Good morning, everyone. I'm Amy Reilly, Senior Vice President, Head of Corporate Communications and Investor Relations at Dyne. Thank you for joining us for Dyne's Virtual Event to present exciting new data for our DYNE-101 ACHIEVE trial in myotonic dystrophy type 1, and our DYNE-251 DELIVER trial in Duchenne muscular dystrophy, which were summarized in the press release that we issued earlier today. Before we begin, 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.
For today's program, John Cox, Dyne's President and CEO, will get us started with some opening remarks. Then Dr. Wildon Farwell, our Chief Medical Officer, will review data from our ACHIEVE clinical trial and data from our DELIVER clinical trial. We will then open things up for Q&A, and our Chief Scientific Officer, Dr. Oxana Beskrovnaya, will join us for that part of the program. You can submit questions at any time using the Q&A box at the bottom of the video player. A couple of notes: You can access the presentation for today's program in the tab underneath the video player. If you experience any technical issues during the broadcast, we suggest that you refresh your browser. If that does not resolve the issue, please message via technical support chat in the bottom right-hand corner of the screen. With that, I'll hand things over to John for opening remarks.
Thank you, Amy. Today marks eight weeks since I joined Dyne, and I couldn't be more proud to be part of this team. I've witnessed the dedication to our mission, and today is another important step forward in our commitment to deliver for patients with serious muscle diseases. I was drawn to join Dyne for its commitment to rigorous science, its dedication to patient communities living with rare diseases, and the opportunity with our FORCE platform to rapidly generate a differentiated pipeline of novel genetic medicines for rare diseases. We believe the data we will present today are best in class and represent an opportunity to transform the treatment of DM1 and DMD. The data are so striking that we felt obligated to share them with the field earlier than planned.
We also have had productive recent regulatory interactions that reaffirm our strategy to pursue expedited approvals for both programs. While today we're focusing on our DM1 and DMD programs, we believe these data also continue to validate the promise of the FORCE platform to develop targeted therapeutics for muscle diseases. The team at Dyne intentionally designed the FORCE platform, choosing a Fab antibody, a clinically validated linker and then selecting payloads that match the genetic basis of the disease. What we observed preclinically with our FORCE platform is now translating into data at higher doses and longer time on therapy in two different patient populations. This builds our excitement for DM1 and DMD, as well as for the potential of the FORCE platform to address other muscle diseases through programs in our pipeline.
In these data, you will see compelling impact on biomarkers in both DM1 and DMD, and meaningful improvement across multiple clinical endpoints that truly matter to patients. In the ACHIEVE trial for DM1, we observed consistent dose-dependent splicing correction across patients at levels not reported before in the field. We also see an improvement in a variety of functional endpoints, myotonia, as well as measures of muscle strength, timed functional assessments, and even patient-reported outcomes. The safety profile for DYNE-101 is favorable, and we have fully enrolled the ACHIEVE trial through the 6.8 mg/kg cohort. The data from the DELIVER trial for DMD underscore that we have the potential to lead in the development of next-generation exon-skipping therapies, starting with DYNE-251 for patients amenable to exon 51 skipping. There remains a huge unmet medical need in DMD.
The standard of care in the U.S. is providing limited benefit, and there are no available therapies for patients in Europe. In DELIVER, at 10 mg/ kg, DYNE-251 reached a level of dystrophin expression far above levels that have been reported with standard of care and exceeded what has been reported for other next-generation exon-skipping therapies in development. We also observed earlier-than-expected trends in functional measures that are important to regulators, such as NSAA and SV95C. We believe DELIVER is the first placebo-controlled trial for exon 51 to demonstrate positive trends in functional improvement in just six months. The safety profile we have seen for DYNE-251 appears differentiating from other exon-skipping therapies in development as well as from gene therapy, and we are now dosing in the 40 mg/ kg cohort.
Given our excitement about the opportunity to make a difference in DM1 and DMD, we continue to work to advance these programs as quickly as possible and as part of our efforts to deliver potential therapies to patients globally. We plan to continue to engage with global regulators this year on the ACHIEVE and DELIVER trials, and by the end of 2024, provide an update on the path to registration for both DYNE-101 and DYNE-251. In DMD, we have confirmed that the FDA precedent for using dystrophin as a surrogate biomarker for accelerated approval remains available. In DM1, based on recent dialogue with the FDA, where we shared data from ACHIEVE, we have confirmed that the accelerated approval pathway is open, including the potential for leveraging splicing as a potential surrogate biomarker. We look forward to further discussions this year.
Now, I'd like to turn things over to Wildon to review this compelling new clinical data from both of our trials.
Thanks, John. I'm thrilled to be sharing data from our co-lead programs. We believe the breadth and depth of these data are truly differentiating. Our robust preclinical work is translating into clinical results, as demonstrated by improvement in key biomarkers and clinical assessments in both DM1 and DMD, as well as favorable safety profiles for both DYNE-101 and DYNE-251. I'll start with our DYNE-101 ACHIEVE trial in DM1. Today, we are reporting higher dose data at longer time points. We are seeing a consistent, robust impact on splicing, deepening improvement in myotonia, and an impact on several clinical endpoints important to people living with DM1. First, a quick review of myotonic dystrophy type 1 or DM1. This is a devastating disease with no approved treatments. As recognized by the FDA, DM1 is a spliceopathy, a triplet repeat expansion disease of the DMPK gene.
Abnormal splicing of many genes results in a wide range of symptoms, often characterized by onset of muscle myotonia, which is the inability of muscles to appropriately relax after a contraction. DM1 patients also experience weakness and atrophy of skeletal muscles and symptoms, including cardiac conduction abnormalities, gastrointestinal and metabolic disturbances, respiratory distress, as well as CNS manifestations. For a rare disease, the DM1 population is quite large, estimated to be over 40,000 people in the U.S. and more than 70,000 people in Europe, which is similar in size to that of cystic fibrosis. To treat the genetic basis of the disease, the key is to knock down toxic nuclear DMPK RNA, which can then correct the splicing defect observed in all patients, with the goal of providing broad functional benefit to patients.
We rationally selected a single-stranded ASO as our payload for DYNE-101 because we know from our data and the literature that ASOs preferentially traffic to the nucleus. Here you see a quote from Sarah, who's living with DM1, and it really underscores how devastating the disease can be. Sarah says, "Every muscle in your body, but also your brain, cognition, your stamina, and your endurance are impacted by this disease." DM1 is a complex, multi-symptomatic disorder, and we are developing DYNE-101 to address these various manifestations with the goal of stopping or reversing disease progression. Moving on to our ACHIEVE trial. Before we go into detail on the data, I want to review the study design. ACHIEVE is a global trial, and we designed it to be potentially registrational. It includes adults living with DM1 between the ages of 18 and 49 years.
The primary endpoint is safety and tolerability. Key secondary endpoints are splicing and multiple measures of muscle strength and function, and we are also evaluating several patient-reported outcomes, including both the DM1-ACTIVc and MDHI, which we are reporting today. ACHIEVE is a three-part study. There is a 6-month placebo-controlled, multiple ascending dose, or MAD portion, a six-month open label extension, and a 96-week long-term extension. Importantly, we designed ACHIEVE to be adaptive in nature so that we can optimize dose and dose regimen within the trial, all part of our effort to move as quickly as possible to advance DYNE-101. We have made tremendous progress in enrolling ACHIEVE. We have enrolled 56 participants across the 1.8, 3.4, and 5.4 mg/ kg cohorts, and most recently, the 6.8 mg/ kg cohort.
The safety profile has supported dosing up to 10.2 mg/ kg, but we have said for quite some time now that based on our preclinical work, our optimal dose is likely between the 3.4 and 6.8 mg/ kg because we would expect to see 20%-25% improvement in splicing. We believe the data you will see today reinforces just that. Here you see the dosing schedule for the active treatment arms in the MAD portion of the trial. The every four-week treatment arm received DYNE-101 every four weeks. The recovery treatment arm received two monthly doses of DYNE-101, followed by placebo in the six-month placebo control period. The every eight-week treatment arm received three monthly doses of DYNE-101, followed by a dose every eight weeks thereafter.
Therefore, the three -month biopsy occurs four weeks after three doses in both the Q4-week and Q8-week regimen cohorts versus two months after two doses in the recovery arm. In addition to the three biopsies in the MAD, an additional biopsy is taken at 11 months in the open label extension. Today, we are sharing a 12-month d ata from the 1.8 mg/kg Q4-week cohort, six months data from the 3.4 mg/kg Q4-week cohort, and three months data from the 5.4 mg/kg Q8-week cohort. Here you see baseline characteristics for these cohorts. As we noted, we have designed ACHIEVE to be potentially registrational, and to maintain the blind, we haven't broken these out by placebo or treatment arm.
Therefore, we are presenting data as a group and not on an individual basis for the muscle biopsy or functional endpoint. Overall, we believe these baseline characteristics are consistent with the general population of adults living with myotonic dystrophy. As you will recall, CASI is the measure for spliceopathy, with zero representing the level in a non-disease population and one representing the level in a most severe DM1 population. The baseline CASIs in ACHIEVE reflect that of what is seen in the natural history. We are very pleased with the favorable safety profile for DYNE-101 observed in ACHIEVE to date, which is based on 56 participants dosed through the 6.8 mg/kg cohort. We did not observe any dose-dependent increase in adverse events, and most AEs were mild or moderate in intensity.
The most common AEs were those that are reported in the general DM1 population. There were four reported SAEs, which were deemed unrelated to study drug. One participant who completed the MAD and after receiving multiple doses in the OLE, withdrew due to an adverse event of infusion-related reaction characterized by rash and fever without respiratory signs or symptoms. Liver enzyme elevations have been reported, but no impact on liver function has been observed, and as we and others in the field have noted, the interpretation is complicated by underlying disease, with DM1 patients having up to 2.5 times greater than normal for liver enzymes. Of note, there has been no persistent related anemia or thrombocytopenia. Approximately 500 doses have been administered in ACHIEVE across the MAD and OLE representing over 40 patient years of follow-up. Moving on to efficacy assessments in ACHIEVE.
Our goal for DYNE-101 is to deliver comprehensive functional improvement and outcomes that matter to patients. It starts with our ASO payload designed to deliver to muscle nuclei to drive changes in splicing, the foundational biology of DM1. These improvements in splicing can then lead to an improvement in myotonia, which is an early indicator of functional benefit. But we know that patients are looking for more. We designed DYNE-101 to go beyond vHOT and deliver broad functional improvement across muscle strength, time function tests, and patient-reported outcomes. This is exactly what we will share with you today. We believe we are beginning to see the translation from targeted delivery to splicing to an impact on clinical endpoints that matter to patients.
Our regulatory strategy reflects this promise as we pursue expedited approval based on splicing, which the FDA understands to be the foundational biology of DM1, and clinical outcomes, reflecting our commitment to advancing DYNE-101 to patients as quickly as possible. Now, starting with splicing. As I mentioned, DM1 is a spliceopathy in which mis-splicing results in a broad range of clinical manifestations. This figure here illustrates how driving this correction of splicing, lowering the CASI or the composite alternative splice index, should lead to functional improvement. We developed our approach to evaluating splicing with input from the community, natural history studies, and thought leaders such as Dr. Charles Thornton, who is also on our scientific advisory board. We measure change in splicing based on a composite splicing index of 22 individual genes, which have been shown to be involved in DM1.
We calculate percent spliced in and normalized to control, and then we compute a mean to represent the composite alternative splice index. Now to the data. First, one note on the placebo bar. You see a worsening in CASI. This is not only similar to the data we reported in January, but it is also consistent with emerging data from the natural history, showing that people living with DM1 can see a worsening in CASI over time. Now to the data for DYNE-101. We see dose-dependent delivery to muscle, and DYNE is the first to report dose-dependent, consistent correction in splicing at three months. Previously, we shared that at 3.4 mg/k g Q 4-week , all evaluable participants demonstrated a splicing correction.
That same consistency is now also observed at the 5.4 mg/ kg Q8-week cohort, with all six participants responding, representing a mean improvement of 27%. We see consistency both in the number of responders as well as in the quality of response across the 22-gene panel. In this chart, we focused on three months data because it is the only time point we have across all three doses cohort in this data cut. At six months, in the 3.4 mg/ kg Q4-week cohort, we see a similar level of splicing improvement to what we saw at three months. As a reminder, we previously shared data from the recovery arm, shown here, where DYNE-101 demonstrated continued correction of splicing two months after the last dose. We believe this supports ongoing evaluation of every eight-week dose in ACHIEVE.
Now, moving on to function. We have said for some time that based on our preclinical work, input from others in the field and the natural history, that a 20%-25% splicing correction is expected to drive functional benefit for patients. While we still have relatively small participant numbers, we believe the data we will share with you today on function reinforce our belief that changes in splicing will translate into functional benefit for patients. First, let's look at myotonia as measured by video hand opening time or vHOT. We see consistent improvement in vHOT that deepens with time on therapy. Placebo is shown in gray and is stable or worsening. In blue, you'll see the 1.8 mg/ kg Q4 week treatment group, which was our lowest dose and has the longest follow-up.
The benefit on myotonia in this group increased from 3.1 seconds at three months to 4.4 seconds at 12 months. At the higher dose, 5.4 mg/kg cohort, we observed the greatest response at the early three-month time point. As a reminder, this is also the cohort that had the greatest improvement in splicing. While all cohorts demonstrated an improvement in vHOT, we observed that the starting baselines for vHOT matter. In our 3.4 mg/kg cohort, we observed a compelling 30% improvement in vHOT at six months. This cohort had a baseline vHOT of 6.5 seconds, which left less room for an absolute improvement when compared to our other treatment cohorts.
This is what we observed in our data, a deepening improvement in the 3.4 mg/kg cohort that reached two seconds after six months. We are very encouraged by this best-in-class improvement observed with DYNE-101 in vHOT. At the same time, we realize that patients living with DM1 experience a range of symptoms beyond myotonia. Based on our dialogue with regulators, we believe that like splicing, vHOT must be linked to other outcomes that are important to patients, and we are excited to also share data on those outcomes today. Turning to measures of muscle strength as assessed by the quantitative muscle testing. Again, cohorts with the greatest splicing correction see the most improvement in strength.
Among the placebo, shown in gray, there is a general worsening, whereas the 3.4 and 5.4 mg/ kg cohorts begin to see improvement with time on therapy. Next, we're seeing encouraging data in timed function tests, the 10-meter walk, run, and 5-time sit to stand. Again, in the cohort with the greatest splicing correction, 5.4 mg /kg we see the greatest functional benefit. We are also seeing encouraging trends in multiple patient-reported outcomes. These assessments are collected at baseline, six, and 12 months. We see encouraging improvement with DYNE-101 in the DM1-ACTIVc , which assesses different activities of daily living that are important to patients, such as eating, bathing, and doing housework. We are very excited to be the first to report data showing a benefit on 17 of 17 subscales of the MDHI.
The MDHI evaluates aspects of the disease, such as peripheral muscle, both skeletal and smooth, as well as the CNS. These subscales represent broad manifestations of DM1 that significantly impact the quality of life for patients and their families. For example, with DYNE-101, we see an improvement in the MDHI myotonia subscale, which is not limited to one muscle group as reflected in vHOT, but rather represents broad patient experience across multiple muscle groups, including upper extremities, lower extremities, and facial muscles. In summary, with DYNE-101, we are the first to report dose-dependent muscle delivery, which is translating into dose-dependent splicing correction consistent across patients. We are showing meaningful improvement in broad collection of multiple clinical endpoints, including myotonia, muscle strength, timed functional assessments, and patient-reported outcomes, reflecting both muscle and CNS manifestations of the disease.
We see a deepening of response with longer time on therapy, all in the context of a favorable safety profile to date. We have fully enrolled now the 6.8 mg/ kg Q8 week cohort. We are extremely encouraged by this striking data set. We continue to be focused on pursuing expedited approval pathways based on recent regulatory feedback, and we anticipate providing an update on the path to registration for DYNE-101 by year-end. Now, moving on to our program in Duchenne muscular dystrophy, a disease many of you are familiar with. People with Duchenne lack the ability to make dystrophin, which leads to progressive muscle weakness, loss of lower and upper limb function, and eventually cardiac and respiratory failure that ultimately results in death, typically around 30 years of age.
Available therapies have demonstrated limited dystrophin production and require weekly administration due to the challenge of delivering enough active drug to the muscle. Our goal is to effectively deliver DYNE-251 to muscle to increase the production of dystrophin, offering a monthly or less frequent dosing regimen for these patients. We are focused on the opportunity to build a best-in-class exon skipping franchise, starting with DYNE-251 for exon 51. Duchenne is a 100% fatal disease. As Alan, who is living with DMD, says, "It's always a big surprise. People die so suddenly from this." So halting the progression would really change everything. People living with Duchenne need new therapeutic options that can provide meaningful benefit as they manage their disease. And in parts of the world, including Europe, there are no disease-modifying treatments available. Moving on to DELIVER and a brief overview of the trial design.
Importantly, it is a Phase I/II global trial that we have designed to be potentially registrational. Similar to ACHIEVE, the DELIVER trial consists of a 24-week multiple ascending dose, randomized placebo-controlled period, a 24-week open label extension, and a 96-week long-term extension. The trial is enrolling ambulant and non-ambulant males with DMD who are aged 4-16 years and have mutations amenable to exon 51 skipping therapy. Patients who have been previously treated with an exon-skipping therapy can enroll in DELIVER after a 12-week washout period. The primary endpoints are safety, tolerability, and change from baseline to dystrophin level, as measured by Western blot. Secondary endpoints include measures of muscle function like NSAA and SV95C, which has been accepted by the EMA as a primary endpoint within the DMD indication. We are also looking at time function tests.
In the MAD placebo-controlled portion of DELIVER, participants are randomized to receive DYNE-251 or placebo every four weeks. Open muscle biopsies are taken at baseline and six months. As we've noted, we are now fully enrolled in the 40 mg/kg cohort, and in that cohort, we have brought in a Q8-week regimen where biopsies are taken at baseline and 12 months. Now, turning to the baseline characteristics for DELIVER. Similar to ACHIEVE, given that we've designed DELIVER to be potentially registrational and to maintain the blind, we have not broken out these by placebo and DYNE-251 treatment groups. Overall, baseline characteristics are similar across cohorts and generally representative of a population of boys living with DMD amenable to an exon 51 skipping therapy.
Moving on to the safety profile, which we believe is favorable to date for DYNE-251, and based on 48 participants enrolled through the 40 mg per kg cohort, we have not seen any dose-dependent increase in reported AEs. Most AEs were mild to moderate in intensity, and many occurred around the time of infusion. Importantly, no participants have demonstrated persistent related anemia or thrombocytopenia. No kidney injury or clinically meaningful changes in electrolytes, including magnesium, have been reported, and no deaths or withdrawals have occurred. With approximately 480 doses administered in over 35 patient years of follow-up, again, a favorable safety profile has supported dosing up to 40 mg/k g. Now, let's turn to muscle delivery. Here, we see DYNE-251 drove dose-dependent increase in PMO muscle concentration. We also saw a dose-dependent increase in exon skipping.
Here, you also see that 10 mg/ kg of DYNE-251 resulted in nearly 2% exon skipping. We are particularly enthusiastic about the dystrophin data, as measured by Western blot. We are seeing greater than 10-fold higher dystrophin levels at six months than have been reported for eteplirsen, the current standard of care for exon 51, with 12-fold lower PMO dose administered four times less frequent. At the 10 mg/ kg dose, DYNE-251 reached 3.2% normal dystrophin, a change of nearly 3% from baseline. This dystrophin analysis is unadjusted for muscle content, and we believe this is an appropriate evaluation of dystrophin. These data are quite striking. However, we know that others in the field have adjusted for muscle content, so we have done that analysis as well. Here, you can clearly see how we have calculated this.
MHC dystrophin divided by percent muscle content. DYNE-251 achieved 7.6% dystrophin at six months. This is a change of 6.9% from baseline. We believe this is the highest level of dystrophin reported for an exon-skipping therapy. Importantly, this is just 10 mg/kg, and we are currently dosing at 40 mg/kg Q8-week. For context, reported data from SRP-5051, a peptide conjugate, showed 5.2% adjusted dystrophin with a 30 mg/kg monthly dose. The 3.2% unadjusted dystrophin expression is nearing the goal of 5%-10% we have said for some time that we believe would drive functional benefit. And what's exciting is that as we near that target level, we see dystrophin production lead to encouraging trends across multiple functional endpoints at just six months.
We see stabilization or improvement with 10 mg/ kg of DYNE-251, while participants who received placebo decline over the same period of time, with an impact on NSAA, time to rise from floor, 10-meter walk/run, and stride velocity. We will continue to evaluate functional endpoint at higher dose and with longer time points. While we recognize that these data are relatively small participant numbers, we are very encouraged by what we see. We believe this data set from DELIVER illustrates the promise of the FORCE platform in developing next-generation exon-skipping therapies and building a global DMD franchise. We are excited about the opportunity to leverage FORCE to address additional mutations. We have preclinical programs targeting additional exons, including 53, 45, and 44. There is a significant need for therapies targeting these exons as well.
Historically, muscle delivery has been the challenge, and these initial data of DYNE-251 demonstrate that targeted delivery to muscle with the potential for a wide therapeutic index where other approaches have struggled. It is good news for the Duchenne community to see multiple therapies in development and the potential for more options for patients. We see the DMD space much like the SMA field, where I'm quite familiar, where you see Zolgensma, a gene therapy, and Spinraza, an oligonucleotide therapy, playing an important role in the evolving standard of care. Gene therapy is not a cure for DMD today, and there will be a need for multiple options for patients globally. So in summary, we believe these DELIVER data reinforce the opportunity for DMD exon-skipping franchise, starting with the differentiated safety and FORCE profile of DYNE-251.
At 10 mg/ kg Q 4-week dose, DYNE-251 showed a compelling profile with 10 times higher dystrophin expression, with 12 times lower PMO dose administered, four times less frequent, versus dystrophin levels reported for the standard of care, eteplirsen, at six months. We observed 3.2% MHC normalized and 7.6% muscle content-adjusted dystrophin expression, improvement in functional outcomes, including the NSAA and SV95C, favorable safety profile to date, with the 40 mg/k g Q 8-week cohort now fully enrolled. We plan to provide an update on the path to registration by the end of the year. Four exon-skipping therapies have been approved in the U.S., leveraging the accelerated approval pathway, with dystrophin as the surrogate biomarker. We have confirmation that this pathway remains available, and we look forward to engaging global regulators further in 2024.
With that, we will open things up for questions.
Great. Thanks so much, Wildon. Why don't we get started here with the Q&A? So first up, John, maybe I'll ask you to take this one. What did you see within these data that led you to accelerate the release of the data today?
Well, thanks, Amy. You know, I hope everybody is excited about the data as we are. You know, I... When I got involved with the company, I really was excited that there was a potential to create best-in-class medicines. And what we started seeing here were early biomarkers that were differentiating and meaningful, and even more meaningful by the fact that those biomarkers started translating into functional effect. And so, you know, you see what we have with dystrophin, but you also see what we have with some of the functional markers and endpoints that Wildon talked about for DMD. And you see the same thing in DM1. And in DM1, Amy, you know, we know that we see vHOT improvement.
We know that we see correlations with splicing index as a surrogate endpoint. But we're also seeing on these patient-reported outcomes that Wildon highlighted, and when you talk to those patients, it's pretty obvious that things like fatigue, CNS manifestations, as well as myotonia, are extremely important to them. So our data, although early, small data sets, I think is very exciting, and it's something we wanted the field to be aware of.
Great, thanks. Got several questions here with respect to regulatory path. Wildon, I'll address these to you. Can you provide some additional detail on your discussions with regulators around the DM1 regulatory path, and can you speak to what your regulatory strategy would be with respect to linking splicing to function, and where does vHOT play into that?
Sure. Thanks, Amy. So yes, we have had a recent interaction with the FDA regarding our ACHIEVE data set and to really understand their perspective on splicing. What we know is that regulators do see DM1 as a spliceopathy. We know the accelerated approval path is open. We know that we need to be able to see improvement in splicing and then correlate that to function. And we believe that the ACHIEVE data set gives us that opportunity to do that.
We also know that vHOT on its own is not enough, that we would need to be able to correlate that to function and patient outcomes as well. This is all very consistent with what we have been saying from the very beginning, that we believe DM1 is a spliceopathy, that we have multiple paths to accelerated approval through splicing or through myotonia and being able to correlate that with function. And so, with this feedback, we are excited to continue to engage with global regulators and provide an update on that later this year.
Great. And then, you know, maybe a little bit more color in terms of as you think about next steps, you know, with regulators across both programs. You talked a lot about a little bit with DM1, maybe any more color there. And then DMD, you know, how do you think about DMD in US and Europe? And then finally, sorry, I'm bucketing all these together: Do you plan to file an IND for DYNE-101?
Right. So, you know, we know the FDA is very excited about our data set. We know that we have a clear path to filing the IND. It is our plan to file the IND this year. We are continuing to engage with the global regulators with both programs. So, over the coming months, we plan to bring additional data to regulators to continue these conversations. We do believe that, as I said, that we have the opportunity for accelerated, expedited pathways in both the programs and, you know, all of the feedback that we've had is consistent with that.
Super, and then maybe anything else that you wanna say with respect to DMD and next steps and how we think about the regulatory path there, and also maybe touch upon Europe?
Right. So with DMD, you know, we know that the accelerated approval path is available there based upon dystrophin by Western blot. That has been confirmed. Multiple other sponsors have had programs approved based upon that. So, we know that that path is available and ongoing. We continue to have engagement around the globe. We, from the very beginning, have believed that with a strong data set, that we can engage with Europe. We have SV95C within our protocol. Europe has agreed that that is an endpoint that can be used for registration, and so, we will continue to collect that data and continue to have conversations with regulators as we move forward.
Great. Couple of questions that have come in with respect to DYNE-101 and the safety profile. Can you share, Wildon, any context on the pulmonary embolism SAEs, you know, any contributing risk factors? And then in addition to that, any comment on the lack of anemia being observed?
Right. You know, unfortunately, people living with DM1 have various clinical manifestations. These people unfortunately are sick. They have significant disease. Unfortunately, two participants in ACHIEVE had pulmonary embolism. One person recently had PE after starting oral contraception. Another had risk factors such as inactivity and infection, and so unfortunately these events occurred. There's not been any relationship with the drug. These are events that unfortunately can occur in this population. We've not seen anemia in either program. And this is something we obviously continue to monitor, to evaluate.
We do believe that our construct is different from others in the field, and so we believe that that plays a role in the efficacy profile that we're seeing as well as the safety profile. We believe that this does allow us to continue to dose escalate, allow us to continue to evaluate different dose levels and different dose regimens. This is an important part of both the ACHIEVE and DELIVER clinical trial.
Great. Couple questions on splicing. Talk a little bit about what you saw at six months, again, in the 3.4 mg/ kg with respect to splicing, and was this similar to what was observed at three months?
Right. The slides in the presentation really focused on three months, because that's the time point that we have data for all of the cohorts that we reported today. The six-month data for the 3.4 mg/kg is consistent with what we reported for the three-month data. What we see is that participants are continuing to see improvement in splicing. It's on a level in between the 1.8 and the 5.4 mg/ kg level. So, we do continue to see a consistent benefit in splicing at the 3.4 mg/ kg at 6 months.
Great. And Oxana, maybe I'll ask you one here with respect to splicing. We have, you know, as you think about the level of splicing that's being observed in the 5.4 mg/ kg, it's above that 20%-25% splicing correction range that we've talked about. So is 5.4 the likely dose to go forward with?
Thank you for your question. Actually, let me start with saying that we are very, very pleased to see our splicing correction reaching up to 27% in the ACHIEVE study. And yes, we have set out our target to be 20%-25% of splicing correction. As we projected this level of correction to translate into functional benefits for patients, which is based on natural history study, our own preclinical work, and published work on genetic studies in models of DM1. We can clearly see now translation of preclinical predictions into clinical results. And we plan to continue to explore this translation as we proceed with additional cohorts with higher and less frequent dosing. For example, we are dosing patients at 6.8 mg per kg every other month.
We are looking to get the best possible therapy for our patients. Importantly, we're able to do all this work and exploration based on our very favorable safety profile so far.
Great, and Oxana, maybe another one over to you, which would be, why was DMPK knockdown not part of the data presentation today?
I think that what we shared previously is that, as we deliver our payload, which is single-stranded ASO, into the nucleus in muscle cells, we know that this is where a mutant DMPK resides. We have done numerous studies preclinically, where we show that we can deliver to the nucleus of DM1 cells, knock down DMPK, and measure splicing as a ultimate readout. In patients, however, we are not able to separate nuclear fraction from cytoplasmic, so we are looking in the biopsy in the total DMPK. And so as projected and shared previously, while we can measure it, and we shared this data earlier, ultimately we want to hang our head on splicing correction.
This is the measure that we expect to translate into the restoration of normal protein function and, ultimately, function that we can measure in the patient. So this is, very consistent with what we communicated previously, and I think we will continue to measure splicing correction as we proceed through our trials.
Great, and then, maybe talking a little bit about, you know, function, Wildon, maybe speak to a little bit in terms of, you know, have you begun to anchor on any functional endpoints, you know, in particular with respect to DM1? And, and, you know, either you or John can maybe add some color about what, what are we hearing from patients and KOLs when they think about sort of what's important when it comes to, to function?
Yeah, maybe I'll start, and John can add. You know, what we know about DM1 is that there is a clinical heterogeneity within the phenotype. People living with DM1 can have various different functional manifestations. We have many of those that we're evaluating within our trial, and we will continue to look at the results from those to really understand the benefit that DYNE-101 is able to bring. What I do wanna point out, though, is what is consistent in all patients living with DM1 is the abnormal splicing. And this is why we focused on splicing as a biomarker, because we believe that as we demonstrate improvement in splicing, we can correlate that to a function.
This is consistent with what we have said from the very beginning. DM1 is a spliceopathy, and so we are focused on being able to show improvement in splicing and then correlate that to function. In our recent dialogue with the FDA, where we provided them data from ACHIEVE, there is an understanding of the importance of splicing and its role in myotonic dystrophy. John, do you wanna add to that?
Yeah, thanks, Wildon. Actually, when I first joined the company, very early on, I had a chance to go to a Myotonic Dystrophy Foundation event to meet patients. And when you talk to patients about what matters to them, I use that expression because, you know, our clinical trial, our medicine is really about positively impacting what matters to them as patients. And when you ask them, you know, part of it is myotonia, but the first thing they tend to bring up is from GI issues to sleepiness to fatigue, and a heterogeneity of the disease becomes very obvious. And the FDA knows it, and they're aware of that.
So, you know, as I said earlier, you know, seeing some of our functional outputs, myotonia clearly affected in a positive way, but as well as all of these other functional factors that we are measuring as a company, are those factors that make a difference for patients? So, that's exciting for us, and as we work with the FDA, I think we have an opportunity to talk about how splicing relates to everything from VHOT to a variety of patient-reported outcomes.
Great. Maybe a question on vHOT here. Can you, Wildon, maybe provide some color around how it compares to others in the field? And the other piece of that, I think, would be, you touched upon this, but can you explain the vHOT, you know, baselines, in particular for the 3.4 mg per kg cohort, and how that's driving, you know, the response there?
Right. So vHOT, or the video hand opening time, this is a clinical assessment of myotonia. It really is evaluating myotonia in the arm, forearm muscle, and really clinically seeing what is the impact of a therapeutic on improving that. Participants in ACHIEVE had vHOT at baseline anywhere between 6 seconds up to 11, 12 seconds. And so what we see in our data set is a very encouraging 30%-40% improvement in vHOT over a relatively short period of time. This is an endpoint that many in the field thought really could change quite quickly because of the correlation in the biology between myotonia and different ion channels, such as the chloride or potassium channels.
And so, we are pleased that we're able to see this amount of improvement. We believe this is similar or better to what others in the field have been able to demonstrate. We're also very pleased that we're able to see benefit not just within the one clinical measure of myotonia, such as vHOT, but in the patient-reported outcome, where patients are asked about their myotonia across multiple different muscle groups. And we see improvement there as well. And so, we do believe that with DYNE-101, we're seeing improvement in splicing, early improvement in endpoints like vHOT, and then broad functional benefit across multiple endpoints, including PROs, which really speak to the benefit that patients perceive in their therapy.
Yeah, and well, maybe staying on the PROs, can you talk a little bit more about that, including around the CNS, which is something that we've talked about before?
Right. So in myotonic dystrophy, the spliceopathy is not limited to the peripheral muscle. There is significant splice abnormality within other tissues, including the CNS, and this can result in manifestations of the disease. We talk about the functional components, about the time function test or about strength, but there are many manifestations of the disease, like sleepiness, like brain fog, like the inability to really ... With the PROs, like the DM1-ACTIVc , like the MDHI, really begin to put the functional data into context. We believe with MDHI, we're able to isolate out some aspects that are more prone to a CNS manifestation of the disease, such as fatigue, such as sleepiness. And so we're seeing broad benefit across these patient-reported outcomes, which again, what we've reported is, with FORCE, we are able to cross the blood-brain barrier.
Oksana and her team generated these data and presented them at ASGCT, just last year. So we believe that this is critical, for patients living with DM1. But this is also an aspect of people living, with DMD and other, neuromuscular diseases. So, we do, believe we have the opportunity within ACHIEVE to evaluate this, and we will continue to do that.
Great, thank you. Maybe switching gears a little bit to DMD here, what level of dystrophin is enough? You know, would you consider filing with these data?
Well, you know, look, we are very excited by this data. Again, the goal in DMD is to really increase dystrophin, and our goal is to generate as much dystrophin as possible. What we have said is that we believe, based upon our models, that in the 10, 20, 40 mg/ kg dose levels, we would be able to see 5%-10% MHC normalized dystrophin. So, and then we know, based on the half-life of dystrophin, that this will continue to grow such that 5%-10% at 6 months could become 10%-20% at 2 years with time on therapy. So with the data we're reporting today, we believe we're right on the cusp of that.
Here's where we're already beginning to see encouraging trends in function across endpoints that matter, including the NSAA, the SV95C, others. So we're very encouraged by what we're seeing in our data thus far. We want to see the data from these other cohorts and really see what we're able to drive for dystrophin production and what we're able to see in the functional assessments there as well. Over the coming months, we'll continue to refine our modeling. We'll continue to have conversations with regulators. We are very focused on getting DYNE-251 to patients as quickly as possible.
Great. Staying on DMD, are you seeing any of the same safety issues that other next-generation exon skippers are seeing with respect to things like, kidney tox, electrolytes, et cetera?
We're not. So we do believe we have a differentiated safety profile. Because of the targeted delivery, because of FORCE, the ability to deliver through the TfR1 receptor, we believe that we are not having the same safety profile that others have reported. We're not seeing anemia, we're not seeing kidney tox, we're not seeing electrolyte abnormalities. Again, you know, people living with Duchenne, these are sick patients. They have chronic manifestations of their disease, and they need drugs that can maintain a safety profile over the long haul. And so, you know, we believe the safety profile we've seen thus far with DYNE-251 is favorable and is truly differentiated across what other programs have reported.
Great. And then maybe could you talk a little bit about sort of the competitive landscape for DMD, you know, especially in the context of, you know, gene therapy?
Right. So again, I call upon my experience in spinal muscular atrophy, SMA, where I helped lead the development of Spinraza. And there is a gene therapy, Zolgensma. I believe the field continues to see the benefit of an oligonucleotide therapy, even when gene therapy is available. The data thus far on gene therapy continue to show unmet medical need, continues to show the need for a therapy. We believe that there will continue to be a role for next generation exon skipping therapy, such as DYNE-251. And so we look forward to continuing to see how our data set matures, continuing to see the data from these higher dose cohorts, and continue to engage with regulators.
Super. John, maybe I'll have you address this one. You know, what's next for the pipeline? You know, when you think about the DMD franchise, FSHD, how are you thinking about capital allocation with everything that you can do from here?
Yeah, I mean, You know, we are, first of all, from a capital standpoint, we're positioned to advance the pipeline, as we've described before. FSHD, there'll be more to follow on that, but we're very excited about it as a candidate. I think this data also, it gives us even more confidence about our DMD franchise. And, I'm sure people are wondering about that, particularly if they have skipping versions of this. So we are working on drug candidates and would like to move those forward. And that's been part of our pipeline. So, all the data, starting with DYNE- 251, as I said, I think it builds the confidence in the technology and confidence in the science, and it gives us confidence in the safety as well. The platform has... To put it simply, the platform has a lot of value.
Super. Well, I think with that, I think, we'll conclude the Q&A session, and I'll turn things over to John for some final remarks.
Thanks, Amy. Listen, during my first couple of months at Dyne, I've had the opportunity to speak with individuals and families living with these diseases, patient advocacy groups, and some of the clinicians who are treating them. It's highlighted for me the tremendous responsibility and opportunity we have to advance DYNE-101 and DYNE-251 by working with global regulators in an accelerated manner. DM1 patients are in need of a therapy, and one that can address the many aspects of their disease: muscle strength, function, and some of the cognitive challenges they face, given the CNS manifestations. In DMD, we believe a next generation exon skipping medicine is needed and will prove an important treatment option in this space.
Today, we have presented what we believe to be best-in-class clinical data in both DM1 and DMD, which is why we felt it so important to share at this time. We will continue to advance both programs in hopes of building on the strength of today's data. Encouraged by recent regulatory interactions, we anticipate providing an update on the path to registration by year-end. Finally, these data show that the FORCE platform delivers therapeutics to muscle in a targeted way. It validates the value of our platform, builds my excitement for our pipeline. We are advancing, as I said, programs from FSHD, additional DMD exons, and other neuromuscular indications. We plan to dedicate some time this year to providing updates on some of our pipeline programs.
This is an exciting time for the entire Dyne team, and we are focused on the important work ahead for those living with rare muscle diseases and creating value for our shareholders. I hope this was a good start to your week. Thank you.