Wave Life Sciences Ltd. (WVE) Earnings Call Transcript & Summary

Good morning, and welcome to the Wave Life Sciences Interim Data from FORWARD-53 Clinical Trial conference call. [Operator Instructions]. As a reminder, this call is being recorded and webcast. I'll now turn the call over to Kate Rausch, 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 31, 2023. We undertake no obligation to update or revise any forward-looking statement 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 Vargeese, 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 N531 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 oligonucleotide leverage the complex places on 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. With in 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 44 amenable DMD further support this threshold and they have baseline dystrophin of around 7% in a milder disease force. Today, we are seeing our exciting approach to DMD, exon-skipping translates in boys with data that include 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 4 additional exon, 51, 44, 52 and 45 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 N531 as a potential best-in-class treatment for exon 53 skipping amenable DMD. Up to 24 weeks of every other week dosing with N531, we observed a mean 9% muscle content-adjusted dystrophin or 5.5% unadjusted, which was quantified as 2 distinct dystrophin protein isoforms. Importantly, the amount of dystrophin expressed across participants was consistently high, with the majority of boys expressing at least 5% dystrophin achievement. 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 N531 is accessing stem cells. As we observed improvements in multiple key markers of muscle health, all with markedly safe and well-tolerated profile. I'll now walk you through the data in more detail. FORWARD-53 is an ongoing potentially registrational open-label Phase II 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, 6 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 prespecified analysis of dystrophin protein in ambulatory patients. 11 boys were enrolled in the study, ranging from 5 to 11 years of age. All boys are on stable steroid regimens. There are 10 ambulatory and 1 non-ambulatory boy. There were 5 different underlying mutations occurring in exon 45 to 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 improved to information on 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 restore the reading frame for dystrophin. To achieve exon skipping, N531 needs to access the nuclei. We confirmed N531 is present in myofiber nuclei as shown with red staining on the left of Slide 17. Once again, we detected 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 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 decreased 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 their renewal capacity of the muscle and initiate productive repair of muscle fibers. We are 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 53 boys with dystrophin levels reaching up to 14% of normal on a muscle content-adjusted measurement. One biopsy was planned to be of too low quality to be analyzed. There was one non-ambulatory patient excluded from this analysis per our prespecified analysis plan. Our reported levels are MHC-normalized. Main absolute dystrophin levels were 9% in the muscle content-adjusted measurement and 5.5% without muscle content adjustment. Our reported dystrophin was quantified from 2 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 differentiate 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 while 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. After the course of this study, we observed clinically meaningful decreases of serum biomarkers indicative 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 dystrophins proper localization in the sarcolemma membrane. The fact that dystrophin is localized properly in these fibers support that it is functional. On Slide 23, we compare the biopsies from a boy who participated in both our Part A study after 6 weeks of N531 shown on the left and FORWARD-53 after 24 weeks of treatment shown on the right. In both the H&E stain sections and those process 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 derisk 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 the 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 2024, which is the first RNA editing program in the clinic for any disease. We also are working towards initiating our first clinical trial in the first quarter of 2025 for our GalNAc-siRNA INHBE program. WVE-007, a potentially breakthrough approach for obesity that leverages siRNA to target INHBE. 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 wholly-owned 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 them further. As we approach proof of mechanism data in RNA editing and move INHBE 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. And with that, I'll turn the call over to the operator for Q&A. Operator?

[Operator Instructions] Our first question comes from Joon Lee with Truist Securities.

Congrats on the impressive data. I have 3 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, I 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 western blot. Would that be comparable to your 9% or you're 5.5%?

Thank you, Joon. To start with your first question, we do believe that we have not plateaued and I'd say that for a couple of reasons. One, we see high levels of muscle concentration sustainably with a 61-day half-life. So a lot of drug in the muscle with continued increase from the 6-week study in exon skipping, 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 in muscle and as Anne-Marie showed, the improvement we're seeing in muscle fibers between 6 weeks and 6 months, and continuing that. One of the other approaches that we believe is as you get better muscle health, you're going to 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 is 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 we'll be measuring in the 48-week time point will be a good another assessment and 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 look 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 muscles. 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 presented because I think it is important that 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, and 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, its fat and muscle all within the biopsy. And so this normalization to 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.

Our next question comes from Salim Syed with Mizuho.

Congrats on the data. I guess 3 for me as well, if I can. Anne-Marie or Paul, I know you mentioned the functional measures were taken at 24 weeks. There really wasn't much detail in the slides, and I appreciate that you might need the 48 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 exon, I believe, like exon 44 typically present with higher baseline dystrophin?

Yes. Thank you very much, Salim. So as you said, in 6 months, the progression that you would expect in this population is somewhat slow, so you wouldn't be able to detect but you're slowing anything on that basis. And that's true actually of all the functional measures, including 95% stride velocity, the digital measure, which is likely to be the most sensitive to all of them. I think what is really encouraging actually is the serum biomarkers, so this reduction is 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 I think we can conclude from this is really encouraging, coupled with the dystrophin and what we're seeing in the tissue. And certainly, the KOLs have looked at our tissue have all said this looks really healthy muscle. So, encouraged. You asked about the 48-week data in the regulatory pathway. So we'll be engaging regulators on the pathway to the accelerated approval. We'll be finishing the study. All of this is going to 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, we're 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 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 thing that this would encompass would be clinical trials with shared placebo arm but 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 patient from having -- not having as many on placebo. You're absolutely right that exon 44 is different from the other exons. And so for exon 54, you would need to have exon 44 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.

Yes. 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 images that you saw and obviously, the clinicians who have been involved in the study. And I think while everything is anecdotal, I think the observation thing we're hearing from families, patients, clinicians that we do recognize they're anecdotal. I think it's important when we actually have heart 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 that where we could use that augmented placebo design. And so we have really put a lot of thought on how to efficiently run a platform design study. And so we're excited to bring that forward as we approach the end of the study, but we will keep you updated in the first quarter.

Our next question comes from Eric Joseph with JPMorgan.

And congrats on the data. I guess just following up on the point of dosing and being in the dynamic range of expression. Is there any benefit -- further benefit that you see to just an expression from perhaps dosing higher? It seems from the safety data, you perhaps have the margins to explore that. Any plan to do so as you kind of move to monthly dosing? . And then secondly, just with respect to the one patients where you didn't get to that 5% threshold. Anything notable there, perhaps a reaction on treatment that sort of undermine the level of expression, your expectation that, that might kind of get above the 5% threshold with continued treatment?

Yes. 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 splices elements works is we're producing protein that 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, we will -- not only we will not lose efficacy, but we continue to preserve in that dynamic range of production of dystrophin. I think the safe profile continues to be important to us as well. And so I think the idea is still a high quantity of dystrophin, so achieving Becker-like dystrophin levels, consistency across patients and across tissues and potential for higher expression in diaphragm and our 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, so the ability to really change families by going in once a month. And coupled that with a safe profile where there's not a sacrifice or a decision to be made by taking safety for that less frequent administration or dystrophin expression. We're always the key components of this program, and 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 happening. You get a window in time. We're encouraged that, that last patient was -- is in the range and very well could have in other samples higher dystrophin. But I think we see that consistently across the range and we'll look at 48 weeks when we'll have other opportunities to evaluate biopsy specimens. But if I think if we look at the 9% dystrophin and seeing 89% of the patients above 5%. I think we're highly encouraged.

Yes. So the non-ambulatory patient had similar concentration and skipping, but I think the most important thing is the KOL responsible. But given the benefit, potential benefits in heart and diaphragm, they would absolutely want to keep those patients on the treatment because of the benefits that they could have later.

And I think that piece echoes the sentiment that -- this exposure to heart and diaphragms 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 2 opportunities, given the profile that we shared today, and then 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 muscles 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 to muscle stem cells, the regenerative cells, the muscle and therefore, potentially delay the progress of losing ambulation or starting to develop new. So I think our opportunity to really reflect on the various stages of the DMD journey. I think we can play an important role there.

Maybe a follow-up quickly good. Just as you look to interact with regulators, how much, if any, in 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?

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.

Our next question comes from Timur Ivannikov with Raymond James.

This is Timur Ivannikov 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 VILTEPSO?

Yes. So we use an outside CRO standardized to run the standard Western blot using the antibodies that have been used with VILTEPSO.

Okay. Got it. And then can you talk about any correlation that you may have seen for week-24 dystrophin expression with respect to the type of exon deletion or baseline, just of an expression, especially for ambulatory patients who had lower expression at week 24? Did they have a different type of exon dilution or perhaps lower baseline dystrophin?

There weren't any patterns that would lead us to believe any particular expression response, better or worse. I think the response was pretty consistent with the majority of patients meeting the 5% or greater threshold.

And we do think that's important as we think about being able to treat exon 53 minimum boys is not to have to. And as you saw in the enrollment, we did have a range of deletions. So seeing consistent dystrophin on top of no changes and output tells us that all the [ lesions should respond similar ].

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?

It's the usual functional measurement, things like NSAA, [ force their climb ], time to rise, pull, et cetera. And this information is in our clinical trial.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 6-minute walk NSAA, et cetera. And of course, these are things we'll be discussing with FDA when we engaged 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 has 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 therapy. So as we think about the community globally, our view would make sure that we continue to build the data set that could support this program and others being available to boys in the U.S. and outside the U.S..

Our next question comes from Lisa Walter with RBC.

Great. This is Lisa on for Luca. Maybe just another one on the regulatory path. 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 the 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.

I'll take the first one and then Anne-Marie can take the second. As it relates to the registration path line having been in meetings with [ Peter Marks ], all 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 there -- from our standpoint, has been no change publicly or 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 now we know, congress is we authorized 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 point out functional changes like we're seeing in CK is a 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 complementary 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 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 compilation.

And one is to remember that there are no fully approved drugs to treat exon 53. So if we think about the current pathway, there are 2 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, one, we want to deliver against high dystrophin, consistent dystrophins 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 an agreement with the FDA when we had built a confirmatory trial design before that use that augmented placebo group. So 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 design, 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 a potential full approval. So we're excited to have those conversations.

Our next question comes from Joseph Schwartz with Leerink Partners.

This is Jenny on for Joe. Just one clarifying question. Could you comment on the baseline distribution expression for these patients? And then our second question is that dystrophin expression was kind of similar as what we see with VILTEPSO, probably where we're going to get the most pushback and they weren't able to show a functional benefit. Can you just clearly walk us through what aspects of Wave N531 and the data you have 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?

Yes. 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 that thing. In terms of the exon 53 space, as we said, there's the 1% 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, are 5.8% that we've seen with VILTEPSO at least posted, that's driven off of outliers. This really gets the consistency and to your question on confirmatory study translation. And that's really what we're focused on is how is dystrophin -- because everybody is talking about a numerical number for a mean dystrophin. But how does that ultimately translate to patient benefit. And 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 every patient level data because the patient level data is ultimately what we believe is going to drive out and function or improvement in running a subsequent study. And so actually, if you remove the outliers from that study, the actual mean dystrophin number dropped substantially into the 3% range. So it's important for us to be thinking about highly consistent, high expression dystrophin. So 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 adjustments 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 issue that you need to distribute to the myofiber, so 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, the 5% is 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 myofiber is 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 exclusively clean.

Thank you. Our next question comes from Madison El-Saadi.

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 given the high exposure and localization within the myocyte on nuclei. And then secondly, just wondering what additional color we make could expect, I believe that your late breaker at World Muscle Society in October?

I'll start with the CK and then hand it over. I think the benefit of the CK, as you pointed out, the slope is continuing to decrease. And 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 slide, 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.

Yes. I mean it's an ongoing study, and we've reported what's in the database. But yes, continued decline is a reasonable thing to expect. And then with regards to World Muscle, we've just got these data and World muscle is a couple of weeks ago -- away. So we're not ready to announce anything yet, but it's certainly on our radar. [ Kathryn ], are you there?

Yes. Can you hear me? All right. Just -- 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?

So 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 -- 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?

Yes. It's hard to do. I mean, CKs are obviously on a dynamic effect and dystrophin kind of punctuated when you get biopsies. And so that's oftentimes why the statistical correlation is more things we can 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 where we can, 6 weeks, 6 months, over 6 months of dosing and trending alongside of that is the CK decline 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, AST is trending along with CKs. 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 cell 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 functional endpoints, but why was the non-ambulatory patient excluded from the dystrophin analysis?

So patients who have lost ambulation. Very often, the skeletal muscle is highly fibrotic and fatty. Once the muscle gets to that point, there's little that can be done to repair that. So we increased non-ambulatory boys in the study because of the promising preclinical data that we have about 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 a subgroup analysis that excludes them. That's what we did.

The reason we also shared on the patient level of data because I think it's important as we had when our KOL community has looked at the data, it was actually highly affirming of the data itself to a patient that you would expect to have a lower amount of dystrophin at that. So again, it was highly affirming, but the patient wasn't included in the total database of safety and evaluation. So again, affirming for us the profile of that is.

I think we have our operator back. So I will turn it over to the last question coming up now.

Our last question comes from Joon Lee with Truist Securities.

Taking a step back, how are you able to get into stem cell's diaphragm and cardiac tissues. My guess is that it's got something to do with the steroid control and PN chemistry, but is this something that you can start to rationally design into your other oligos going forward? Or maybe apply AI to improve upon? And what is Chandra thinking on this as you plan to tackle other exons?

Okay, 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 -- over a decade and understanding chemistry and PN chemistry and what it's really giving us access to. I think when we said early on that we were going to 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 its 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 forward. And I think it really does speak to the power of our chemistry. That's just 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 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 exon. 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 that will help drive forward the approach to DMD more broadly. But we appreciate the recognition that the differentiation we brought today really comes from chemistry. And I think accessing of various cell types opens up promising therapies across a range of diseases.

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.