Dyne Therapeutics, Inc. (DYN) Earnings Call Transcript & Summary

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 the part of the program. [Operator Instructions] With that, I'll hand things over to John for opening remarks.

Thank you, Amy. Today marks 8 weeks since I joined Dyne, and I couldn't be more proud to be part of this team. I 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 from 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 plan. We also had productive recent regulatory interactions that reaffirm our strategy to pursue expedited approvals for both programs. While today, we are 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, time functional assessments; and even in patient-reported outcomes. The safety profile for DYNE-101 is favorable, and we have fully enrolled the ACHIEVE trial to the 6.8 mg per 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 per 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 and functional improvement in just 6 months. The safety profile we have seen for 251 appears differentiated from other exon-skipping therapies in development as well as from gene therapy, and we are now dosing in the 40 mg per 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 impact on several clinical endpoints important to people living with DM1. First, a quick review of myotonic dystrophy type 1, or DM1. This is [ peaking ] 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 contraction. DM1 patients also experience weakness and atrophy of skeletal muscles and symptoms, including cardiac conduction anomalies, 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 literature that ASOs preferentially traffic to the nucleus. Here, you see a quote from Sarah, who is living with DM1 and it really underscores how devastating this 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 multisymptomatic 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 a dose 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 3-part study. There is a 6-month placebo-controlled multiple ascending dose or MAD portion, a 6-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 per kg cohorts and most recently the 6.8 mg per kg cohort. The safety profile has supported dosing up to 10.2 mg per 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 per kg because we would expect to see 20% to 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 4-week treatment arm received DYNE-101 every 4 weeks. The recovery treatment arm received 2 monthly doses of DYNE-101 followed by placebo in the 6-month placebo-controlled period. The every 8-week treatment arm received 3 monthly doses of DYNE-101, followed by a dose every 8 weeks thereafter. Therefore, the 3-month biopsy occurs 4 weeks after 3 doses in both the Q4 week and Q8-week regimen cohorts versus 2 months after 2 doses and the recovery arm. In addition to the 3 biopsies in the MAD, an additional biopsy is taken at 11 months in the open-label extension. Today, we are sharing our 12-month data from the 1.8 mg per kg Q4 week cohort, 6-month data from the 3.4 mg per kg Q4 week cohort and 3-month data from the 5.4 mg per 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 endpoints. 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 0 representing the level in a non-disease population and 1 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 and achieved to date, which is based on 56 participants dosed through the 6.8 mg per 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 4 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 2.5x 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 for 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 within 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 normalize 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 you 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 worse mean 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 3 months. Previously, we shared that at 3.4 mg per kg Q4 week dosing, all evaluable participants demonstrated a splicing correction. That same consistency is now also observed at the 5.4 mg per kg Q8 week cohort, with all 6 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 3-month data because it is the only time point we have across all the 3 doses cohort in this data type. At 6 months in the 3.4 mg per kg Q4 week cohort, we see a similar level of splicing improvement to what we saw at 3 months. As a reminder, we previously shared data from the recovery arm shown here where DYNE-101 demonstrated continued correction of splicing 2 months after the last dose. We believe this supports ongoing evaluation of every 8-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% to 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 per kg Q4 week treatment group which was our lowest dose and had the longest follow-up. The benefit on myotonia in this group increased from 3.1 seconds at 3 months to 4.4 seconds at 12 months. At the higher dose, 5.4 mg per kg cohort, we observed the greatest response at the early 3-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 baseline for vHOT matter. In our 3.4 mg per kg cohort, we observed a compelling 30% improvement in vHOT at 6 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. And this is what we observed in our data, a deepening improvement in the 3.4 mg per kg cohort averaged 2 seconds after 6 months. We are very encouraged by this best-in-class improvement observed with DYNE-101 and vHOT. At the same time, we realized 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 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 per kg cohorts begin to see improvement with time on therapy. Next, we're seeing encouraging data in time function tests, the 10-meter walk/run and 5x sit to stand. Again, in the cohort with the greatest splicing correction, 5.4 mg per kg, we see the greatest functional benefit. We are also seeing encouraging trends in multiple patient-reported outcomes. These assessments are collected at baseline, 6 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 1 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 a broad collection of multiple clinical endpoints, including myotonia, muscle strength, time 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 per kg Q8 week cohort. We are extremely encouraged by the 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 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 the 96-week long-term extension. The trial is enrolling ambulant and non-ambulant males with DMD who are aged 4 to 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 in 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 for every 4 weeks. Open muscle biopsies are taken at baseline and 6 months. As we've noted, we are now fully enrolled in the 40 mg per 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 have designed the DELIVER to be potentially registrational and to maintain the blind, we had 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 the reported AE. 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 per kg. 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, we also see that 10 mg per 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 tenfold higher dystrophin levels at 6 months than have been reported for eteplirsen, the current standard of care for exon 51, with 12-fold lower PMO dose administered 4x less frequent. At the 10 mg per 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 6 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 per kg, and we are currently dosing at 30 mg per kg Q8 week. For context, reported data from SRP-5051, a peptide conjugate, showed 5.2% adjusted dystrophin with a 30 mg per kg monthly dose. The 3.2% unadjusted dystrophin expression is nearing the goal of 5% to 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 6 months. We see stabilization or improvement with 10 mg per kg of DYNE-251, while participants 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 demonstrates the 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 oligo nucleotide 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 sum. We believe these DELIVER data reinforce the opportunity for DMD exon-skipping franchise, starting with the differentiated safety and efficacy profile of DYNE-251 at 10 mg per kg Q4 week dose, DYNE-251 showed a compelling profile with 10x higher dystrophin expression with 12x lower PMO dose administered 4x less frequent, versus dystrophin levels reported for the standard of care, eteplirsen, at 6 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 per kg Q8 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. I hope everybody is excited about the data as we are. 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 differentiated and meaningful, and even more meaningful by the fact that those biomarkers started translating into functional effect. And so 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, 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 to field to be aware of.

Great, thanks. I got several questions here with respect to regulatory path. Wildon, then 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 spicing. 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 maybe a little bit more color in terms of as you think about next steps with regulators across both programs. You talked about a little bit with DM1, maybe any more color there? And then DMD, how you think about DMD in the U.S. and Europe? And then finally. Sorry, I'm bucketing all these together. Do you plan to file an IND for DYNE-101?

Right. So 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 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, as I said, that we have the opportunity for accelerated, expedited pathways in both programs, and all of the feedback that we've had is consistent with that.

Super. And then maybe anything else that you want to 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, we know the accelerated approval path is available there based upon dystrophin at -- 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 the strong data set, we can engage with Europe. We have SV95C within our protocol. Europe has agree 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. A couple of questions that have come in with respect to DYNE-101 and the safety profile. Can you share, Will, then, any context on the pulmonary embolism SAEs? Any contributing risk factors? And then in addition to that, any comment on the lack of anemia being observed?

Right. 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 has 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 trials.

Great. Couple of questions on splicing. Talk a little bit about you saw at 6 months, again, in the 3.4 mg per kg with respect to splicing. And was this similar to what was observed at 3 months?

Right. The slides of the presentation really focused on the 3 months because that's the time point that we have data for all of the cohorts that we reported today. The 6-month data for the 3.4 mg per kg is consistent with what we reported for the 3-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 per kg level. So we do continue to see a consistent benefit in splicing at the 3.4 mg per kg at 6 months.

And Oxana, maybe I'll ask you on here with respect to splicing. We have -- as you think about the level of splicing that's being observed in the 5.4 mg per kg, it's above that 20% to 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 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 in our translation of our 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. And we are looking to get the best possible therapy for our patients. And importantly, we are 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?