Good day and thank you for standing by. Welcome to Dyne Therapeutics Update on DYNE-101 for myotonic dystrophy type 1 conference call. At this time all participants are in listen only mode. After the speaker's presentation, there will be a question and answer session. To ask a question during the session, you will need to press star one one on your telephone. You will then hear an automated message advising your hand is raised. To withdraw your question, please press star one again. Please be advised that today's conference is being recorded. I would now like to hand the conference over to your speaker today, Mia Tobias, Investor Relations.
Please go ahead.
Good morning everyone. I'm Mia Tobias with Investor Relations. Thank you for joining us for today's event to review our updated plan for accelerated approval and new long term clinical data for DYNE-101 for myotonic dystrophy type 1. 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 first provide an overview of our recent regulatory progress and updated plan for DYNE-101 as well as our new long term clinical data. Dr. Doug Kerr, Dyne's Chief Medical Officer, will then review our development plan and latest clinical results in more detail. John will provide some closing remarks and then we'll open the call for Q& A. Our CFO, Eric 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 excited to share our latest advances by providing an update on our plan for obtaining accelerated approval for DYNE-101, sharing new long term data, and announcing an important regulatory achievement for our DM1 program. Let me start with the regulatory achievement. We are extremely pleased to share that following the Type C meeting with the FDA in May, the Agency granted Breakthrough Therapy Designation to DYNE-101 in myotonic dystrophy type 1. This designation is a testament to both the significant unmet need in DM1 and to the strength of our clinical data indicating that DYNE-101 has the potential to provide substantial clinical benefit to individuals living with DM1.
Second, during the FDA Type C meeting we discussed the appropriateness of vHOT, a measure of myotonia, to serve as an intermediate clinical endpoint for accelerated approval. The FDA agreed that the next step toward accelerated approval was to submit for review a revised protocol for the ongoing registrational expansion cohort of the ACHIEVE trial with vHOT as the primary endpoint, and that revision was submitted this month. I would like to provide you with more detail on this change in the primary endpoint. Our updated clinical plan now includes the use of an intermediate clinical endpoint for accelerated approval. An intermediate clinical endpoint, like a surrogate biomarker endpoint, is uniquely available to the accelerated approval pathway and is defined in the regulations as having the potential to detect a drug effect earlier than other clinically meaningful endpoints and is a measure reasonably likely to predict clinical benefit.
Previously, our regulatory approach leveraged splicing correction as measured by CASI- 22 as a potential surrogate biomarker for accelerated approval. Although this approach is still viable, based upon our most recent engagement with the FDA, it became apparent that pursuing a novel molecular biomarker as the primary endpoint will require additional qualification work and time. I want to be pragmatic. Based on FDA feedback and supported by our new long term results which we are sharing today, we determined that leveraging vHOT as an intermediate clinical endpoint is a more optimal path to accelerated approval. To recap, our previous protocol used CASI as the primary endpoint and vHOT as the first secondary and now we have simply switched the order of these two endpoints. Another pragmatic update is that we have increased the number of patients in the registration cohort to 60, resulting in enhanced.
Power for vHOT and an increased ability.
To demonstrate trends on other functional measures. Critically, we can make all of these updates to the registration expansion cohort seamlessly with no impact to ongoing enrollment and dosing. Lastly, moving on to our new data, these results out to 12 months reinforce the compelling profile of DYNE-101 as a potentially transformative treatment for DM1 and support our updated regulatory approach for accelerated approval. As Doug will review in more detail, myotonia is a common early symptom of DM1. With DYNE-101 treatment, we saw robust improvement in vHOT as early as three and six months. The new long term data you are about to see support improvement in vHOT as an early indicator of clinical benefit.
These new clinical data at the 6.8 mg/ kg registrational dose show early and sustained improvement in vHOT as well as robust longitudinal improvement across multiple measures at both 6 and 12 months. For example, strength as measured by QMT improved by approximately 10% at 6 months and by 20% at 12 months. Very importantly, we also continue to see a favorable safety profile with FDA Breakthrough Therapy Designation, a revised protocol for accelerated approval and positive efficacy and safety results out to 12 months. We feel confident in the updated plan to deliver functional improvement to the DM1 community with a potentially best in class medicine.
As I just mentioned, we have already submitted the revised protocol for the Registration Expansion Cohort of ACHIEVE to the FDA and we intend to leverage data from this cohort along with data from the MAD and long term extension portions of ACHIEVE for a potential submission for accelerated approval in late 2026. Before turning it over to Doug, I want to reinforce that all of us at Dyne are determined to rapidly and effectively advance in treatment to deliver meaningful functional improvement to the approximately 40,000 Americans living with DM1 in this first phase of our global plan for DYNE-101. Now I will ask Doug to outline our updated plan for accelerated approval and how our 6 month and new 12 month clinical data support that plan.
Doug, 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 almost always includes myotonia, which is a failure of relaxation of muscle after contraction, as well as muscle weakness, cardiac dysfunction, respiratory weakness, and CNS manifestation. There are no approved therapies to slow, let alone stop or reverse, the progression of this disease. 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. You've seen this slide before, so I'll be brief. The central pathobiology of DM1 is that it is a spliceopathy, meaning misplicing of key genes due to DMPK.
DYNE-101 utilizes a TfR1 Fab to deliver efficiently to tissues relevant to DM1, including muscle and importantly the CNS, and the ASO payload uniquely gets into the cells and nucleus. DYNE-101 knocks down DMPK in the nucleus with the goal of restoring a more normal splicing pattern. As shown in the appendix of today's presentation, DYNE-101 treatment resulted in durable splicing correction with data now out to 11 months. In addition, a revised approach using a median of samples will help mitigate the low risk of intra-patient sample variability as we saw in the six-month results, and this methodology we will use moving forward in the ongoing registrational expansion cohort. As we have stated previously, the consistent impact on splicing correction is one of the key points of differentiation for DYNE-101 and a core reason to believe in our mechanism of action.
Given that splicing abnormalities are central in the pathobiology of DM1, our initial focus for potential accelerated approval was to leverage.
CASI as a surrogate biomarker.
However, as John mentioned, based on our most recent interactions with the FDA, we believe a more optimal regulatory path would leverage improvement in myotonia as measured by vHOT as an intermediate clinical endpoint by making it the primary endpoint in the ACHIEVE Registrational Expansion Cohort. Although the FDA agreed that splicing correction is core to the disease and could potentially serve as a surrogate endpoint, it would have required more work. On the other hand, vHOT is an objective clinical measure and our data, in particular our new 12 month results, support improvement of myotonia as an early indicator of clinical benefit with DYNE-101. Now let me tell you how we plan to leverage vHOT in our path to potential accelerated approval. We have submitted the revised protocol for the registrational expansion cohort of the ACHIEVE trial.
As a reminder, the multiple ascending dose portion of ACHIEVE is complete and as of January all cohorts have been escalated to 6.8 mg/kg Q8 week. In the long term and open label extension portions of the study, we have elevated vHOT at six months to the primary endpoint and secondary endpoints include CASI, muscle strength as measured by QMT, the 10 meter walk run and the five time sit to stand timed function tests, and the MDHI patient reported outcome which captures multiple aspects of the disease that matter to patients, including CNS manifestations which we believe DYNE-101 is uniquely positioned to address. We have increased target enrollment to 60 participants to further enhance our powering to meet the primary endpoint and our ability to show trends on the secondary endpoints.
As a result, we are adding additional sites including in the U.S. in order to facilitate rapid enrollment. In addition, as it relates to vHOT, it's important to note that across the 56 patients in the MAD portion of ACHIEVE the average baseline value was 9.2 seconds and we would expect the average vHOT baseline value for the 60 patient registrational expansion cohort to be similar with 60 participants. We now expect to complete enrollment in Q4 this year and data from this cohort is planned for mid-2026. Let me now review in more detail why we believe vHOT is an appropriate endpoint to support accelerated approval. As we all know, accelerated approval allows the FDA to approve drugs for serious conditions with an unmet medical need based on either a surrogate or an intermediate clinical endpoint.
As John described, an intermediate clinical endpoint is a measure of the therapeutic effect that is considered reason likely to predict the clinical benefit of a drug and has the potential to detect a drug effect that may predict clinical benefit earlier than other endpoints showing clinical benefit. Our data from ACHIEVE, in particular our most recent 12 month results for the 6.8 mg/ kg cohort, support improvement in vHOT as an early indicator of clinical benefit with DYNE-101. In addition, the sustained improvements across multiple clinical endpoints we observed at 12 months give us further confidence in the six month results, which is the time point for the primary analysis in the registrational expansion cohort and what we plan to use in support of a potential BLA.
Submission for accelerated approval.
Lastly, we are excited to see a continued favorable safety profile for DYNE-101 which is critical for both regulatory approval and potentially for commercial differentiation. In the next few slides I'll walk you through the justification for our updated.
Plan for accelerated approval.
Let me now discuss why we believe our data support vHOT improvement as an early indicator of clinical benefit for DYNE-101. We have seen robust improvement in vHOT across multiple doses and time points, showing not only an early effect but by six months in the 6.8 mg/ kg cohort, an improvement of almost 40% relative to baseline. This improvement was also associated with improvements in other endpoints such as QMT, timed function tests, and the MDHI here shown at 12 months. These data make the case that DYNE-101 improves myotonia at six months with associated improvements from baseline across four different and diverse clinical measures at 12 months.
Beyond the data on these plots, we conducted an additional assessment and found that all patients at the top three doses who improved in vHOT at six months also improved in muscle strength five times sit to stand and or the 10 meter walk run test at 12 months. Let's now get into the detailed data demonstrating that the new 12 month results bolster our confidence in the compelling data we had previously shared at 6 months. Here you can see how treatment with DYNE-101 led to rapid improvement in vHOT as early as 3 months, continuing to deepen at 6 months and with a sustained effect at 12 months, providing further conviction in the 6 month results. Although improvement in vHOT may be an early indicator of clinical benefit, our goal is to provide broad functional improvement for patients far beyond myotonia.
Let's look at what else we've seen in terms of clinical endpoints. Now, unlike vHOT which focuses on a single finger, here we are looking at QMT which offers a more comprehensive perspective on patient function, specifically strength. A composite QMT score in DM1 combines measurements from several key muscle groups such as hand grip, elbow flexion and extension, ankle dorsiflexion, and knee flexion and extension. This approach provides a more holistic view of muscle function than assessing individual muscle groups in isolation. Strength gets better at three months and deepens further at six and 12 months. It's worth noting that we were very pleased with the six month results demonstrating an improvement of 5.2% predicted normal when compared to baseline.
We were even more impressed when we saw these 12 month data reaching an improvement of 10.3% predicted normal compared to baseline, which represents an unprecedented 20% relative improvement in muscle strength. Moving on to the next slide which shows improvement in two important functional measures. The ultimate goal of a treatment for DM1 is to improve how patients feel and function and these time function tests offer a view on a patient's ability to perform important activities of daily life such as walking, standing and climbing stairs. The 10 meter walk run and the five times sit to stand tests assess functionality reflecting lower limb strength and also stamina and balance. Here again we see sustained improvement from baseline out to 12 months compared to a worsening on placebo and again these data increase our confidence in what we are seeing at six months.
Another measure of how patients feel and function is the MDHI patient reported outcome. MDHI is a composite patient reported outcome in DM1 consisting of 17 subscales across multiple domains including myotonia, strength, function and CNS related manifestations. It was developed to capture the totality of the burden of disease from the patient perspective. We previously reported a robust 44% improvement from baseline in MDHI at six months at our registrational dose and we were excited to see a further deepening of effect at 12 months which again gives us even greater confidence in the effect and demonstrated at six months. Having treated hundreds of individuals living with DM1, I never thought that there would be a day when patients would report such substantial improvement across a variety of domains. I believe these data indicate that DYNE-101 has the potential to become a truly transformative therapy.
As we said before, we believe a key differentiator for DYNE-101 is that it delivers to the CNS, potentially enabling an impact on other critical aspects of the disease. I'll show now the benefit we saw on six subscales measuring CNS manifestations which are a significant burden for many patients living with DM1. Let me draw your attention to the sustained improvement out to 12 months in these CNS related measures. We continue to see improvements from baseline across the subscales of cognitive impairment, sleep, fatigue, communication, emotional issues, and pain. Now turning to safety. What you are seeing here is our standard reporting of safety but now updated to April 23rd of this year and the important thing is that there is really nothing new here. Approximately 1,000 doses of study drug representing 93 years of patient follow up and there are still no serious related TEAEs.
As a reminder, our FORCE platform utilizes a Fab that is designed to minimize disruption to the TfR1 receptor to maximize the therapeutic index. Although transient anemia can occur in any patient due to phlebotomy, we have been closely monitoring for persistent anemia with DYNE-101 and notably we have seen no evidence of persistent related anemia to date. Overall, we are building a substantial body of evidence supporting a favorable safety profile for DYNE-101. Before I hand it back to John, let me briefly summarize the rationale for leveraging vHOT as the primary endpoint too.
Support potential accelerated approval.
Myotonia is an early and common sign of DM1. This is the first symptom reported for 38% of patients and is prevalent in 88% of patients. Overall with DYNE-101 we have shown a robust improvement in vHOT as early as three months. In fact, at both three and six months we see the greatest magnitude of change in vHOT as compared to any other functional endpoints relative to baseline. Lastly, the long term data presented today further support improvements in vHOT as an early indicator of clinical benefit for DYNE-101 as defined by the plots on the right which show that improvement in myotonia was associated with later improvement of multiple other functional endpoints.
Shown here is a summary of the comprehensive development program for DYNE-101 starting with the successful MAD portion of ACHIEVE followed by the ongoing registrational expansion cohort and next into a confirmatory phase III study which we expect to initiate in the first quarter of next year. We continue to finalize the design of the phase III study based on a thorough and productive discussion with the FDA in the Type C meeting. We are also engaging with regulators outside the U.S. with the aim of harmonizing feedback and finalizing a design that meets the confirmatory requirements in the U.S. and supports submissions globally. Additionally, for the phase III, we are keenly focused on an endpoint strategy that captures the holistic and broad impact of DYNE-101 beyond myotonia.
In order to maximize our clinical and commercial differentiation across both the accelerated approval and confirmatory phase III portions of the clinical development program, we will leverage the Breakthrough Therapy designation to continue to engage with the FDA as we advance DYNE-101. As a scientist and especially as a physician, I am truly humbled by the opportunity to deliver this potentially transformative therapy to the DM1 community in the U.S. and eventually other geographies. Let me turn it over to John for closing remarks.
Thank you, Doug. We're very pleased with where we are in the development of DYNE-101 and delivering on the promise of functional improvement for the DM1 community. What are the key takeaways from today? As you just heard, Breakthrough Therapy designation gives us the opportunity for enhanced engagement with the FDA, de-risking our development plan. Following the Type C meeting, we moved diligently and submitted a revised protocol to the FDA. We increased the number of participants in the registrational expansion cohort to increase the power and further support our accelerated approval plan and are adding clinical trial sites in the U.S. to support rapid enrollment. Critically, we are implementing these updates without impacting the current progress in enrolling and dosing patients in the Registrational Expansion Cohort.
Our most recent data demonstrating longitudinal functional improvement give us increased confidence in the profile of DYNE-101 and the appropriateness of vHOT to serve as the primary endpoint in our registrational expansion cohort. We have set clear timelines based on our updated plan and are focused on execution as all of us at Dyne drive toward complete enrollment, generating data and a BLA submission for U.S. accelerated approval. As a company, we are building momentum toward two potential launches in 2027, starting with DYNE-251 in DMD in the early part of that year, followed by DYNE-101 toward the end of that year. While not the focus for today, it's important to remember that there is enormous unmet need in DMD globally. Even in the U.S., individuals with DMD are underserved or unserved by currently approved treatments, including individuals with mutations amenable to exon 51.
Skip it. Given the unprecedented DYNE-251 data presented earlier this year, we believe we have the opportunity to deliver a reducible DMD therapy demonstrating clinically meaningful and sustained functional improvement with a favorable safety profile. As a reminder, the registrational expansion cohort for DYNE-251 is fully enrolled and we are on track for planned data from that cohort late this year. Operationally, we believe the launch sequence and spacing for DYNE-251 and DYNE-101 will allow for an efficient and effective rollout, leveraging a rare disease sized commercial team with synergies across DMD and DM1 call points. We look forward to the critical upcoming data readouts later this year and next year to enable potential submissions for both products in 2026. A few final comments before closing.
As you will note at the bottom of this slide, we are pleased to be narrowing our cash runway guidance into the fourth quarter of 2026 versus previous guidance of second half 2026. This has been accomplished through a diligent refinement of our financial projections led by our new CFO Erick Lucera, whose expertise will be invaluable as we prepare for potential commercialization.
Now I guide you to the top of the slide.
First and foremost, we are on a mission and remain unwavering in our commitment to delivering functional improvement to those living with neuromuscular diseases. In DYNE-101 and DYNE-251 we have two impressive late stage assets and registrational cohorts, both with near term value drivers. Further data from our clinical and preclinical programs demonstrate that Dyne's platform is truly differentiated and addresses one of the most significant biological challenges in biotech, effectively and broadly delivering therapeutic payloads to target tissues. Dyne has evolved significantly over the last 12 months to ensure we have the right team in place as we approach our first potential launches in 2027. Today our leadership team has the experience and expertise to take Dyne to the next level. Said differently, we are building an organization that not only believes in its mission, but one that has the culture, capabilities and drive to achieve that mission.
Our North Star is delivering functional improvement for those suffering from neuromuscular diseases and in doing so we hope 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. With that, we will open it up 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 Gavin Clark- Gartner with Evercore ISI. Your line is now open.
Hey, guys, congrats on the additional data and all the progress here. I just wanted to ask one specific question on vHOT. I believe the data on slide 13 is showing the raw data. And then with the chart on slide 11, you have the MMRM analysis which does reduce the variability in the data. I just wanted to confirm that you're still using that MMRM analysis in the registrational cohort and ask if you discuss this with the FDA. Thank you.
Doug, do you want to tackle that?
Yeah, sure. So you're correct. Slide 11 is the least squares mean MMRM, whereas slide 13 is the simple raw change. We are using this in the Registration Expansion Cohort. This is a standard methodology and it's exactly what we will use going forward.
Can you share any of your powering analyses and where the additional patients put you in terms of vHOT power?
Yeah. What I'd tell you, Gavin, is we have looked at this very clearly. We've increased the sample size, we've gone through this with very conservative estimates in terms of the effect size that we will see, the variability around the measure and the methodologies.
We're very comfortable.
We're fully powered for vHOT in the Registration Expansion Cohort. Great.
Thanks, guys.
Thank you. Our next question comes from the line of Paul Matteis with Stifel. Your line is now open.
Hey, thanks so much for taking my questions. I hope you don't mind if I ask a few. I guess taking a step back here, I think one of the challenging things for investors to try to make sense of is the reality that you guys are using vHOT for accelerated approval. There is another company in the space that's running a larger phase III study looking at vHOT for full approval, and we're all trying to reconcile that. I would be curious if you could kind of just give context around your update in the context of the broader space. Secondarily, I guess, do you guys not view vHOT as an endpoint that could allow for full approval? If not, what's that based on? What do you think might be the right endpoint for full approval? Thank you so much.
Yeah, Paul, thank you. We had a little static, but I think I got your question. First of all, let me say this. From the standpoint of context, it's a change. We acknowledge it. It's a switch from a novel surrogate molecular marker to an intermediate clinical endpoint. That's a change. I think if people step back for a minute, they'll appreciate that. Overall we reduced the risk with the accelerated approval. With only a slight shift in timelines, a few key points, we've maintained the accelerated approval path as our primary strategy to get to the market significantly faster than full approval. We're using vHOT as the primary endpoint for accelerated approval, which removes a lot of concerns that some people had with using a novel surrogate biomarker as the primary.
Critically, vHOT also appears to be a very promising early indicator, as you saw from the data that Doug just presented in predicting or likely predicting clinical benefit, which you saw over six and 12 months, which is the definition required for accelerated approval. I would say, you know, in contrast to your question about primary endpoint for traditional approval, you've got to demonstrate clinical benefit with the primary endpoint for traditional approval. We think for that purpose and clinical meaningfulness, there will be other endpoints beyond vHOT for our phase III that may be more representative of clinical benefit. Time function test as you just saw, the strength data with QMT was really remarkable. Our five time sit to stand is very important for patients. Doug is really right now thinking through the different options.
The beauty of the data we presented today, you can see that we have multiple options to provide an endpoint that is truly clinically meaningful and beneficial to patients. We think that would really differentiate us. In terms of phase III and a couple other points, I think the breakthrough designation is huge. That gives us. It came out after we had the meeting. It gives us an opportunity to have further engagement around that topic of future endpoints for a phase III and maybe just a couple other quick points. As you know, we've been adding. We decided to add some U.S. sites. People asked about that, we increased the sample size and as Gavin was asking about powering, it gives us robustness, even more powering and robustness vHOT.
It gives us a great opportunity to also show that we have strong trends in these other functional benefits longitudinally, which we want to do. Finally, this latest clinical data, at the end of the day, is really strong both in terms of efficacy and safety. That's a bit of the context and also a bit of how we think about the phase III implants.
Thanks, John.
Appreciate it.
Thank you.
Our next question comes from the line of Andrew Tsai with Jefferies. Your line is now open.
Hey, good morning.
Congrats on the breakthrough designation and the.
Regulatory achievement with the FDA. As we think about your accelerated approval strategy, you said it was more.
Pragmatic to switch to vHOT because splicing would require more qualification work and time. When would the splicing work be done?
Exactly, because it will still be a.
Secondary endpoint of yours when you report the data.
Could it be done by the time of top line data actually? And then is splicing, is it truly being quote unquote downgraded to a secondary endpoint? Because this was your prior strategy, the.
Data did look differentiated or does look differentiated. I just wanted to ask more about that. Thank you.
Yeah, thanks, Andrew. Nice to hear from you. I know we've had plenty of conversations with you on this topic. Yeah. The splicing correction, you've seen some of the data and we have data in the appendix that shows that the splicing correction is still highly supportive of the underlying pathobiology and the mechanism of action of our drug. We think that will play out over time and that that will be appreciated by regulators in the U.S. but also throughout regulators globally. We're going to continue with it. I mean, you can call it a downgrade.
I think of it very much as kind of a switch and we will submit that as a secondary and we can continue to do work on qualification of that assay and so on. But frankly, going forward we've got an intermediate clinical endpoint that we believe in and we think the data, particularly as we've added now, and you saw what we introduced, the 12 month data being predictive of kind of sustained long term meaningful effect, really puts us in a good, a good place. So CASI continues to tell us about the underlying pathobiology. I think we're the only ones that will have both that underlying pathobiology being confirmed by CASI as well as vHOT being an indicator of clinical benefit over time.
Makes sense.
Thank you again.
Thank you.
Thank you. Our next question comes from the line of Ry Forseth with Guggenheim. Your line is now open.
Good morning. This is Ry on for Debjit. Two questions from us. Number one, does the 101 accelerated approval pathway change if Avidity files for full approval ahead of Dyne? And the second question is related to.
vHOT for the expansion cohort, what is the clinical team doing to ensure baseline?
What time is optimized? Say approximately 9 seconds for robust signal detection. Also, is there any alteration to a standardization of measurement to control for confounding environmental factors that affect myotonia?
Let me start with the first one and I'll touch on the second and then let Doug add a few points. In terms of full approval, accelerated approval, I do want to make it clear that our accelerated approval approach.
It.
Allows for speed, but it is very much a robust, data-driven type of analysis. Keep in mind that we're going to have 60 patients in the Registration Cohort, which we will have data on, submitted with all these different measures that you just saw us present. The time function test, MDHI, CNS subscale measures. We'll also have 50-plus patients from the multiple ascending dose that have been dose escalated. So we end up with a very robust set of data that gets close to 110-120 patients. We think that puts us in a good position whether you call it accelerated or full.
Now, from the timing standpoint, I think regardless of if Avidity gets full approval, this is a field with unmet need and if there's unmet need, then the FDA is fully at an opportunity to give us a grant accelerated approval, that would be their call. The fact that we've been having these conversations and that the FDA has been open to this approach, I think is a positive signal for us. I'll leave it there with that one. On the vHOT question and baseline, I'll just remind you that one of the reasons we're at 60, we picked 60, is that if you look at the 56 patients, just the way the patients are characterized, the way the patients are screened and the way we, the patients that enter this study, we end up with a baseline on average of about 9.2 seconds, I believe.
Right. That puts us in a pretty good spot and we're at the 60 again. We think with all those kind of conditions it puts us in a place that we should be in a good place from a baseline standpoint. Great.
Thank you. Our next question comes from the line of Kostas Biliouris with BMO Capital Markets. Your line is now open.
Thanks for taking our question and congrats on the data.
A couple of questions from us.
Can you clarify what percentage of patients?
Improved on vHOT versus baseline at six months? I think the plot is on slide 11.
The second question is, can you.
Also clarify what improvements exactly the FDA will require for accelerated approval improvement in the secondary endpoints. If they had defined which secondary endpoints need to also show improvement and whether these improvements need to be statistically significant or not. Thank you.
Let me start with the second one. I want to think about the first one for a second. But listen. Nice to hear from you. For accelerated approval to be clear, statistical significance on the secondaries is not required. That is one of the, you know, having the bar be that you need to hit trends and across measures is appropriate for us. Now, whether it is three or two or one, that is in the eyes of the FDA, they can make the judgment on that.
From a regulatory standpoint or a guidance standpoint, all we have to do with expedited approval is show statistical significance on our primary and then show that we are reasonably predictive of improvement on other measures. You can see that we have clear improvement, really clear improvement and significant improvement across multiple measures just on the data that we've shown you today. I think we're in a very good position to meet the bar for the accelerated approval requirement. Now the vHOT question.
Let me just make sure I understand the question. Slide 13 is showing the change in vHOT over six and twelve months. That is the raw analysis. You can see the numbers there on the slide. Slide 11 reflects the more sophisticated analysis that we will use going forward, which is the MMRM to account for baseline and intra-patient variability. I'm not sure I got the entirety of the question. We will provide some more data at a later point if that would be helpful.
My question was whether 100% of patients improved on vHOT versus baseline or there is a percentage of patients that did not improve versus baseline at six months.
Thank you.
Yeah, we haven't given individual level data on changes over time.
We'll do that at a later point.
Thank you. Our next question comes from the line of Mike Wolf with Morgan Stanley. Your line is now open.
Good morning. Thanks for taking the question. Maybe just another follow up on the confirmatory study. Can you just comment on some of the endpoints you're considering and if you're.
Planning to sort of wait for some.
Additional data there to help inform that decision. Are you thinking about a 12 month endpoint? Thanks.
Yeah, why don't Doug, you're the man working through that.
I mean we are looking to globalize regulatory feedback from around the world. We do not know exactly what that is going to look like. That is going to start in Q1 of 2026. The strategy though is to demonstrate broad benefit of DYNE-101. We can tell you that that primary endpoint will not be vHOT. There is a series of other ones that we are working through, harmonizing with global regulators, and we will get back to you on the exact details of that.
Thanks.
Thank you. Our next question comes from the line of Brian Skorney with Baird. Your line is now open. Brian Skorney, your line is open. Please check your mute button.
Thank you.
Sorry about that. Thanks for taking the question.
I'm just noticing in the appendix, you.
Have some new CASI 22 data with 11 month analysis and also a new revised approach to the assay. Can you walk through sort of single aliquot vs median of multiple aliquot? When I look at the data, it doesn't jump out to me that there's an additional benefit on the 6.8 mg/ kg versus 3.4 mg or 5.4 mg.
Can you just review.
Was that discussed at all with the FDA?
Why?
Given the totality of data, the 6.8 mg/ kg dose is the right dose to move forward in pivotal.
Yeah, let me start on this one. You know, we wanted to be transparent with the CASI data because you recall that some folks. We transparently presented, I think back in January, that we'd had a six month data point that had a couple of outliers and there have been some analytical issues with that and we explained it. Some of you wondered, is it really an outlier or will you see reasonable results when you take your next 11 month sample? You can see that. I think we've confirmed that that one data point from six months, from the six months, was indeed an outlier. The CASI scoring confirmed the underlying pathobiology.
Once again, I'll just say in general, Brian, we had used CASI as a very meaningful way to determine an optimal dose. It guided us. I think I've said to people before, if we hadn't used CASI, we could have stopped at a low dose because we saw effect, we saw vHOT, but with CASI we wanted to get to about a 20% correction. We had gotten there at 5.4 mg, we'd gotten there at 6.8 mg. I would remind you that what we saw importantly at 6.8 mg was that in the MDHI patient reported outcome, there were subscales, the six subscales that Doug has now highlighted again, that we highlighted at six months had made a dramatic shift in improvement across those subscales. Every single one of those. Doug had at that time had said, man, this is telling us we may be getting to the CNS.
CNS is a huge issue for these patients. Our drug was designed to get to the CNS and so we're going to pick the 6.8 mg, which has given us an opportunity potentially to penetrate the CNS. Now we've seen at the 12-month data that that CNS apparent effect on MDI has held up. We haven't had further discussions about that data necessarily with the FDA, Brian, if that was your question. In terms of selecting dose, if anything, the 6.8 mg/ kg data thus far and the fact that it's kind of extended out to 12 months makes us feel really good that we selected.
The right dose, only to add that the safety profile is also very good. We are very comfortable with the safety across 6.8 mg. We have seen nothing that would dissuade us from that dose. You know, John mentioned the MDHI and the totality of that measure showing a robust benefit both at 6 and 12 months, QMT as well. The data that we shared with you today really argues for, I think, 6.8 mg as the most compelling dose.
Thanks for the question, Brian.
Thank you. Our next question comes from the line of Edward Tenthoff with Piper Sandler. Your line is now open.
Great, thank you. Good morning and thanks for updating 12 month data and changes to ACHIEVE and congrats on Breakthrough Therapy designation. Kind of a follow up on those comments. You ended with this CNS benefit as potential benefit differentiator from the competition. What kind of magnitude difference are you anticipating showing here? And is this something that you think could actually get into the list? I mean certainly it's something that patients and physicians will see in the real world. But you know, is this something that you think could actually be expressed in the label? Thanks.
Let me start with the initial comment, Ed, nice to hear from you. I think you know very well that if you talk to clinicians they will almost invariably bring up a significant portion of the patients. Their biggest issue with CNS.
The FDA has been clear with us that getting to a patient reported outcome and something that is meaningful to patients, particularly in this phase III is what they want to see. The MDHI data you saw in that six month data, a number of those measures have moved by something like 40% improvement. And then you saw it again in the total numbers out to 12 months. That data holds up. I would think we would expect that to make it to the label. Now that's an FDA call, but we certainly hope it would because you know, as I just said, this CNS issue is a really meaningful issue. I'll remind you that I know you followed us for a long time. I mean this, this platform was specifically designed with a Fab to be able to enter the CNS and to be.
Able to deliver high levels of oligo.
In a way that would potentially hopefully not cause anemia. In other words, be safe. Now we're seeing that if we deliver at 6.8 mg, we're seeing these kinds of signals around the CNS. That's very, very important to us and to patients.
Great.
Thanks, John. Thank you. Good.
Our next question comes from the line of Martin Auster with Raymond James. Your line is now open.
Congrats on the update. Thanks for taking the question.
Just curious if you could address as.
You're preparing for accelerated approval filing towards late 2026, if you could talk about any additional sort of major CMC work that needs to be completed or any other clinical or nonclinical studies that will need to be conducted ahead of that. Thanks.
Yeah, I was having a little trouble hearing but I think you said additional CMC and other things for preclinical. Listen, I think we're on track with all aspects of what we need to do for a submission. You know, CMC, we've got our activities related to validation and also future scale up for commercial launches. All of that is moving and all on track. I think our preclinical, same story, everything is where it needs to be. We believe so. Anything we need to add to that?
I don't think so.
I don't think so. I think that, you know, I'm glad you're asking the question about launch or being ready for that because that's how our mind is. That's what we're geared for. When you think about this program and DMD, both of these programs we're targeting launches in 2027. That is right around the corner and we're launching into markets where there is such significant unmet need. We're spending plenty of time on CMC and supply planning, I can assure you.
Thanks John.
Thank you. Our next question comes from the line of Luca Issi with RBC Capital Markets. Your line is now open.
Oh great. This is Shelby on for Luca and thanks for taking the question. Circling back on a prior question, what is your take of the recent PepGen data showing a pretty meaningful benefit in vHOT for placebo. I guess the question is, given that vHOT can be fairly variable, what gives you confidence that your phase three is powered conservatively enough to hit the stats, especially given your competitor has a much larger trial. Any color there.
Much appreciated.
Thanks.
Let me just comment a bit on, you know, in terms of vHOT and the powering. I know people have been kind of comparing the number of patients. I think if you do, Shelby, many of you will do this if you kind of look at the data we've made available and you do your own analysis and stats work. We don't need 100+ patients to hit on vHOT. I don't know why anybody does, unless you're trying to hit on other measures as well. I think we can stand pretty firmly behind the fact that we felt that we had good numbers even at 32-48, and furthering that to 60 to be even more conservative, more robust made a lot of sense to us.
I don't have a comment on the PepGen data at this time, but I think we stand behind where we are on vHOT. And we see, as you can see from our data, we've had meaningful early improvement on vHOT, which we think is consistent with what we're trying to accomplish with AA. Thank you for the questions .
Got it. Thanks.
Our next question comes from the line of Louise Chen with Scotiabank. Your line is now open.
Hi, this is Hannah Liu. I'm on for Louise Chen. So we wanted to ask you have two potential drug launches in 2027. Do you feel confident that you can successfully commercialize two drugs at once? And will you be marketing DYNE-101 and DYNE-251 to the same doctors, or how much overlap is there here?
Thank you.
Yeah, I love the question on commercialization. First of all, I mentioned in my script a little earlier about us building out our team and our leadership team. One of the key areas is on the commercial side because I think everybody on this team has launched some major rare disease drugs in their career. We know you've got to start preparing now. Last year we hired Johanna Friedl Naderer, who has launched rare disease drugs globally in the past, including SPINRAZA successfully. Our analysis and her analysis so far is that there is tremendous overlap in terms of doctors in the United States and in terms of doctors globally. The beautiful thing here is they're both rare diseases, with a lot of the same call points. We think we can do it efficiently. There is some.
There's a lot of leverage and kind of synergy, I think, financially to pull that off. We don't need a huge commercial organization to do it, but we do need a lean, efficient, smart organization to do it. We are building that. We've got the right people on top of it. I think we made a minor, another, a minor point that Eric is our CFO, has paid attention to, and that is that they're not right on top of each other. Simultaneous in terms of launch, there will be a number of months apart, same year, but a number of months apart. We can kind of stage it. I think we can do this in a very successful way and have successful launches. We're excited for that. We're looking forward to it.
Thank you. Our last question comes from the line of Tess Romero with JP Morgan. Your line is now open.
Hi, good morning. This is Caroline Pocher on for Tessa Romero with JP Morgan. Thanks for taking our questions. Just two from us. What time would you expect a response from the FDA on the revised protocol you just submitted, and in what forum? Would that be a written response or another meeting? Would there be some risk that there could be other questions or changes to the protocol? To double click here, how much power do you have based on your assumptions?
Yeah. Hi, Caroline, thanks for the questions. As a reminder, we've got the breakthrough designation that gives us a chance to have this engagement and get timely feedback. There's no kind of formal regulatory requirement in terms of timing response on our protocol, but the Breakthrough Designation by definition means you have timely interactions and responses from the FDA. I think if there's any significant change to what we're planning to do, then we can be clear about that and let people know. I think what you should plan on is what we're planning on, which is to execute without interruption. That's what we're doing, adding some U.S. sites and we'll be just simply switching the endpoints, but keeping the program going exactly as we had talked.
The second.
Half of the question.
Yeah. Just how much power do you have based on your assumptions?
Yeah. So we're not given exact kind of power calculations, but I think in terms of stats, you can see the numbers and what we've made available, it is powered for success, and we think we're quite robust on this.
Great. Thank you so much.
Thank you. I'm showing no further questions at this time. Thank you all for your participation. This does conclude today's conference call. You may now disconnect.