Good morning, and welcome to the Dyne Therapeutics call to review the top-line clinical results from the DELIVER trial in Duchenne muscular dystrophy. Today's call will be hosted by John Cox, President and CEO, and Doug Kerr, Chief Medical Officer. CFO Erick Lucera will also be available to answer questions. I will now hand over to Mia Tobias to start our call.
Good morning, everyone. I'm Mia Tobias with Investor Relations. Thank you for joining us for today's event to review the positive top-line results from the registrational expansion cohort of the DELIVER trial for z-rostudirsen in DMD. Before we get started, I'd like to remind everyone that we will be making forward-looking statements today that are subject to the safe harbor protections provided under the Private Securities Litigation Reform Act of 1995. Actual results may differ materially from these forward-looking statements as a result of various important factors, including those discussed in the risk factor section of our most recent Form 10-Q. These statements represent Dyne's views as of today's date, and we disclaim any obligation to update these statements except as required by law. For today's program, John Cox, Dyne's President and CEO, will first provide some opening comments. Dr.
Doug Kerr, Dyne's Chief Medical Officer, will then review our latest data from the DELIVER trial supporting the potential for U.S. accelerated approval. John will provide some closing remarks, and then we'll open the call for Q&A. Our CFO, Erick Lucera, will also be available to answer questions. I will now pass the call to John.
Thank you, Mia. At Dyne, we are on a mission to deliver functional improvement for people living with genetically driven neuromuscular diseases. This morning, we are incredibly excited to share the positive top-line results for z-rostudirsen from the DELIVER trial in boys with Duchenne muscular dystrophy, amenable to Exon 51 skipping, bringing us one step closer to our first potential commercial launch. The registrational expansion cohort, or REC, met its primary endpoint with compelling results that will form the basis of our BLA submission for U.S. accelerated approval, which is on track for Q2 of 2026. Specifically in the REC, treatment with z-rostudirsen led to a statistically significant and robust increase in dystrophin expression, replicating the same sevenfold change we observed in the MAD portion of the trial, and we saw a continued favorable safety profile.
Importantly, we also saw improvement across all six functional endpoints assessed in the top-line readout of the REC at six months. These clinically validated outcome measures assess the critical manifestations of the disease, including ambulation, upper limb function, and lung capacity, and are widely used in DMD trials. Two of these generated nominal p-values less than 0.05, the time-to-rise velocity and the 10-meter walk/run velocity, despite the study not being powered to demonstrate statistical significance in any of the functional measures. We were pleasantly surprised to also see preservation of lung function, a result that we did not expect in a short six-month duration. This functional data was further supported by new positive results from the long-term portions of DELIVER, which showed sustained improvements from baseline across multiple functional endpoints out to 24 months.
It is also impressive that we have been able to observe these results in Exon 51 skip-amenable boys, a population that typically has lower baseline dystrophin with a faster progression of disease. Although our focus today will be on the positive data from DELIVER, I'd also like to highlight the positive read-through these results have for validating the potential of our FORCE platform to deliver payloads to targeted tissues with a favorable therapeutic window. This same platform is being used for our very promising program in DM1, as well as our early-stage pipeline in FSHD and Pompe disease. And importantly, we now have the clinical validation to continue the development of our programs targeting other exons in DMD, which could roughly triple the addressable population of our franchise, all using the same basic PMO chemistry and Fab.
With these results in hand, we are on track to finalize a BLA submission for U.S. accelerated approval in Q2 2026, which would set us up for our first potential U.S. launch in Q1 2027 if priority review is granted. We are also excited to initiate a robust phase three study planned to start in Q2 2026, which will be designed to provide confirmatory evidence and also to support potential ex-U.S. submissions. We will provide more details on that study design as we get closer to study initiation. Before we dig into the details, I'd like to reflect on what these results mean for the DMD community and our opportunity to potentially transform the quality of life for these families.
For the first time, a potential therapy for Exon 51 DMD has shown early and sustained functional improvement across multiple endpoints, including those that assess upper and lower limb function and, importantly, preservation of lung function, the loss of which is a leading cause of mortality in DMD. We are honored to be able to make this announcement today and are proud to be working every day towards bringing these families the treatment that they have been waiting for and deserve. With that, I'll turn the call over to Doug to go through the DELIVER results in more detail.
Thanks, John. Before I dive in, let me start with a brief review of the unmet need in DMD and how we've designed z-rostudirsen to provide the kind of functional improvement that this community has been awaiting. As a reminder, DMD is a devastating, progressive disease with significant unmet need. People with Duchenne lack the ability to make sufficient dystrophin protein, which leads to progressive muscle weakness, loss of lower and upper limb function, CNS-related symptoms, and eventually cardiac and respiratory failure that are leading causes of death. Although the first therapy for Exon 51 skipping-amenable DMD was approved almost 10 years ago, there remains serious unmet need for meaningful functional improvement. Exon 51 skipping-amenable DMD represents the most prevalent mutation at approximately 13% of the entire DMD population, and this form of the disease is particularly challenging.
These patients typically show greatly reduced or absent baseline dystrophin levels lower than most other DMD mutations. This results in a faster rate of functional decline and an earlier loss of ambulation. The current standard of care PMO for Exon 51 has demonstrated limited dystrophin production, less than 1%, and requires weekly administration due to the challenge of delivering enough active drug. This dosing burden is a frequently cited reason for treatment discontinuation or treatment avoidance by patients, with further patient burden often coming from the need to utilize an implantable venous access port for weekly dosing, and questions remain around gene therapy due to the potential limited functionality of microdystrophin, unknown durability, and an inability to redose and concerns around safety. In summary, despite some available options, there is a tremendous unmet need in Duchenne muscular dystrophy, particularly in addressing the underlying cause of the disease.
As many of you know, z-rostudirsen was designed using our FORCE platform to overcome the challenge of targeted delivery. By conjugating a PMO designed to enable production of near full-length dystrophin to a Fab against TFR1, we have aimed to deliver a precise genetic medicine targeted to tissues that matter in DMD, namely muscle, including the diaphragm and heart, as well as the CNS. As a neurologist and neuroscientist, having spent much of my career taking care of patients living with DMD, I have seen this community waiting for decades to have a therapy that can meaningfully change the trajectory of the disease and provide functional improvement. The FORCE platform is why I joined Dyne, because of the opportunity to transform DMD for patients and their families, and the data I will share with you today has the potential to bring us closer to that reality.
Let me now turn to the exciting positive top-line results we announced this morning from the DELIVER trial. DELIVER was designed from the beginning to support a potential U.S. accelerated approval submission, with both a multiple ascending dose portion, or MAD, to enable selection of an optimal dose, and then a registrational expansion cohort, or REC, to generate additional data at the go-forward dose of 20 mg/ kg, Q4 weeks, to support a potential BLA submission. DELIVER includes a total of 86 participants across a broad and representative population. The primary endpoints are change from baseline in dystrophin at six months, as well as safety and tolerability.
Although not powered for other endpoints, the trial also includes a number of functional assessments to gauge how these boys respond to treatment, including through the multi-year open-label extension and long-term extension, which I will collectively refer to as the long-term portions of the study. It's first important to note that the baseline characteristics across the cohorts we'll discuss today were generally well-balanced and demonstrate the broad population across ambulatory status studied in DELIVER. As we've discussed previously, the 20 mg/ kg Q4 week cohort from the MAD was slightly older and more advanced in disease as compared to the younger 10 mg/ kg Q4 week cohort. However, the 20 mg/ kg Q4 week REC cohort and pooled placebo group were quite similar at baseline. Importantly, the overall safety and tolerability profile of
z-rostudirsen, 20 mg/ kg Q4 week, remains favorable based on the additional data from the REC, along with all of the data from the MAD cohorts, as well as the long-term portions of the study, including a total of 86 patients followed for up to 36 months. Most related TEAEs were mild or moderate, and the most frequent related TEAEs were fever and headache. No serious related TEAEs were observed during the placebo control period for 20 mg/ kg Q4 week MAD and the REC. I will note that we have seen two new related serious TEAEs of fever and/or malaise at the 20 mg/ kg Q4 week dose in the long-term portions of the study. Both participants fully recovered and have continued to receive z-rostudirsen without interruption.
At our go-forward dose, no participants have demonstrated persistent related anemia, and no participants at this dose have demonstrated persistent related thrombocytopenia. With over 1,400 doses of z-rostudirsen to date and 113 patient years of follow-up, we have a favorable long-term safety database to support BLA submission. We are very excited to share that the registrational expansion cohort met its primary endpoint, demonstrating a statistically significant increase in dystrophin expression compared to baseline, reaching 5.46% at six months on a muscle content-adjusted basis, with a p-value of less than 0.0001. This robust increase is precisely what we wanted to see, and we are pleased with the strong statistical significance demonstrated here. In addition, we replicated in a cohort here of 24 boys what we had seen previously in a smaller cohort from the MAD.
Although the numerical results differ slightly between cohorts, including a lower baseline in the REC, we saw the same sevenfold change from baseline in muscle content-adjusted dystrophin production in the REC that we saw previously in the MAD cohort with the same 20 mg/ kg Q4 week dose, lending further support to the robustness of these data. On an unadjusted basis, dystrophin expression in the REC increased to 2.87% at six months, with a pre-specified nominal p-value less than 0.0001 compared to baseline. This represents a greater fold increase than we observed in the corresponding MAD cohort, again supporting the robustness of these data. Looking at dystrophin production on an unadjusted basis can help facilitate comparisons to other studies with all of the usual caveats about cross-trial comparisons.
Here, we show an approximately tenfold higher level of dystrophin production at six months than what has been reported in a phase three study for the current standard of care for Exon 51, with a significantly lower PMO dose administered, four times less frequently. Although there is no indication that a statistically significant impact on function would be required for U.S. accelerated approval, and the DELIVER study was not powered for these endpoints, we do believe the ultimate clinical value of z-rostudirsen will come from its ability to provide meaningful functional improvement for patients. To that end, we pre-specified the analysis of a number of clinically validated outcome measures in DELIVER, including measures relevant to both ambulatory and non-ambulatory patients.
Here, we will be showing data for time to rise and 10-meter walk/run in terms of velocity, which was a pre-specified method to analyze these data in our statistical analysis plan. We had made this adjustment based on precedent from the phase 3 studies of other DMD therapies, as well as the fact that using velocity is a statistically more rigorous approach. Additionally, per the pre-specified statistical analysis plan, placebo data were pooled from both the MAD and the REC for these functional assessments. We were incredibly excited to see improvement relative to placebo across all six of these endpoints at six months within the REC. The results from DELIVER continue to be unprecedented in Exon 51 DMD. Let me start with the time to rise from floor, here shown as velocity. Treatment with
z-rostudirsen led to a meaningful improvement from baseline in TTR velocity compared to a decline on placebo, and the delta versus placebo exceeded the published MCID impressively at only six months. Put another way, the boys on drug got faster, and those on placebo got slower. In a post-hoc analysis, the delta versus placebo generated a nominal p-value of less than 0.05, a compelling result given the sample size and short duration, which we attribute to the strength of the FORCE platform. The 10-meter walk/run test is another common timed function test used to assess the functional capabilities of DMD patients, and here we have shown again a meaningful improvement from baseline, with a benefit over placebo closely approaching the published MCID again at only six months. The boys on drug got faster. Those on placebo got slower.
Just as with the time to rise, in a post-hoc analysis, the delta versus placebo generated a nominal p-value of less than 0.05. Again, impressive. The North Star Ambulatory Assessment is a 17-item scale measuring ambulatory function, which has been widely used in the DMD field. Here, yet again, we saw functional improvement from baseline versus a decline on placebo, and the delta of over two points versus placebo closely approaches the published MCID. In a post-hoc analysis, the delta versus placebo generated a nominal p-value of 0.09. The stride velocity 95th centile is a digital outcome measure of the 5% fastest strides taken during everyday living. Here, we again saw improvement from baseline. I will note that the comparison to placebo is potentially confounded by a single placebo participant who achieved a surprising change from baseline of 0.46 m/s at six months.
Excluding this participant, the mean change from baseline at six months for the placebo group would have been much lower at 0.02 m/s , more in line with what might be expected based on natural history. The magnitude of the impact of this patient on the placebo mean was augmented by the fact that the placebo sample size for SV95C was smaller. Nevertheless, the increase from baseline with z-rostudirsen treatment represents an impressive improvement at only six months. Let me now turn to two additional functional measures that are included here because they assess whether z-rostudirsen impacts other aspects of DMD beyond lower extremity function and walking, and therefore can be assessed in both ambulatory and non-ambulatory boys and young men.
We are excited to share data on these measures for the first time, starting with upper extremity function, which is particularly relevant as it impacts the ability of boys living with DMD to do things like brush their teeth and take care of themselves. In the REC, treatment with z-rostudirsen led to an improvement from baseline and benefit over placebo in the Performance Upper Limb scale, which is a 22-item scale measuring upper limb function. The progressive loss of pulmonary function is unfortunately an inevitable and particularly debilitating aspect of DMD, starting with these boys having difficulty catching their breath and culminating in the use of respirators and eventually complete loss of pulmonary function, which is a leading cause of death. This is why we were particularly moved when we saw data indicating that z-rostudirsen could preserve this vital function.
The cohorts shown here started in DELIVER with relatively high values for forced vital capacity, a global assessment of lung function, at approximately 90% of predicted based on age, sex, and height. Therefore, we believe it is quite compelling that treatment with z-rostudirsen led to preservation of lung function at six months as compared to the declines seen in the placebo group. To summarize the top-line results from the DELIVER registrational expansion cohort, we see a compelling and potentially transformational profile for z-rostudirsen, supporting the potential for U.S. accelerated approval and addressing the significant unmet need in DMD. We demonstrated a statistically significant and robust increase in dystrophin production at six months, with levels well above the current standard of care. We have seen a favorable safety and tolerability profile with data out to 36 months. We have compelling results supporting the potential of
z-rostudirsen to enable functional improvement across multiple clinical endpoints. Specifically, we saw improvement relative to placebo across all six of these diverse and validated clinical measures. As I mentioned, a post-hoc statistical analysis comparing the data from the REC treatment group to pooled placebo at six months generated nominal p-values of less than 0.05 for two of these endpoints: the time to rise velocity and the 10-meter walk/run velocity. A truly remarkable achievement that bodes well for the potential impact z-rostudirsen may have on this devastating disease. This is all in the context of a Q4 week dosing profile, which may help address the significant infusion burden of the current weekly standard of care. As a reminder, we had not set expectations to provide new data from the long-term portions of DELIVER in conjunction with the top-line results from the REC.
I am so thankful that our team was able to analyze and prepare these additional impressive long-term data while finalizing the comprehensive analysis required for the top-line REC readout. Let me now turn to these new long-term data from DELIVER, which showed sustained functional improvement across all six functional measures out to 24 months. This is a snapshot of our latest results in the long-term portions of the study. What's important here is that across three cohorts and six endpoints for a total of 18 assessments, we are showing sustained functional improvement from baseline in every measure out to 18 and 24 months. This is an unprecedented breadth and durability of effect in Exon 51 DMD.
From left to right, the cohorts include the original 20-mg/kg Q4 week cohort from the MAD, now out to 18 months, and in the middle, a pooled analysis of both the 10- and 20-mg/kg MAD cohorts out to 18 months, followed by the 10-mg/kg MAD cohort, which then transitioned to 20 mg/kg, now out to 24 months. I'd note that the final pre-specified statistical analysis plan includes imputation for missing or out-of-range data, which was not done previously in order to maintain blinding. This is the way we have presented the data here and the way we will be presenting the data to regulators in our planned BLA submission, so in the context of a progressive disease where you would generally expect these measures to get worse over time, these patients showed actual functional improvement, not just a slowing of decline.
Before I conclude, let me briefly discuss the broader positive implications we see from these data as they validate the potential of the FORCE platform. Our platform was designed to leverage TfR1 to enable the targeted delivery of rationally selected payloads to address the underlying disease biology. In the case of z-rostudirsen, this has translated in the DELIVER trial into a statistically significant and robust increase in dystrophin production. In addition, our TfR1 binding Fab was designed to enable robust and widespread tissue distribution, which we believe is a key reason we've been able to show early and sustained functional improvement across multiple clinical endpoints. In terms of safety, our Fab was designed to not interfere with the natural biology of TfR1, specifically its role in iron homeostasis.
In DELIVER, we believe these features have contributed to the favorable safety and tolerability profile, including the lack of persistent related anemia or thrombocytopenia at the 20 mg/ kg Q4 week dose, and finally, our platform was designed to be re-dosable with less frequent dosing, enabling us to achieve these results for Z. Rossederson with only Q4 week dosing, which we believe is a significant patient advantage versus the standard of care weekly therapy. We believe the strength of these data bode well for our broader pipeline, including z-basivarsen in DM1, which is currently being evaluated in the registrational expansion cohort of the ACHIEVE trial, as well as our earlier stage pipeline in FSHD, Pompe disease, and other exons for DMD, where we have the opportunity to build a portfolio leveraging the FORCE platform.
Before I turn it back to John for some closing comments, I just want to express that I wish something like z-rostudirsen was available when I was treating DMD patients.
Thank you, Doug. With these positive results in hand, we are quickly turning our focus to executing on the compelling commercial opportunity we see with z-rostudirsen as we are poised to enter an established market with significant unmet need a little over a year from now, assuming priority review. We believe the data from DELIVER, including from the MAD, the REC, and the long-term portions of the study, demonstrate a strong value proposition for addressing the unmet need in DMD.
We believe the robust increase in dystrophin production, the favorable safety and tolerability profile, and the sustained functional improvement observed across multiple clinical measures, all based on convenient Q4W dosing, provide a compelling justification for patients to consider our therapy if approved. We are building a capital-efficient operating model to deliver on the potential for patients, our company, and our shareholders. We have a leadership team in place with the right expertise in rare muscular diseases and are taking a disciplined approach to building out our commercial organization with an eye toward expected future synergies with our opportunity in DM1, as well as the obvious overlap with our programs for other exons in DMD. At the same time, our CMC activities are on track to support our expected timelines for BLA submission and launch. As always, we plan to grow the company while ensuring disciplined capital allocation.
In summary, we now have the data in hand to support a planned BLA submission for accelerated approval in Q2 of next year based on the positive results from the DELIVER trial. And we are more excited than ever about the broad opportunities for our pipeline based on the FORCE platform, which has enabled the positive results we announced today. In addition to z-rostudirsen serving as our first potential launch, we remain on track with zapnometran in DM1 for a potential second launch roughly one year later. We continue to expect to complete enrollment in the registrational expansion cohort of the ACHIEVE trial in early Q2 of next year, and we look forward to presenting that data in Q1 2027. We would like to thank the DELIVER trial participants, their families, and the Duchenne community for their trust and commitment as we continue to advance this promising therapy.
As always, we remain steadfast in our mission to deliver functional improvement for those suffering from neuromuscular diseases. In doing so, we help to transform the lives of patients, their families, and communities while also driving growth and tangible value for all stakeholders. Thank you for your attention. And with that, we will open it up for questions.
We will now begin our Q&A session. If you have a question, we ask that you please use the raise hand function at the bottom of your Zoom screen. Once your name has been announced, you can ask a question. If you want to withdraw your question, please lower your hand using the raise hand function. Thank you. And a moment for the first question. Our first question comes from Paul Matteis at Stifel. Please unmute your line.
Hey, thank you. Can you hear me okay?
We can.
Great. Good morning.
Congrats on the data. Thanks for taking my questions. I really appreciate it. I just wanted to clarify a couple of things about the functional data, which looks super promising. Can you just clarify why all of this is referred to as post-hoc and whether or not the analyses that you're showing us were, for lack of a better term, I guess, always the plan from just the endpoints and the methodology? And then second to that, as it relates to pooling the placebo arms, was that also always the plan? And I guess if you didn't pool it and you used the concurrent placebo, does anything change as it relates to these sort of effect sizes and the overall conclusion? Thank you.
Yeah, let me, Paul, thanks for the question. And also thanks for the Stifel report this morning. Let me turn it over to Doug.
I think he can handle both of those.
Yeah, Paul, it's a great question. Thanks for asking it. This was not a post hoc analysis in the sense that you're probably used to seeing it. We pre-specified the analysis of all of these functional endpoints, including the methods for imputation and how to pool the placebo group. The only thing on the functional data slides that was post hoc, if you will, is the statistical testing to generate the p-values because our pre-specified SAP did not include an alpha-controlled hierarchical testing of any endpoint beyond dystrophin. The only endpoint formally analyzed from a statistical standpoint was the primary endpoint because that is the focus for accelerated approval. All we wanted to see from the functional endpoints was trends.
As a reminder, the study was not designed to demonstrate efficacy on any functional measure, so we view these results, especially the nominal p-values, as pure upside.
Thanks. And on the pooling placebo question, Doug?
Yeah, so we had pre-specified, obviously, the pooling. We wanted to see a really robust measure assessing the functional outcome. That's better done with the pooled placebo from the MAD and the REC. That's why we set it up in the top line that way. So we're really more confident because the pooling of that placebo gives us greater power to understand the difference between those two groups.
Okay. Thank you. Congrats again.
Thank you.
Thank you.
Our next question comes from Moritz Rittstieg at Guggenheim Securities, if you would like to ask a question.
Hi. Congrats on the data, and thanks for taking my question. I have two questions on the time function tests.
First, could you elaborate on the precedent for using velocity instead of time for time to rise in a 10-meter walk/run? And secondly, if you were to analyze your data from these endpoints based on time instead of velocity, would the results still be stat sig? Thanks.
Doug?
Yeah, great question. We made the adjustment to velocity based on precedent from the phase 3 studies of other DMD therapies, as well as the fact that using velocity is statistically more robust. So when you look at other recent studies and how the DMD field has moved, these include, for example, the phase 3 givinostat study, phase 3 Regenxbio microdystrophin, phase 3 viltolarsen, phase 2b vamorolone. They have all transitioned to velocity instead of time. There is a statistical basis for this. It creates a more robust assessment of the data. Importantly, the MCIDs are only available in velocity.
That's why we did that. We'd set that up in a pre-specified way to increase the robustness of the analysis.
Great. Thank you.
Our next question comes from Michael Ulz with Morgan Stanley. If you'd like to unmute yourself and ask your question.
Hey, good morning. Can you hear me?
Yes, I'm Mike.
Hey, it's Avi Novick on the line for Mike. Thank you for taking our questions and congratulations on the data. So I guess just following up on the functional endpoints, I guess, have you done any market research that I guess as to which clinicians would find which of these endpoints most compelling? And you think there's a possibility of driving switch from standard of care?
In addition, I guess, which of these do you see as, I guess, driving the highest probability, or should we view as driving the highest probability of success in an eventual phase 3 confirmatory study? Thanks.
Maybe I'll touch on this. Doug can always add. When we talk to clinicians, and by the way, Doug is one who has treated DMD patients, every one of these six top-line measures is important. They're all clinically meaningful. The time to rise is particularly followed from a young age where they're trying to determine how long it takes for a child to get up and stand up from the floor. It is particularly predictive of how soon that boy will be in a wheelchair, for example. That one is extremely important. The 10-meter walk/run also has an MCID, also very important.
We were particularly impressed with the lung function maintenance, the testing around FVC. That one appeared to preserve lung function, which is absolutely related to mortality with this disease, so I think all of these, the fact that all six of those had moved in a direction that was compelling and favorable leads to answering the second part of your question, which is in terms of kind of the commercial opportunity. We do think that with this type of data, we have an opportunity to be first in class, best in class, and become the standard of care in this field,
and maybe the only thing to add is we do know clinicians appreciate each of these measures. They have been used in DMD clinical trials. Importantly, they're measuring different aspects of the disease, so many of them are about ambulation and lower extremity strength, which is obviously important.
But it's also important to assess the impact of drug on other aspects of DMD progression, including upper extremity strength and pulmonary function. And we had hoped to see that there was movement in a couple of these, but we've seen movement in all of them encompassing a diverse aspect of DMD disease progression. And that's what makes this so gratifying today.
Thank you. And then I guess with respect to the upcoming phase 3, I guess, which of these do you see as most important for, I guess, confirming functional benefit?
Do you want to cover that one, Doug?
We've been thinking a lot about the phase 3. It's really important. It will start in Q2 of 2026. So we're deep in the thinking about this. We have not externally discussed what the details are of that phase 3 confirmatory trial. That's coming.
That will come as we get closer to initiating that trial.
I might add, I think any number of these measures, any number of these measures end up being very important in the phase 3. I think it's a chance for us and Doug to have a field-defining type of confirmatory trial that would apply for the United States for the first time, somebody showing an Exon 51 actual efficacy and functional benefit in a confirmatory trial, as well as having a trial that meets the requirements of ex-U.S., such as the EMA.
Great. Thank you for taking our questions.
Thank you. Our next question comes from Andrew Tsai with Jefferies. If you'd like to unmute yourself and ask your question.
Hey, good morning. Congratulations on the very strong results. Thanks for taking my question. As we think about the path ahead, obviously, it's submitting for accelerated approval.
So can you talk about your overall confidence in CMC manufacturing? 20 mg/ kg seems like a lot of drug to produce. So I just want to understand how de-risked CMC and supply are at this juncture and how you're ensuring that won't be a risk during the FDA review. Thank you.
Yeah, thank you, Andrew. Well, CMC is something that we have been working on for a long time. And we're prepared. So our tracking of timelines for CMC starts with ensuring that everything that needs to be done for the BLA, which is Q2 of this coming year, is on track. And it is. That's process validations, analytical method qualifications, etc. So those activities are there. Our commercial supply chain has been established. That has been in place. And so we are preparing for a launch in Q2 or, I'm sorry, in early 2027.
BLA submitted in Q2 of 2026 and a launch in early 2027. All of that is on track. So I think I'll leave it there, Andrew. We feel confident about CMC.
Great. Thank you.
Thank you. Our next question comes from Martin Auster with Raymond James. If you'd like to unmute yourself and ask your question.
Hey, guys. Thanks for taking the question. Congratulations on the data this morning. I was wondering if you could talk a little bit more about the global commercial opportunity just in terms of how important that is. Right now, there's just a drug approval in the U.S. But if you could address kind of how you see this opportunity sort of playing out globally and then maybe touch on where you see the regulatory path and the requirements for gaining access both in European as well as sort of rest of world markets. Thanks.
Yeah, Marty, thanks for the question. So the number of patients in the United States is roughly 1,500. There's at least that many in Europe and obviously many more throughout the world. I think with this data, there will absolutely be interest from regulators in different parts of the world. We have intention of being in Europe. And our intention right now, as I was mentioning before, base case is that we would be expected to complete a phase 3. But we'll have conversations with the EMA based upon the data that we've had. We feel the same way about Japan. And there are plenty of other markets, for example, in the Middle East where there will be interest in this type of medicine. So our plan is to be a global commercial organization starting first in a very efficient way in the United States.
Great. Thank you.
Thank you.
Our next question comes from Edward Tenthoff with Piper Sandler. If you'd like to unmute yourself and ask your question.
Great. Thank you. Good morning. Can you hear me okay?
We can, Ted.
Excellent. Oops. Sorry. So firstly, congratulations. Another big win for this is the second big win for DMD patients in just under a week. So really exciting to see these results. I was so impressed by the consistency of the data. Obviously, the focus is on zotadirsen, but now with positive pivotal data in hand, how quickly do you think you could advance these other four drugs that treat other exons into the clinic? And what do you think the regulatory path might be? Is there any chance that those move directly into registration cohorts, or do you think it would mirror the way you've advanced 251? And
thank you very much. Yeah.
Ted, thanks for the question. Good to hear from you. We are very excited about the potential of building out a franchise here. I think you may have heard us talk a bit about the exons that we have in the pipeline. Moving those forward would roughly triple the market size and could do that fairly rapidly. We like the platform guidance that the FDA has put forth. We think is really ready-made for our particular type of platform. Every one of these different exons that we would go after uses the same Fab, the same linker, the same manufacturing process, the same quality testing, same disease. It is just a handful of oligonucleotide changes. So it is kind of ready-made for a platform type of designation. And we would like to pursue that with the FDA.
Our hope would be to get more to what you just pointed to would be a regulatory path that would include a basket-type trial that would allow us to move rapidly. That's not set, but that is something that we would love to pursue with the help of the FDA based upon the data we've seen so far.
That makes a lot of sense. And again, congrats on the data and this really important work you're doing for these boys.
Yeah. Thank you, Ted.
Thank you. Our next question comes from Catherine Novack with JonesTrading. If you'd like to unmute yourself and ask your question.
Hi. Good morning, everyone. Thanks for taking my questions. I just wanted to ask a little bit about, again, questions about the endpoints, ideal for the registrational study. Do you expect to have a similar age group and mix of ambulant versus non-ambulant patients?
So we can get a sense of which endpoints would be more ideal, let's say, something that is more sensitive in a younger population versus those who are a bit older.
You're talking about for the confirmatory trial, Catherine?
For the confirmatory trial, yes.
Doug, you want to tackle that?
Well, we haven't really talked about the details. We are interested, obviously, in a very robust field-defining confirmatory trial that will be initially in ambulatory patients. We're also interested in studying the impacts of the disease in non-ambulatory patients as well. Details of that and endpoints and size are coming, but we're not ready to externalize that at that point. We've done a lot of thinking about it. We're very excited about these trials, but we'll talk about that as we get closer to the initiation of that trial.
Got it.
And then just on the commercial opportunity, do you have a sense that there's any kind of loyalty whatsoever to current exon skippers? Or is, once a drug with superior dystrophin expression is available to patients, is dystrophin alone something that would encourage providers to change treatment? And additionally, with the monthly versus weekly dosing, would this encourage some patients who are not on drug to potentially look at being prescribed?
Yeah. Catherine, we estimate that there's roughly about 400 patients on a weekly standard of care today out of about 1,500 patients. Whether they're on the standard of care or they're not on any care at all other than maybe steroids, what the field has been looking for, I think what families have been looking for is not just a dystrophin number, but actual functional improvement. And this is the data we've been waiting for.
I think it's the data they've been waiting for. So today, people are being dosed on a weekly basis. Evidence of functional improvement is hard to find. So I think this is something that is in a really good position to create some value for patients and rapidly.
Got it. Thanks for taking my questions.
Thank you.
Thank you. Our next question comes from Gavin Clark-Gartner with Evercore . If you'd like to ask your question.
Hi. Good morning. We just had one question on the two new safety events. Just wondering what was the time course of onset and then the resolution for the events post-infusion. Thanks so much.
Yeah. So we reported those two new serious-related TEAEs in the open portion of the study. Those occurred essentially two to six days after the drug administration. Out of caution, patients were admitted to the hospital. They were evaluated.
They recovered. They were discharged. They did not miss a dose. They continue in the study without dose interruption at 20 mg/kg Q4.
Great. Thank you.
Thank you. Our next question comes from François Brisebois with LifeSci Capital. If you'd like to ask your question.
Hi. Thanks for taking the question, and congratulations on the data, especially on the functional side here. Can you maybe help us understand kind of two questions here? The force platform, you touched on it, but what do you think might be the secret here to getting this kind of dystrophin function, especially in DMD? And then on the commercial side, maybe just help us understand a little bit more the expertise of the team. It seems like the team has been brought in on the commercial side for a while now. How ready are you guys to take this on here?
Thank you. Hey, Frank. So maybe I can start. I'll start with the commercial side, and Doug can jump in on kind of the special distribution that we see with the platform. We brought in approximately a year ago a commercial leader, Johanna Friedl-Naderer, who had one of the drugs she had launched globally was Spinraza. And so she has been building out a team. We've also been adding medical leadership, medical affairs, and MSLs. We've been building a team regionally at the kind of management and upper management level. We're doing it in a staged approach. We're trying to be, I think, kind of capital-efficient here and responsible about it. But in rare diseases, the beautiful thing about being in rare diseases is that you don't need a massive commercial workforce.
You need a workforce that is experienced in neuromuscular rare diseases and have the right type of relationships. And I think we're partially built. We're continuing to build it, and it's all right on track. So we feel good about that. And then I would just add to that that the other piece that I know our CFO likes is that that infrastructure will be leveraged for DM1 approximately one year later. So we can do this in a very capital-efficient way. As far as the platform and its distribution, Doug, you want to take that?
Yeah. It's a great question. And I mean, I think the way I would answer it is we've said, and we are on a mission to increase the functionality to result in functional improvement of these boys. It turns out it's not just the dystrophin number. It is really delivery and dystrophin.
That's key to the success of the FORCE platform in DMD. The FORCE platform was designed to deliver the genetic payload, which in this case is a PMO, to all of the tissues that matter in DMD, and even within the tissues in a diffuse way that really allows the muscles to function. When the payload gets to the muscle, it increases dystrophin really 10x better than existing standard of care. This is near full-length, highly functional dystrophin. The last aspect maybe is time on drug matters. We are seeing a sustained benefit out to 18 and 24 months in which DMD patients, despite having a progressive disease which would cause decline in function, are not. They are actually functionally better at those long time points than they were at baseline on drug.
So we think all of those aspects are really keys to the secret sauce of what we're doing here and why this is so transformational for functional improvement in DMD.
Great. Thank you and thanks for including all that new long-term data too. Appreciate it.
Thanks, Frank.
Thank you. Our next question comes from Brian Skorney with Baird. If you'd like to unmute yourself and ask your question.
Great. Thanks, everyone. Congrats on the data. I think you had previously talked about dystrophin-positive fibers, and generally, we sort of see a correlation between expression and positive fibers. But I'm just wondering if you've analyzed the IHC from these patients yet and what it looks like both in terms of dystrophin-positive fibers as well as any staining for restoration of the dystrophin sarcoglycan complex to show localization.
Yeah. We don't have those data at this point.
We were really laser-focused on top-line readout, the data that we would need to support accelerated approval. Obviously, we've got those biopsies. We'll look at them, but we haven't looked at them at all at this point.
Great. Thank you.
Thank you. Our next question comes from Keay Nakae with Chardan Capital Markets. If you'd like to ask your question.
Thank you. What is your understanding of what the EMA is going to require in terms of functional improvement measurement of the ones that you're assessing?
Okay. We know that the EMA likes stride velocity 95th centile. You've seen the improvement that we've shown from baseline. They have a clear MCID that they call to as well. So we would anticipate that the EMA would be looking at stride velocity, but the other data that we've shown across these measures will be important too.
So stay tuned on kind of the phase three confirmatory trial designs and what endpoints we'll have for Europe as well as for the United States.
Yeah. Appreciate that. I guess just in thinking of the multiple goals of the confirmatory phase three, will it be driven more by seeking to expand into the EMA or more checking the box of the U.S. requirement of the confirmatory to back up the accelerated approval in whatever measurement they want to see?
We're going to address both. I don't know if you want to add anything to that, Doug.
Absolutely. We think we can do both with a single really good, really robust field-defining study.
Thanks.
Thank you. Our next question comes from Tessa Romero with J.P. Morgan. If you'd like to ask your question.
Hi, John and team. Thanks so much for taking our questions here.
First one is, do you intend to have a pre-BLA meeting ahead of your planned BLA submission in the second quarter? And if so, has this meeting been scheduled, or when do you expect it would take place? And then the second question is, to be clear, you did not see any thrombocytopenia at the 20 mg/kg dose. Can you just clarify exactly what you saw?
Yeah. Let me start with the regulatory piece. We haven't been providing kind of the play-by-play, but you can expect a pre-BLA. We've had breakthrough designations, so we'll be following the normal course that you would do with that, which includes a pre-BLA, but we haven't been giving kind of timing. You can anticipate, though, that we're going to be filing in Q2 of next year, so it's not too far off into the future.
And then as far as the thrombocytopenia, Doug, you want to touch on that?
Yeah. I mean, we've seen no persistent, related thrombocytopenia in the trial. And the reason we include the word persistent here is because in the context of a clinical trial with lots of phlebotomy, you see fluctuations just randomly of laboratory measures. What really matters is if you have a sustained drop in any of these hematologic parameters. The FORCE platform, remember, was designed not to interfere with the things that would do that. What we're saying here is, indeed, that is the case. We're not seeing persistent, related drops in hematologic parameters due to drug.
Okay. And how do you define persistent?
Persistent really is essentially three months, right? If you have something that comes and goes, random fluctuations of a laboratory measure, that's one thing. If it persists, that's something that could be clinically meaningful.
We're not seeing that.
Thank you.
Thank you, Tess.
Thank you. Our final question comes from Will Pickering. If you'd like to unmute yourself and ask your question.
Hi. Thank you very much for taking my question and congratulations on the data. I was wondering if you could describe the imputation approach you used in the REC, how much of the data was imputed, and any related sensitivity analyses you may have run. And it looks like you used imputation for all endpoints except FVC. So could you describe the rationale for that? Thanks so much.
Yeah. Okay. So the data, obviously, as per ICH guidelines, if you're submitting a data package to regulators, you must account for missing or out-of-range data. That is why the imputation. This was pre-specified in the SAP. It was done before data was unblinded.
It's a fairly standard methodology in that if there's missing or out-of-range data, then you are imputing things that increase the robustness of those data. That's how we did it. We specified that in the statistical analysis plan. Those are the data that we're going to use to regulators. Those are the data that we showed you today. FVC was not imputed. You saw that on the data. This is a tough measure. It's very tough for young patients to actually complete the task. Especially for younger children, it's an onerous task for these patients to do. It requires putting on a mask, putting on a nose clip, forming a tight seal, inhaling completely, and then exhaling through the tube without allowing any air to escape. That's challenging. In some cases, those data would fail QC. They actually couldn't do the task.
Now, there's no clear way for what you would do to impute in that. You just can't get the data. So we presented it as is for that.
Thanks so much, and congrats again.
Thank you. This concludes today's call. I will now hand back to Dyne Therapeutics for closing remarks.
Well, thank you all. Obviously, we are really, really excited about where we are today. Moving forward with the accelerated approval package is top, top priority for us. Seeing six functional measures move the way they did, it certainly feels transformative for the field. And we're really excited for the patients and families, and we're going to do our best to get this drug out there as soon as we can. Thank you.