you very much.
Thank you. Our next question comes from Lisa Walter with RBC. Your line is open.
Oh, great. Thanks so much for taking our questions. This is Lisa on for Luca. Maybe just another one on the regulatory path. You know, given the FDA has increased scrutiny over the accelerated approval pathway in recent years, is it fair to assume that accelerated approval would not be granted until a phase III study is well underway and perhaps close to full enrollment? And just another on the confirmatory phase III. Just wondering how you might be thinking about the trial design here. Would this include a placebo control, or would you have to do a head-to-head study versus Vyondys 53? So any color here would be helpful. Thanks so much.
I mean, I'll take the first one, and then Anne-Marie can take the second. You know, as it relates to the registration pathway, and having been at meetings with both Peter Marks and Paul, time talking about DMD to the community, I think it's very clear that there's a commitment from the agency to make sure that patients have access to therapies quickly. So, from our standpoint, there has been no change publicly or in assumptions that the pathway has changed for accelerated registration. I think affirming for us in that approach was we were granted by the FDA both pediatric designation, which, you know, now we know Congress has reauthorized it, but also we received orphan drug designation.
So across the recognition that there's unmet need here and the FDA is wanting to work with companies to expedite the development of meaningful therapies in DMD, and I think these data today on high protein expression, consistent protein expression, distribution, Anne-Marie pointed out, functional changes like we're seeing in CK, so response, monthly dosing. These are important for the community, and we know the community is excited to work with us to advance these. So I think very much the path that existed before is very much the path that exists today.
Thanks, Paul. In terms of the trial design for the confirmatory study, FDA typically wants a placebo-controlled study or confirmatory study rather than a head-to-head with an active comparator. And as Paul mentioned, we already have success in negotiating ways to augment placebo and reduce placebo. And so, you know, whichever way things, progress with the FDA, we've got, plans on how we can make this as efficient and, short as possible to get to confirmation.
One has, and one has to remember that there are no fully approved drugs to treat Exon 53. So if we think about the current pathway, there are two commercial products Vyondys that has 1% dystrophin, Viltepso, which has, if we think about moving out the outliers, low dystrophin expression. So as we move into the space, you know, one, we want to deliver against high dystrophin, consistent dystrophin, and a profile, and then, as Anne-Marie said, be able to continue to take that program forward.
I think, again, when we think about the placebo design, that was one of the plans that we had had prior arrangements and agreement with, with the FDA when we had built the confirmatory trial design before, that used that augmented placebo group. The one aspect that we continue to really think creatively about is for rare diseases, how do you run platform studies where you could look at different exons, deliver on a confirmatory trial result, but reduce the number of placebo patients that need to be on the study so you can efficiently run the study, but deliver the data that would be required for potential full approval? So we're excited to have those conversations.
Great. Thanks so much for taking our question.
Our next question comes from Joseph Schwartz with Leerink Partners. Your line is open.
Good morning, guys. This is Jenny on for Joe. Thanks for taking our question. Just one clarifying question. Could you comment on the baseline dystrophin expression for these patients? And then our second question is that dystrophin expression was kind of similar as what was seen with the Viltepso, is probably where we're gonna get the most pushback since they weren't able to show a functional benefit. Can you just clearly walk us through what aspects of WVE-N531 and the data you generated here that hasn't been seen with other skippers, and why you think this data could suggest that there will be a functional benefit? Thank you.
Yeah, I mean, baseline levels in Exon 53 are very low. That's what makes it unique from exon 44. So very, very little, like less than 0.5% dystrophin. So these patients are really building up from nothing. In terms of the Exon 53 space, as we said, there's the 1% with Golodirsen, which is the actual leader in the market for 53. I think that is succeeding despite the 5% dystrophin from Viltepso, and as you pointed out, a 5.8% that we've seen with Viltepso at least posted. That's driven off of outliers, and this really gets to consistency and to your question on confirmatory study translation, and that's really what we're focused on is how is dystrophin? Because everybody's talking about a numerical number for a mean dystrophin, but how does that ultimately translate to patient benefit?
That is why, when we had as part of our criteria what success in this study would look like, it wasn't just achievement of a mean number. It's why we wanted to show everyone the patient-level data. Because the patient-level data, ultimately, what we believe is gonna drive output and functional improvement in running a subsequent study. Actually, if you remove the outliers from that study, the actual mean dystrophin number drops substantially into the 3% range. It's important for us to be thinking about highly consistent, high expression dystrophin. Yes, we achieved similar unadjusted. As we know, it's important, and that is why the shift to muscle adjustment is coming.
Some of our peers are now only reporting muscle adjustment because the realization is if you take a sample and have fat in that same sample, you're negating what's actually happening in this tissue that you need to distribute to, the myofiber. So when we can say 9%, there's a better way now beyond MHC to normalize across studies to be able to actually look at exposure of dystrophin in the requisite cell type that could actually drive benefit. And so that's why the 9% number is important.
But yes, so the 5% seeing and we saw 5.5% consistently in the unadjusted, but 9% is really the best way to look at it in terms of the myofibers, where we're going to see a potential benefit. So we believe that across the field, we're getting much better consistency, higher dystrophin than the current market leader within the Exon 53 space, Golodirsen, monthly dosing over weekly dosing, and a safety profile that's exquisitely clean.
Thank you. Our next question comes from.
Hi, good morning, guys, and congrats on the really great data. Thanks for taking our questions. So a couple from us. Looking at the serum CK chart, so it looks like you have this more than 50% reduction in almost kind of binary distribution, where the slope is not yet plateauing. So wondering if you're thinking that is going to go lower with subsequent readings, and how does this inform what one could expect on your functionality endpoints, especially also giving the high exposure and localization within the myocyte on nuclei? And then secondly, I just wondering what additional color we may could expect, I believe, at your late breaker at World Muscle Society in October. Thanks.
I'll start with the CK and then hand it over. I think, you know, the, the benefit of the CK, as you pointed out, the slope's continuing to decrease. I think that's a great sign. I mean, as Anne-Marie said earlier, the fact that we're seeing that on top of steroids and seeing effects that are greater than when you start steroids, I think is highly encouraging. And as we saw the histology slides, it means that functional dystrophin is protecting muscles. That's exactly what you would expect if you are protecting muscles and improving muscle function. We absolutely, as we said, being in that dynamic range, would expect to see CKs continue to decline. So it's something we'll continue to follow over the course of the study.
Yeah, I mean, it's an ongoing study, and we've reported what's in the database, but, yeah, continued decline is a reasonable thing to expect. And then with regards to World Muscle, you know, we've just got these data, and World Muscle is a couple of weeks away, so we're not ready to announce anything yet, but it's certainly on our radar.
Got it. Thanks, guys.
Catherine, are you there?
Yeah. Can you hear me?
Okay. We'll go to the I think I can run it here. Catherine, you're up.
All right. Thanks very much. Sorry, my phone dropped off earlier. I don't know why. Just a couple of questions. One, I'm not sure if I missed this, but what was the baseline mean dystrophin level for these patients?
The baseline levels, because we don't have baseline biopsies, but it's consistent across placebo cohorts in both approved products, as well as we have patients who have the same deletions, amenable back, even in suvodirsen, where we could look, where we saw very low to no dystrophin levels in those patients. So baseline is less than 0.5%.
Okay. And then I'm not sure if you've done this analysis yet, but do you think, you know, would you see a correlation between dystrophin expression and the CK and AST biomarkers? Obviously, it was very encouraging to see both of those lowering.
Yeah, it's hard to do it. I mean, CKs are obviously on a dynamic effect, and dystrophin's kind of punctuated when you get biopsies, and so that's oftentimes why the statistical correlation is more things we could work on, but I think what's important to us is really the fact that we see high levels of expression going, and we can chart that between this, you know, where we count six weeks and six months, over six months of dosing, and trending alongside of that is the CK declines substantially, so I do think the biomarkers are trending. I think sometimes I know there's a lot of focus on CK.
AST is important because it gives us another surrogate and correlate to be able to look back and say, "Well, if AST is trending along with CK, it's even more affirming that, we're seeing those improvements." I think the best sign of improvements are where we have histological biopsies, where we continue to see improvement in muscle health itself, with more clearly defined muscle fibers and nuclei. So I think, again, kind of stepping back to the macro picture, where we actually can look at muscle tissue, it looks like muscle tissue is getting better.
And then just lastly, I understand why this would be excluded from a, you know, functional endpoint, but why was the non-ambulatory patient excluded from the dystrophin analysis?
So, patients who have lost ambulation, very often their skeletal muscle is highly fibrotic, and fatty. And once the muscle gets to that point, there's little that can be done to repair that. So, we included non-ambulatory boys in the study because of the promising preclinical data that we have about, you know, exposure in diaphragm and heart. But we recognized prospectively that on a measure of skeletal muscle, the non-ambulatory patients would have less opportunity for benefit. So there should be, you know, a subgroup analysis that excludes them. That's what we did.
The reason we also shared it on the patient-level data, because I think it's important, is we had. When our KOL community would look at the data, it was actually highly affirming of the data itself, so that a patient that you would expect to have a lower amount of dystrophin had that. So again, it was highly affirming, but the patient was included in the total database, safety and evaluation. So again, affirming for us the profile at it.
Got it. Well, thanks very much, guys. Thanks for taking my question.
Thank you.
Congrats.
Thank you.
I think we have our operator back, so I will turn it over to Yep, and we have got the last question coming up now.
Thank you. Our last question comes from Joon Lee with Truist Securities. Your line is open.
Hey, guys. Thanks for taking our follow-up question. Taking a step back, how are you able to get into stem cells, diaphragm, and cardiac tissues? My guess is that, you know, it's got something to do with the steroid control and PN chemistry. But, you know, is this something that you can start to rationally design into your other oligos going forward or maybe apply AI to improve upon? And then what is, what is Chandra's thinking on this as you plan to tackle other exons? Thank you.
Hey, I'm looking at the smiles in the room. I think you understand very much the work that's been happening now over the last decade in understanding chemistry and PN chemistry and what it's really giving us access to. I think when we said early on that we were gonna be accessing muscle, there was always this question of: Do we need antibodies? Do we need some sort of conjugate to get access to tissue? And we said the challenge wasn't the requirement to put something else on the medicine there, that chemistry and rational design alone could get us access. We saw that today here. We see that in neurons with the first demonstration in humans of allele-specific silencing in neurons.
We're excited to bring ADAR-based, and I think it really does speak to the power of our chemistry. That's what's giving us access to making meaningful medicines. I think as we think forward, I think it does open up a host of genetic targets to pursue, where we can see this convergence now, as, as we brought forward with obesity and INHBE novelly, how do we find convergence of novel chemistry with really unique biology that then opens up new possibilities? I think the team, as we said on the call earlier, does have.
We see better dystrophin in the other exons. I think we are taking this deliberate approach of, we have a 48-week study, we'll deliver that. We're working on the engagement with regulators, and then ultimately, you know, that will help drive forward the approach to DMD more broadly. But, we appreciate the recognition that the differentiation we've brought today, really comes from chemistry. And I think the accessing of various cell types opens up promising therapies across a range of diseases.
Great. Thank you.
Thank you. There are no further questions. I'll now turn the call back over to Paul Bolno for closing remarks.
Thank you, everyone, for joining the call this morning. I am grateful to every Wave employee for their dedication and focus on our mission and on the patients and families we serve, and thank you again to the DMD community for your support and partnership. Have a good day.
Thank you for your participation. This does conclude the program, and you may now disconnect. Everyone, have a great day.