Please be advised that today's conference is being recorded. I would now like to turn the conference over to your speaker today, Mike Hankey, Investor Relations. Please go ahead.
Thank you. Good morning, everyone. I'm Mike Hankey with Investor Relations. Thank you for joining us for today's event to review exciting new data for our Dyne-101 program for myotonic dystrophy type 1, as well as an update on Dyne-251 for people with Duchenne muscular dystrophy who are amenable to Exon 51 skipping. 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 factors 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 provide an overview of today's results and our next steps to advance both programs. Dr. Doug Kerr, Dyne's Chief Medical Officer, will then review the clinical results and our development plans in more detail. I'll now pass the call to John.
Thank you, Mike. Our mission is to deliver life-transforming therapies for patients with neuromuscular diseases, starting with myotonic dystrophy type 1 and Duchenne muscular dystrophy. Today, we will focus on new results from the ACHIEVE trial in DM1, where Dyne-101 has shown substantial clinical improvements across a wide range of endpoints measuring multiple aspects of this devastating disease. First, I want to briefly highlight the value proposition of our company. We have two late-stage programs, Dyne-251 for DMD and Dyne-101 for DM1, each positioned to potentially deliver best-in-class therapies for patients in the near future. In fact, we anticipate readouts from our registrational expansion cohorts in 2025 and 2026, respectively. Dyne's FORCE platform is a versatile vehicle for delivery of different types of payloads to muscle as well as to the brain.
We have demonstrated proof of concept in humans for two different diseases with two different genetic medicines, an ASO for DM1 and a PMO for DMD. We are also leveraging the FORCE platform to expand the pipeline with two preclinical candidates. Our FSHD candidate uses the FORCE platform to deliver an siRNA, while our candidate for Pompe disease leverages that same platform to deliver a recombinant enzyme to cardiac and skeletal muscles, and importantly, to the brain. Finally, I highlight that our pipeline assets are fully owned by Dyne and that our company is well capitalized to advance the pipeline towards commercialization and in disease areas where there is significant unmet need and substantial market opportunities. Now, let me turn to some key takeaways for Dyne-101.
The registrational expansion cohort has been defined, meaning we have selected our dose, enrollment target, and the clinical endpoints to enable a planned submission to the FDA for accelerated approval in the first half of 2026. The data from the completed multi-ascending dose portion of ACHIEVE supports our belief that Dyne-101 will have a best-in-class profile, and finally, Dyne-101 also showed a favorable safety profile with no serious related treatment-emergent adverse events at any dose. Let me also provide a brief update on Dyne-251 for the treatment of those living with DMD who are amenable to Exon 51 skipping. Importantly, the registrational expansion cohort from our DELIVER trial is on track to be fully enrolled this quarter with an anticipated readout by year-end, followed by a planned submission for U.S. accelerated approval in early 2026.
I remind you that the continued development of Dyne-251 is supported by early evidence of unprecedented levels of dystrophin expression and clinically meaningful functional benefit at the registrational dose of 20 mg/kg Q4W, as we have previously reported. We recently met with the FDA to discuss aspects of our registrational plan. Based upon their feedback, we continue to pursue U.S. accelerated approval based on dystrophin expression. Finally, we are also providing updated safety data.
All patients receiving Dyne-251 in the open-label extension and long-term extension portions are now being dosed at the 20 mg/kg registrational dose, and we have not seen any serious related treatment-emergent adverse events since our last update. We now have approximately 1,700 doses of study drug administered and 135 patient years of exposure with the platform across two programs, with no serious related treatment-emergent adverse events in either the DELIVER or ACHIEVE trials at the selected registrational doses. With that, I'd like to now pass the call to Doug Kerr.
Thanks, John. Let me start with a brief overview of DM1. This is a progressive disease with a life expectancy of 45-60 years. The clinical presentation is varied, but includes myotonia, which is a failure of relaxation of muscle after contraction, as well as muscle weakness, cardiac dysfunction, respiratory weakness, and CNS manifestations. There are no approved therapies to slow the disease, and DM1 is likely highly underdiagnosed. Importantly, the manifestations in DM1 are caused by a toxic gain of function related to mutant DMPK RNA that is trapped in the nucleus, which results in abnormal splicing of a variety of other RNA molecules. The central pathobiology of DM1 is that it is a spliceopathy, meaning missplicing of key genes due to the DMPK mutation results in varied clinical manifestations of this disease. How do we believe Dyne-101 is acting? It starts with delivery.
The TfR1 Fab delivers nucleic acid payload efficiently to tissues relevant to DM1, and the ASO payload gets into the cells and nucleus with the goal of addressing the nuclear events that cause DM1. Dyne-101 knocks down DMPK with the goal of releasing sequestered splicing proteins such as MBNL and restoring a more normal splicing pattern to the MBNL target genes across different muscle tissues as well as the CNS. Preclinical data indicate that the release of MBNL sufficient to result in splicing correction of at least 20% enables normal RNA splicing and protein function. In ACHIEVE, we have observed those levels of splicing correction with Dyne-101 and, in turn, have seen an improvement from baseline in function, not just a slowing of decline on a wide range of functional endpoints and patient-reported outcomes.
Dyne-101 was designed to uniquely address the core pathobiology of the disease in an effort to reverse the disease and restore function. On the next slide, we'll briefly touch on the various manifestations of DM1 and, as a neuromuscular neurologist who has treated DM1 patients, I will call out those aspects of myotonic dystrophy which are particularly meaningful to patients in addressing their disease, including the CNS. DM1 is a heterogeneous disease affecting multiple organ systems. While the disease name highlights myotonia because it is an easily diagnosed feature of DM1, it is not the feature which is the most troubling or burdensome to patients. Rather, in many patients, it is the muscle weakness that really matters. DM1 also manifests as a decline in overall function, such as walking and rising from a seated position.
Importantly, cardiac and respiratory dysfunction are the major causes of death in DM1 patients, and preclinical evidence suggests Dyne-101 efficiently accesses those tissues as well. In many patients, the CNS manifestations are the most burdensome aspect of the disease. These manifest as cognitive dysfunction, fatigue, excessive daytime sleepiness, inability to concentrate on tasks and behavior, and personality changes. Let me now touch on the FORCE platform, which uses a Fab against TfR1 to bring payload into relevant tissues in neuromuscular disorders. We've known for decades that naked ASOs are challenged in being able to deliver enough payload to tissues such as muscle and the CNS. Various strategies to enhance delivery have been explored, including the use of self-penetrating peptides, which have tolerability and safety issues.
TfR1 is an ideal protein receptor to bring payload into tissues such as the muscle and CNS, but not all TfR1 approaches are the same. We have extensive preclinical data with FORCE showing penetration and biological activity in the CNS, and I would refer you to our presentation in May 2023 at ASGCT, and the ASO is a key selection of payload here because it localizes to the nucleus, and that is where the core pathobiology of DM1 starts. Let me now touch on the design of the ACHIEVE trial. ACHIEVE was designed with a MAD portion to determine safety, the optimal dose, and whether splicing could be a feasible surrogate endpoint, and we've done exactly that. Dyne-101 also demonstrated signs of benefit on multiple measures that we will discuss.
We have now completed the MAD portion of the ACHIEVE study based on 56 patients' dose, and today we are reporting those study results as well as the dose selection for advancement into the registrational expansion cohort to support a planned submission for U.S. accelerated approval. We are also continuing to evaluate the patients already in the study, most of whom have been dose-escalated to the go forward dose of 6.8 mg/kg and will be followed as part of the open-label extension and long-term extension portions of the study, and so, by the time of submission for approval, we expect we will have over 1,600 doses of Dyne-101 with 180 patient years of follow-up on drug, and some patients will have been on study drug for greater than three years. We expect this will result in a very robust data set.
Now, let me turn back to our central hypothesis of delivery to DMPK knockdown, to splicing correction, to functional benefit. Let's dig in, starting with the next slide. This is a high-level view that we have indeed done what we hope to do with ACHIEVE. The core principle is that with the FORCE platform, we get enough ASO to modulate the core pharmacology of DM1, DMPK knockdown, and splicing correction, unlocking functional improvements. We see here that we effectively delivered the drug to muscle in humans. Next, we see that Dyne-101 knocks down DMPK, and at the go forward dose of 6.8 mg/kg, it knocks down DMPK profoundly and more consistently than we saw with the lower dose cohorts.
And it corrects splicing, as defined by a normalization of the CASI, or the Composite Alternative Splicing Index, which measures the key set of genes that are misspliced in DM1 and which we have directly determined through discussions with the FDA can be an appropriate surrogate endpoint for accelerated approval in the U.S. Finally, Dyne-101 showed broad functional improvement across multiple endpoints, which I will discuss. Turning now to safety. What you are seeing here is our standard reporting of safety, but now updated to December 6th of 2024, and the important thing is that there is really nothing new here. 855 doses of study drug representing over 72 years of patient follow-up on study drug, and there are exactly zero serious related TEAEs. Notably, we have also seen no evidence of persistent related anemia or thrombocytopenia in the study.
Now, let's look at a broad view of efficacy measures that we have assessed in ACHIEVE. The conclusion from the MAD study is that our go forward registrational expansion cohort will use a dose of 6.8 mg/kg and CASI at three months as our surrogate endpoint for predicting meaningful functional benefit at six months. So the next few slides drill into the three-month pharmacology at 6.8 mg/kg and the six-month functional results. First, as shown on the left, we show CASI correction at three months of greater than 20% for the 6.8 mg/kg dose, and we show that this is associated with unlocking broad improvement across multiple functional measures at six months. In each of these functional measures, the 6.8 mg/kg cohort is always to the right of placebo and to the right of the no effect line here shown at six months.
While each of these measures may not be statistically significant individually, we believe the data is indicating a broad and deep impact. We've shown these data to our advisors who are world experts in treating DM1 patients, and they are excited. They're excited by the breadth of improvement across multiple measures, including the CNS, and also by the depth of improvement on each of these measures. So we believe CASI correction at three months is a relevant and suitable marker for accelerated approval in the U.S. that potentially allows us to quickly get to market with a drug that impacts DM1. Before we get into some more details of the data from ACHIEVE, I want to tell you what this has enabled in terms of a path forward.
Our regulatory strategy is designed to enable us to do two things: move quickly to get this to DM1 patients and also to demonstrate a differentiated product profile. We believe we can determine an effect on many aspects of myotonic dystrophy within a registrational expansion cohort in the ongoing ACHIEVE study, and here's what it looks like. We plan to soon begin enrolling this cohort at 6.8 mg/kg q8 week, approximately 32 patients. Splicing correction at three months as the primary endpoint and additional functional and patient-reported outcomes at secondary endpoints at six months. In terms of endpoints, CASI and vHOT are key, and we have powered the cohort to detect statistically significant changes on both. Based on our data, as well as natural history data, we believe CASI is a better predictor of clinical benefit across a variety of measures that matter to patients relative to vHOT.
Beyond CASI and vHOT, we've seen clinically meaningful impact on multiple other measures, and listed on this slide are the additional endpoints we plan to assess. Our belief is that directionality on these additional measures, as associated with splicing correction, can support accelerated approval. Let me turn to more details on the data, all at our go forward dose of 6.8 mg/kg q8 week. You've seen this earlier, but I want to emphasize the relevance of the core pathobiology and pharmacology. We believe that any drug designed to alter the core pharmacology of DM1 should knock down DMPK in order to show functional improvement. Dyne-101 does. And this, in turn, is associated with a robust splicing correction all at three months. So let's see how that is manifesting in our clinical endpoints. Here is myotonia, as defined by the vHOT of middle finger relaxation.
This is a key early endpoint in DM1, and most experts consider this the earliest clinical marker to potentially respond to treatment, and we show improvement with our 6.8 mg/kg dose, deepening between three months and six months, with an improvement of 38% or 2.9 seconds at six months, even with a relatively low baseline compared to other cohorts. While we're excited about these data, myotonia is not the most important measure to DM1 patients, so let's look at what else we've seen in terms of clinical endpoints, starting with strength. Strength gets better at three months and deepens further at six months. We believe that a 10% relative change from baseline is a clinically meaningful level of improvement, and one other point, we are not talking about a slowing of decline. We are talking about an improvement from baseline.
Moving on to the next slide, which shows improvement in two functional measures. The 10-Meter Walk/Run Test is a standard functional assessment in muscle disorders, and Dyne-101 shows an improvement in this measure at both three and six months, while the placebo-treated patients show worsening by six months. Similarly, the 5X Sit to Stand assesses functionality reflecting lower limb strength, but also stamina and balance. It too shows a benefit both relative to baseline and relative to placebo at both three and six months. And this benefit, while with small numbers, is over a 10% change from baseline, which is clinically meaningful. Let me now turn to one of the highlights of the data for us. In ACHIEVE, we wanted to ask whether Dyne-101 could reach other tissues and potentially impact even more of the clinical aspects of DM1.
To assess that, we looked at the MDHI, which stands for Myotonic Dystrophy Health Index, a composite patient-reported outcome in DM1. What we show you on the next slide is that Dyne-101 seems to beneficially impact MDHI as well. Looking at the MDHI total score between the 6.8 mg/kg cohort and placebo, we see a really important 44% change from baseline for treated patients. The MDHI has a composite of 17 subscales, some of which are asking patients about myotonia and strength and function, but we became very interested in the other subscales, those that might indicate improvement in other aspects of myotonic dystrophy, such as the CNS manifestations. Indeed, when we look at the subscales of the MDHI related to CNS manifestations of DM1, each of them shows improvement on Dyne-101 relative to control and relative to baseline.
This includes measures of cognitive impairment, sleep, fatigue, communication, emotional issues, and pain. We were very excited to see that these data, these data, and will continue to evaluate the impact of Dyne-101 on these subscales. We believe that showing improvement on CNS measures such as these will be a valuable and differentiated aspect of Dyne-101. So let me just finish up with a few additional slides, which are a bit of a deeper dive on the data I have shown you so far. First, we wanted to assess whether baseline differences in cohorts could explain the observed apparent functional benefits. So we applied a statistical method, a mixed effects repeated measures model, MMRM, to account for the differences between the cohorts and asked whether the apparent improvements seen with Dyne-101 persist. They do. They get stronger.
What you are seeing here is a variation of the overall efficacy assessment that you saw previously, but this time, the statistical model has incorporated differences between the cohorts to more deeply assess the benefit. The improvement persists on all measures and is even stronger than shown previously with unadjusted changes from baseline. Notably, with this more rigorous analysis, none of the assessed functional measures touch the no effect line, and none of them overlap with placebo. Overall, these adjusted results provide further support for our development plans and our excitement about the program. Importantly, the MMRM is a statistical model that we plan to utilize in the registrational expansion cohort in ACHIEVE. Again, our accelerated approval registrational plan is based on three-month CASI and six-month functional endpoints. However, I do want to show some longer-term data from other cohorts just to finish the data presentation.
This slide includes biomarker data, including both DMPK and CASI measures, as well as vHOT from additional doses and time points. Based on our data, we believe that Dyne-101 is exerting the desired biological activity at all doses and that the effect is durable. I do want to mention a CASI data point with the six-month 6.8 mg/kg dose that is a clear outlier. These data were confounded by missing baseline data and intra-patient sample variability, and in light of all the data we've seen, we don't view this as a valid result. Closing out this section, I want to finish by showing the functional assessments across longer time periods and across cohorts. What you are seeing here is the 10-meter walk-run, but this time with longer-term data, including the 3.4 and 5.4 mg/kg cohorts. Sorry, this is a 5X Sit to Stand.
This is baseline adjusted and so reflects the statistical methodology described previously. You'll note a few points. Placebo is virtually unchanged or potentially worsening across these measures, as expected. All three treated groups show improvement in these measures. 6.8 and 5.4 are similar, although 6.8 mg/kg may show a modest improvement relative to 5.4 mg/kg at six months on both measures. Importantly, on the 5X Sit to Stand, we see a deepening of improvement out to 12 months with both the 3.4 and 5.4 mg/kg cohorts. Let me now summarize the update on DM1. We are excited about the data from ACHIEVE, and these data have allowed us to do each of the three things it was designed to do.
The data has helped us select what we believe to be the optimal dose going forward, and we are now initiating a registrational expansion cohort for which we hope to complete enrollment in mid-2025. We have demonstrated that splicing correction is associated with broad functional benefit, as shown through clinically meaningful endpoints that matter to patients. Based on previous feedback from the FDA, we believe that splicing correction, as measured by CASI, can be a surrogate endpoint to support an accelerated approval. Finally, we have determined that Dyne-101 has a favorable safety profile in humans. Let me turn quickly to DMD. Dyne-251 has potential to become the best-in-class exon-skipping therapeutic. There remains serious unmet need for meaningful functional benefit despite approved therapies, and exon 51 is the largest population of skipped amenable DMD patients. We have made excellent progress advancing our Dyne-251 clinical program.
The MAD portion of the DELIVER study is complete, and we have been rapidly enrolling the registrational expansion cohort at 20 mg/kg q4 weeks. We are today providing updated safety results from our program that reflect a data cutoff of November 21, 2024, and that is shown on the next slide. The safety profile of Dyne-251 has been favorable based on a meaningful database, including over 65 patient years of therapy and well over 800 doses administered. Most treatment-related AEs seen to date have been mild to moderate, and notably, no participants have demonstrated persistent-related anemia or thrombocytopenia, and there have been no new serious-related treatment emergent adverse events since our last update. Overall, this is a favorable safety profile, which gives us further confidence in Dyne-251 as a potential highly differentiated exon 51 skipping therapy for DMD.
As a reminder, at the 20 mg/kg q4 week dose of Dyne-251, we saw unprecedented levels of dystrophin expression in the field of exon 51 DMD patients. We also previously reported unprecedented improvements on multiple functional measures, including the North Star Ambulatory Assessment and stride velocity 95th centile, which we expect will be important regulatory measures. Based on our strong efficacy and safety results, we are rapidly advancing our registrational expansion cohort. This cohort includes approximately 32 patients with DMD, randomized three to one between active and placebo, which we expect to be fully enrolled later this quarter, setting us up for data expected late this year. Based on recent feedback from the FDA, we continue to pursue U.S. accelerated approval based on dystrophin expression as a surrogate endpoint measured at six months. In this study, we will also collect functional measures such as North Star Ambulatory Assessment and SV95C, where we believe Dyne-251 will be well positioned to demonstrate a meaningful impact. I'll now pass the call back to John for closing comments.
Thank you, Doug. As I think we have shown today, we are making excellent progress advancing our two lead programs for DM1 and DMD. Our success with these programs also strengthens our conviction and our platform and additional opportunities to deploy our technologies. We continue to advance our DMD franchise with multiple exon-skipping candidates. We also have promising programs targeting FSHD and Pompe disease, which highlight the breadth of our platform. To conclude, we are making progress on our mission to deliver life-transforming therapies for patients with neuromuscular diseases.
Today, we presented compelling clinical data on DM1, and we expect to soon be initiating the registrational expansion cohort and are working toward a planned submission for the U.S. accelerated approval in the first half of 2026. In DMD, we believe Dyne-251 is in the leading position of next-generation exon 51 skipping medicines with unprecedented dystrophin data and evidence of clinically meaningful functional improvement, and with a path to submission for U.S. accelerated approval in the first half of 2026. In short, we are building momentum to launch two very important neuromuscular disease medicines in 2027, which we believe will be transformative for patients and our company and will create significant value for our shareholders. With that, we'll open the call for questions.
Thank you. As a reminder, to ask a question, please press star one one on your telephone and wait for your name to be announced. To withdraw your question, please press star one one again. Our first question comes from the line of Debjit Chattopadhyay with Guggenheim. Your line is now open.
Hey, good morning. Well, thanks for taking my questions. I've got two. First, thoughts on why CASI seems to sort of max out in the mid to high 20% range across the two high-dose cohorts? And then could you also sort of elaborate on CASI at monthly likely to be predictive of functional benefits? Sort of, have you analyzed the individual patient data on a blinded basis? Thank you so much.
Yeah. Well, let me just start. I will tell you, and I'll turn it over to Doug, but I will tell you, looking at that data, Debjit, and I know you've followed the CASI closely, we have used CASI to guide our dose decision, and we've done it in a very disciplined way. I love the way the CASI numbers have increased as we've gone up in dose. If you look at 5.4 and 6.8, we're hitting above the 20% kind of splicing correction, which was always our target that we've talked about, and we've always believed it would unlock significant functional benefit. Both the 5.4 and 6.8 functional data looks great, and I think it gave Doug and his team a chance to really look closely at both of those doses and make a final decision. So I'll turn it over to you, Doug.
Yeah, no, I think that's right. I mean, I think we have always talked about a threshold level of CASI correction that will begin to unlock functional benefit. We've seen that. We saw that at 5.4. We've seen that at 6.8. More time on drug matters, and you're not going to get complete correction in a very early time point. But this is crossing a threshold, both at 5.4 and 6.8, but we're really pleased with each 6.8, and it does predict functional benefit. So we've shown that. The data that we've shown today indicates that there is a manuscript which is coming out, which is available on the web right now, which says exactly that point, that CASI correction predicts functional benefit, and that really was a critical piece of the puzzle for us to demonstrate that it can be used as a surrogate endpoint for accelerated approval.
I might add just one other point too, and that is when we really went through this data, you see that in the slides that Doug covered. At 6.8, we started seeing CNS signals on the MDHI. And in this disease of functions, CNS may trump everything else. And so getting to a CASI that is where we want it to be, seeing functional benefit that was predicted by CASI as we hoped at both 5.4 and 6.8, and then seeing in the MDHI and multiple subscores a potential CNS effect at six months, that was a big factor in our decision-making.
Thank you.
Thank you. Our next question comes from the line of Paul Matteis with Stifel. Your line is now open.
Hey, thanks for taking my questions and congrats on the data. I was wondering if you guys would be willing to elaborate a little more on the six-month splicing data at the high dose and what the effect might look like if you exclude the patient with the biopsy issue. Then just taking a step back, I guess the clinical data looks pretty consistent, but the splicing data does have some noise in it and some variability time point to time point. Why is it the right move to rely on splicing, and what gives you the confidence that some of the signal-to-noise stuff you're seeing in this study is not going to play out in the larger ACHIEVE cohort? Thanks so much.
Let me just start it, and then I'm going to turn it over to Doug. First of all, Paul, I think you had even pointed out in your note, which I appreciate, that we're really trying to be very transparent about the data set that we have in total, which is why we showed even the longer-term data we talked to you and others in the past that we would be making our decisions based upon three-month data, six-month data, we'd be reporting CASI, and we'd also be reporting function. This six-month time point clearly is an outlier. It's kind of remarkable and small data set numbers like we've had in each one of these cohorts that you've seen such robust CASI improvement over time and at different doses, and it's totally inconsistent.
This one time point, why we showed you all of that data, is completely inconsistent with what we saw with DMPK knockdown and completely inconsistent with what is ultimately important here, which is function. And so even though three-month CASI is what we have determined is highly predictive for us of at least various functional benefits, a number of functional benefits, we felt it important to be comprehensive and show you everything that we had. Let me just turn it over to Doug to follow up.
Yeah, I mean, I think that's the right answer. I mean, this is a small data set, and there were technical issues. And the challenges at the 6.8 mg/kg six-month, it's not biology. It's technical. We didn't have a baseline, and so that's not included despite the fact that at later time points, that individual had a very good CASI correction. And one of the other patients had discordance between two adjacent muscle biopsy samples, and we haven't seen that before. You just saw it here. And so when you start to get down to very small numbers and you look at that, it is technical. It's not biology.
And the further evidence for that comes from that slide where you see profound and deepening DMPK knockdown at that time point, and you see myotonia robustly improved at that time point. So we're very confident in CASI. It has been quite good for us. Occasionally, with small numbers, there are technical issues. We're really pleased with the other markers and certainly the functionality that we exhibited.
Thank you. Our next question comes from the line of Edward Tenthoff with Piper Sandler. Your line is now open.
Great. Thank you. And congratulations on this update. Really impressive data, and I agree with respect to the consistency across all the measures. Just if you could kind of go back through the timing again just to make sure that we've got this all right. So we could be getting Dyne-251 data by year-end NDA filing next year. And the DM1 data, would you anticipate that early next year, or when should we anticipate that data? Thank you very much.
Yeah, Ted, thanks for the questions. So just to be fairly specific, because you saw in the presentation, we were trying to provide some real clarity around the regulatory timing and how soon we possibly could be launching two major drugs. On DMD, we are rolling, as Doug has said, very, very well with DMD with the registrational expansion cohort, and that's going to be wrapped up this quarter. We will have completed enrollment this quarter, and that's a six-month dystrophin endpoint. So we would anticipate being able to have data from that registrational cohort by the end of the year.
With DM1, we are anticipating enrolling again in this registrational expansion cohort by mid-year. With three-month CASI, six months against multiple functions, that takes us out around the end of the year. So sometime early next year, first half of next year, we would anticipate having data from that registrational expansion cohort as well. Does that answer it, Ted?
Yep. It sure does. Thanks so much. I'm excited for the data and the filings next year.
Yep. We are too. Thank you, Ted.
Our next question comes from the line of Mike Ulz with Morgan Stanley. Your line is now open.
Good morning. Thanks for taking the question. Just curious if you guys have had a chance to sort of share this updated DM1 data with the FDA, and maybe secondly, if you can just talk to your level of confidence in an accelerated approval path based on the data you have so far. Thanks.
Well, maybe I'll start this one as well, and if you have something to add, Doug. Listen, the conversation that we have based our confidence on has been the conversation we've talked about with the FDA, where we had asked for what it would take in terms of accelerated approval, and particularly around the surrogate endpoint of CASI. And what they had provided to us, and we've talked about that, was that you needed to be able to have reasonable likelihood of being able to predict functional benefit.
And the FDA was hoping that that was expected or wanted that to be across multiple functions, and also in terms of benefit that would be meaningful for patients. They were pretty clear that vHOT was certainly a sensitive clinical endpoint, but that we would also need to be showing functional benefit and other features. I think the data you saw here today, Mike, has given us confidence that we are reasonably able to predict benefit across a number of important functions that matter to patients, including the MDHI PRO.
And we can do that at a three-month time point with CASI, and that is unlocking multiple functional benefits. So all of that gives us a belief that we have laid out and accomplished exactly what we need to do in the multi-ascending dose piece, and we're essentially laying out a registrational cohort that Doug has defined. We will be powering that for CASI. We'll also power it for vHOT, and we will be looking at a number of different functional benefits that we have listed on the slide.
Great. Thank you.
Thank you. Our next question comes from the line of François Brisebois with Oppenheimer. Your line is now open.
Hi. Thanks for taking the questions, and congrats on the data here. One slide that I thought was particularly interesting is this slide 23, where you adjust your baseline and balances on a lot of these functional scores. Can you just help us understand? I think you mentioned that you're going forward with this, and just maybe the FDA's perception of this adjustment, because it does seem to have helped the data here. So a little more clarity on the MMRM would be helpful. Thank you.
Doug?
Sure. I mean, mixed effects repeated measures model, very standard methodological approach to interpreting change from baseline data. And so it is clearly one of the statistical methods. It is used in many, many trials. It's quite common. So I mean, what it does is we've presented data earlier as a raw kind of change from baseline, but the statistical model incorporates baseline imbalances and visits over time to create a more rigorous methodological approach to understanding the change from baseline. So it will be one of the methods going forward, pretty standard. Nothing special to that from our perspective.
Yeah. I might also add we have provided the unadjusted data in this deck as well. And the purpose sometimes people will do an adjustment in order to improve or see where the data will take them or adjust in such a way that the data will look better. But in this case, if you look at our baseline data, both 5.4 and 6.8, both look great. And so from that, Doug and his team said, "Well, if we're selecting 6.8, let's make sure that we're not being that the baseline data is not biasing us in some way to pick 6.8." Instead, when he does the adjustment, which is the type of thing you do in the regulatory filing with these types of stats, it actually improves.
Interesting. And then there's one thing I just wanted to ask about. On the CNS side, I think you guys have had data showing that you target and you hit the CNS in the past, but just how do we feel comfortable? That seems like a potential very important differentiator here. How do we feel comfortable that this was not a fluke in terms of slide 22, where all these CNS improvements are shown here? Thank you.
Well, I'll start that one as well, and then we can take it, we can even take it a little deeper. But listen, the platform itself, when I joined the company, when Doug joined the company, one of the things that we immediately gravitated to was the preclinical data related to CNS penetration with our particular platform. Not only is TfR1 found on muscle tissue, it is also found for the CNS as well, and significantly. And the data we had from animal studies showed deep, broad penetration into the brain with an IV administration, even comparing it to intrathecal deeper, broader penetration in animal studies.
And so we've always had a belief that we may have the potential of affecting the CNS in DM1. And if you look at if you meet DM1 patients and you talk to the clinicians in this field, they will tell you that the CNS effects are most devastating for many, many of these patients. So if we can do that, it would be phenomenal. Now, this is our first signal around it, and you've seen it across multiple subscores, and it gives us a chance now at the 6.8 mg/kg dose to evaluate that across 32 more patients, and we'll be dose-escalating 50+ patients from the current ACHIEVE trial with another opportunity to look across a broad set of patients for that.
And I'd point to one other recent presentation that we did at World Muscle on Pompe disease in a preclinical model, and we showed glycogen clearance clearly in the brain. So the platform is designed to do it. We're not surprised to see that result, and hopefully, it is not a fluke, and hopefully, that holds up over time with the cli nical data.
And it was really robust, the 44% decline on MDHI at the 6.8 mg/kg. It did not disappear when you baseline adjusted. In fact, it got stronger. And then when you look at the subscales, which are assessing CNS, it's virtually all of the subscales of the MDHI are showing that benefit. So it's a very robust finding, and we think it's a key differentiator because it is so deeply impactful to myotonic dystrophy patients.
That's great. Thank you. That's it from me, and congrats again.
Thank you.
Our next question comes from the line of Luca Issi with RBC Capital Markets. Your line is now open.
Oh, great. Thanks so much for taking my question, and I'll be congrats on the data. Maybe, Doug, circling back on a prior question, it sounds like you're going to pitch the FDA the design that you outlined on page 16. Hopefully, the FDA buys into that design and the rest is history. However, should it not be the case, what is plan B here? Is there a scenario where the FDA ultimately asks you to run a trial that is much larger and uses vHOT as the primary endpoint as they have done for one of your competitors? Any thoughts there? Much appreciated. Thanks so much.
Yeah. I mean, just to give you some color around the plan and why we strongly believe it, right? We've had discussions with the FDA. They were very engaged with CASI as a surrogate endpoint for accelerated approval. It was a very dynamic back-and-forth discussion. We got all the clarity we need. We also knew that we needed to show that CASI change was predictive of functional benefit. We've done that. That is the truth. That is really kind of the hallmark of a surrogate endpoint for accelerated approval. We're not the only ones who have shown that. The DM1 field has been looking for a predictor of functional benefit. There's a paper that is available publicly right now with the first author, Provenzano et al., that shows exactly that, that CASI predicts functional improvement.
So that's why that discussion and really a very clear roadmap from the FDA as to what we needed to get accelerated approval is what we've laid out there on that slide. I will tell you that vHOT is not as good a predictor of functional benefit. vHOT is a clinical manifestation. It's not intrinsically meaningful to patients in the way that some of the other things we've spoke about, but that predictive capability of CASI to unlock a variety of other functions is really what drove us.
Got it. Thanks so much.
Thank you. Our next question comes from the line of Brian Skorney with Baird. Your line is now open.
Hey. Good morning, everyone. Thank you for taking the question. Maybe just starting to clarify on Ted's question on data readout, I didn't quite get it. Will we get three-month CASI from the pivotal cohort when it is available, or are we waiting on the six-month results before unblinding so we get three-month CASI and all the six-month functional data at one time? And then just on the safety slide, it looks like placebo and treatment are still pooled by cohort. Are you still blinded to placebo versus treatment comparisons here, or can you comment at all on any differences between placebo and treatment? I assume the data safety monitoring board at Nationwide has sort of evaluated .
That's a good thing.
Yeah. We are blinded, and so the table data you're seeing there is blinded data. It's an ongoing study. We've got to protect the blind to enhance the rigor of the study, so that's how we've approached it. And then the other question, I think, was, will we disclose three-month CASI or wait for the full data set of six months for the registrational expansion cohort?
Well, listen, I don't think we're going to get that specific about when we roll it out. Ultimately, yeah, we're not going to get too specific on that. But six months, three months, I would think what we really want to see is the functional benefit is going to be the key, supported by CASI as an indicator, so. But we'll get more to timing later.
Okay. Thanks.
Thank you.
Our next question comes from the line of Andrew Tsai with Jefferies. Your line is now open.
Hey. Thanks. Good morning and congrats on all the progress and the data. Just wanted to just triple-check that there is basically, for the registrational pathway, at least four other ways to win, assuming you hit CASI, even if vHOT didn't succeed. Just wanted to confirm this specific alignment since my understanding is your previous pathways in DM were slightly different. And then secondly, will the registrational portion be powered on an MMRM-adjusted basis for vHOT as well as unadjusted, and will the FDA accept MMRM analysis when analyzing the pivotal data for an approval? Thank you.
Yeah. Thanks, Andrew. You want to run?
I mean, MMRM, yes. I mean, that's a fairly standard methodology to assess change from baseline. We will be powered for CASI. We will be powered for vHOT. We have substantial power to detect differences on functional measures as well as PROs. Whether CASI hits or not, it will hit. We're powered. We're very confident about it. vHOT is important, but it's not the whole show. So we have to get some directionality on strength, function, or PRO. That's the path forward for us.
Great. Thanks.
Thank you. Our next question comes from the line of Ryan Deschner with Raymond James. Your line is now open.
Good morning. Regarding the interim six-month splicing correction data point, does this occurrence change the way you're thinking about powering a biopsy protocol for the registrational cohort, and will you be reporting longer splicing correction follow-up for the 6.8 mg patients in today's presentation and have a follow-up? Thanks.
Look, in terms of reporting CASI data, I don't know if we'll be reporting more six-month or longer-term over time. As we move forward, our focus is three months for the reasons that Doug has described. We feel very good about the three months in terms of being a reasonably strong predictor of functional benefit across multiple measures, and that's how our trial is going to be based. So at a minimum, we'll be talking to three-month CASI and six-month function. Anything to add to that, Doug?
I don't think so.
Got it. Thank you very much. And then quickly, just wanted to clarify. In the press release, you mentioned 32 patients in the 6.8 registrational cohort. Is that 24 treated 6.8 and 8 additional placebo patients, or how is that broken down? Thanks.
It is. That is correct.
That's what I thought. Thanks.
Thank you.
Our next question comes from the line of Tessa Romero with JP Morgan. Your line is now open.
Good morning, team. This is Caroline Palsha on for Tessa Romero with JP Morgan. Thanks for taking our questions. Just two from us. So in the press release, you spoke to your previous dialogue with the agency around the accelerated approval pathway for Dyne-101 in the U.S. based on splicing as a surrogate endpoint. Can you just clarify when this last interaction with the agency was? And with these data in hand, to just be clear, when do you expect to interact with them next and get definitive sign-off that this pathway is open? And then I just have a follow-up.
Yeah. Caroline, so thanks for the question. So we had spoken, as we've said publicly, in May of last year. We had a very significant meeting with the FDA. They gave us the clarity. We don't need to gain that clarity again. We had it. And they were clear about what the expectation was. And that expectation we've described here, reasonable prediction that a surrogate endpoint would predict functional benefit and functional benefit that would make a difference for patients who would be clinically meaningful.
And I think if you look across this data set, typically with a surrogate endpoint, you're expecting functional benefit at some point at a later stage, long-term. We're seeing functional benefit clearly at six months so far. So that puts us in a good place, I think, to go forward with our plan and the expansion registration cohort we described, which was always part of the plan with the AG protocol. Now, in terms of further interactions, we mentioned that we had an interaction recently with the FDA and DMD. I would anticipate us having another interaction with the FDA in terms of an end-of-phase two type of interaction for DM1.
Part of the expectation, as you know, with accelerated approval, is that you conduct a confirmatory trial. And with this data that we have from ACHIEVE, the fact that we're seeing functional benefit, and as Doug was talking about, powered for vHOT and also reasonably powered to see trends in other functions, we'll see what that data ends up telling us, but it puts us in a position to be getting an approval with a variety of functional benefits. And then with a confirmatory trial, we can further expand over time with a longer trial, the kinds of functions that we could even strengthen a label and provide more data. That would be a discussion we want to have with the FDA this year.
Okay. Great. And then just one quick follow-up. Can you just clarify what recent means in regard to your interaction with the FDA around Dyne-251? Just clear up the timing on that. Thanks.
Yeah. So I mean, we're talking in the last two months, let's say. Even less. For DMD. You're asking about DMD, right?
Yes .
Yeah. So recent was very recent. It was very recent.
Okay. Great. Thank you so much.
Thank you. I'm currently showing no further questions at this time. This does conclude today's conference call. Thank you for your participation. You may now disconnect.