Avidity Biosciences, Inc. (RNAM) Earnings Call Transcript & Summary

Good morning, and thank you for joining us today. I'm Mike MacLean, Chief Financial Officer at Avidity Biosciences. Today, we will be sharing Topline del-zota data from our Phase I/II EXPLORE44 Trial. Before we get started, I would like to share an excerpt from our forward-looking statement. This presentation contains forward-looking statements as defined under applicable law. Forward-looking statements involve risks and uncertainties, both known and unknown, which may cause actual results to differ from the forward-looking statements contained in this presentation. So you are cautioned not to place undue reliance on these forward-looking statements and refer to the more detailed cautionary language in this slide and in the Risk Factors section of our recent reports filed with the SEC. And now I would like to hand over to our President and CEO, Sarah Boyce.

Thank you, Mike. At Avidity, our vision is to profoundly improve people's lives by revolutionizing the delivery of RNA therapeutics. In the case of DMD, that's boys and young men like Yannick, with his megawatt personality. As we move 3 programs to commercialization, that vision to impact many people's lives expands. The del-zota, there are about 900 boys and young men amenable to exon skipping in the U.S. and we have aligned on our path for accelerated approval and are so excited to be moving to progressing our first BLA towards the end of this year. For del-desiran, we're tracking to be both first-in-class and best-in-class, the first-ever globally approved drug for the treatment of myotonic dystrophy. And for del-brax and FSHD, the first-ever globally approved drugs for FSHD. It's incredibly exciting around the impact that we have the potential to make. We've made great progress across all 3 of our programs. And this is as we log across both showing functional improvements having agreed on regulatory pathways in the case of DMD and myotonic dystrophin, and we look forward to providing an update on FSHD in Q2 of this year and now have all 3 of our programs in the registrational phases. This is also all underpinned by a favorable safety and tolerability profile that we really see being consistent across program to program. So for today's update, we're getting into a couple of things. Firstly, we'll share with you the top line data from the EXPLORE44 trial. What you see is unprecedented levels of dystrophin production that is consistent across both doses studied, as well as a very consistent favorable safety and tolerability profile across both doses. We have selected 5 milligrams per kilogram every 6 weeks as our dose for registration. We are on track to submit our first BLA towards the end of this year for accelerated approval in the U.S. and the dystrophin data that you will see today supports that BLA submission. The open-label extension study is fully enrolled, and that is to support the BLA submission. We are now also very excitingly guiding to share functional data from the explore open-label extension study in Q4 of this year. So from a data highlights of what we're going to show you today, it really sits into 4 aspects. Firstly, unsurpassed muscle delivery, consistent delivery of PMO to skeletal muscle cells with both doses. What we've seen is consistent increases in exon skipping as well as unprecedented increases in dystrophin production with a 25% sustainable increase across both doses. And then what that translates to is something that has never been seen before, which is profound reductions in creatine kinase of 80%. This is taking creatine kinase to the upper limit of normal, and that creatine kinase level goes down and stays down. Joining me on the call today are several members of our team who you know well. We're also joined by Husam Younis, who is our Senior Vice President and Global Program Head for our DMD programs. I'm also delighted that Dr. Kevin Flanigan has graciously given us his time our Q&A session. And I will introduce Dr. Flanigan in more detail as we go into that Q&A session. For now, I'm going to hand over to Steve, who's going to take you through the data. Steve, over to you.

Thank you, Sarah. I'm very excited to be able to share with you the unprecedented and consistent top line data from the EXPLORE44 study today. But first, I'm going to give you a little background and information on the disease and the study design. Duchenne muscular dystrophy is an X-linked recessive muscular dystrophy caused by mutations in the dystrophin gene that results in dramatically reduced levels of functional dystrophin. This, in turn, produces our relentless and severe muscle damage, inflammation and loss of function. DMD44 is amenable to exon skipping of exon 44 and affects about 900 boys in the U.S.A. with a similar number in Europe. It is a severe muscular dystrophy, resulting in loss of ability to walk by the teenage years and a considerably reduced life expectancy. No exon skipping therapies are currently approved in DMD44. So there's a high unmet need for an effective treatment. Next slide, please. Here, we can see the normal dystrophin gene at the top, the typical dystrophin produced by del-zota directly under, and that produced by synthetic microdystrophin gene therapy at the bottom. As you can see in the figure, with exon skipping in contrast to gene therapy, the dystrophin produced is near full length, retaining the key domains required for optimal functionality. Next slide, please. With these advantages of exon skipping in mind, we believe del-zota sets a new standard for the treatment of DMD44 with promotion of muscle integrity, prevention of muscle damage to unprecedented levels of near full-length dystrophin, which is evidenced near normalization of CK that's sustained over time and combined with the safety profile that is consistent and favorable across both doses, and a convenient once every 6-week dose regimen. This once every 6-week regimen is in contrast to the current generation of exon skippers that are administered weekly. So once every 6 weeks will allow families to go on vacation, will not lead to significant disruption of school or days away from the office. In the EXPLORE44 trial, we saw that the effects of del-zota on reducing muscle damage was seen early and were sustained over 1 year of treatment. And although we're not showing functional data today, we have seen early and encouraging signs of clinical data and we plan to share the long-term functional data from the OLE study in Q4. Next slide, please. Over the next few slides, I'm going to walk you through the top line data from the EXPLORE44 study, but first I would like to take a few moments to review the study design. EXPLORE44 is on the left of the slide. It had a health and T component, Cohort A, which received single doses and we've already presented the data for this cohort previously. The B cohorts, Cohorts B1 and B2, enrolled boys with DMD44, and these boys could roll into the openable extension, which is on the right of the slide on completion of the EXPLORE44 study. EXPLORE44's randomized double blinded and placebo controlled targeting 12 boys with DMD44 in each cohort. Randomization was 3:1 del-zota to placebo. Each B cohort received 3 doses of del-zota with Cohort B1 receiving 5 mg per kg given every 6 weeks and Cohort B2 receiving del-zota 10 mg per kg every 8 weeks. Muscle boxes were taken 4 weeks after the third dose. The dose interval is important because it means that boys at 5 mg per kg only receive about 33% less drug over time than those at 10 mg per kg. Participants in -- data from the EXPLORE44 and the OLE will support BLA submission towards the end of the year, and we have enrolled an additional 16 participants at 5 mg per kg every 6 weeks in the OLE in order to bring the overall exposure database up to the range of other filings for DMD. And of course, both studies, we have a total of 39 participants. Of note, these new participants enrolled in the OLE need to undergo any muscle biopsies as we already have sufficient dystrophin data to file for a BLA. Next slide, please. The EXPLORE44 study enrolled patients across a wide age range from 7 to 27 and included both ambulatory and non-ambulatory. We also enrolled a number of different genotypes. The primary objective was to evaluate safety and tolerability with the PK and PD endpoints being secondary, exploratory endpoints evaluated muscle function PROs and health-related quality of life. And now we've all been waiting for the top line data from the study. Next slide, please. Starting with the baseline characteristics, we can see that all participants had very high CK levels and the majority were receiving corticosteroids and a range of mutations were included. Next slide, please. The safety profile was extremely favorable at both doses. On the left of the table are the EXPLORE44 cohorts and on the far right, the safety data from the OLE participants with a data cut point of January 22 this year. 38 of the 39 total participants are included in this analysis as the last additional OLE participant had not been dosed at the time of the data cut. The overall frequency of TEAEs is well balanced between del-zota and placebo and the most common AEs, those occurring in 3 or what participants were procedural pain from the muscle biopsies and headache. We have not seen any symptomatic changes in hemoglobin or events of hypomagnesemia. As we disclosed previously, 2 participants in the 5 mg per kg cohort discontinued early, one due to a case of anaphylaxis, which was the only SAE we have seen in the studies and one due to a moderate infusion reaction. We have not seen any similar reactions at the higher 10 mg per kg dose. In the open-label extension, all AEs have been mild or moderate and there have been no SAEs or discontinuations. Next slide, please. And now turning to PK. Muscle tissue concentrations were similar at each dose at around 100 nanomolars reflecting the exceptional delivery to muscle of the AOC platform. The similarity in muscle tissue concentrations is not surprising since as I mentioned earlier, the longer dose interval at 10 mg per kg means that the total exposure over time was very similar to that of 5 mg per kg. Next slide, please. Exon skipping was also similar between the 2 doses with a large approximately 40% increase at each dose compared with placebo, where there was no increase in exon skipping. Next slide, please. Once again, we are seeing remarkably consistent results with unprecedented increases in near full-length dystrophin of around 25% age dose, with overall dystrophin levels of up to 58% and increases were seen across all genotypes. No increases were seen in the placebo participants. Of note, these dystrophin levels are the raw values from the western blot normalized to myosin heavy chain, and we have not performed any additional adjustment for the muscle content of the biopsies. Next slide, please. When looking at creatine kinase, a biomarker for muscle damage, once again, we see CK levels coming down almost into the normal range at both doses, reflecting the very high levels of near normal dystrophin that are being produced. Next slide, please. And when we look at boys that switched from placebo in EXPLORE44 to del-zota in the open-label extension, we again see near normalization of creatine kinase with reductions of over 80%. Also, if you look at the green squares, which represent the boys that started treatment with del-zota at the beginning of EXPLORE44, you can see that the CK levels are staying down at almost 1 year. This level and duration of CK reduction has not been seen with other treatments for DMD and reflects the exceptional ability of the AOC platform to deliver RNA to muscle. And once there, the RNAs are incredibly effective at correcting the underlying disease biology. Next slide, please. And we see this consistency again on this slide with similar increases in dystrophin and decreases in CK in both ambulatory and non-ambulatory boys. Lower CK levels at baseline in nonambulatory patients is consistent with what is described in the literature and is due to a combination of less muscle mass overall and less muscle movement of the large muscle groups in the legs. Next slide, please. When we look across other biomarkers for muscle damage, we once again see highly consistent results. I would like to draw your attention to the bottom 2 lines on each of these figures since these are the del-zota treated boys. We can see that in addition to CK, ALT and AST were reduced to within the normal range at both doses and myoglobin was reduced to near normal levels. No matter which way we look at markets at muscle damage, we see profound improvements reflecting the very high levels of near full-length dystrophin that are produced by del-zota. So in summary, the new data shared today have recapitulated the remarkable and unprecedented improvements that we had already shared at the 5 mg per kg dose last year and reinforce the potential for del-zota to be the new standard for treatment of DMD44, with favorable and consistent safety and tolerability at both doses and a convenient once every 6-week dose regimen. We have seen unsurpassed delivery to muscle, which drives significant exon skipping and unprecedented levels of near full-length and functional dystrophin, resulting in a reduction of the biomarkers of muscle damage, which come down to near normal or normal levels and stay down over the long term. I will now hand back to Sarah.

Thank you, Steve. As Steve said, what we're seeing is unsurpassed delivery to muscle, significant increases in exon skipping, unprecedented dystrophin production and profound reductions in creatinine kinase. Del-zota is the first AOC in our DMD franchise. We deeply understand the responsibility to get treatments to patients as quickly as possible. FDA has granted del-zota, orphan drug, Fast Track, rare pediatric designations and EMA has also granted del-zota orphan designations. We have alignment with the FDA on the accelerated path in the U.S. and enrollment is now complete. And it is data from these studies that support the BLA filing for accelerated approval at the end of the year. In addition, we're advancing additional exons and DMD45 is in IND-enabling studies. Del-zota is on track to be our first commercial launch at Avidity. We are now deep in our launch preparations and building our commercial team in the U.S. to make sure that we have a rigorous go-to-market strategy. In addition, preparations for 3 launches are now well underway, and each of our programs is in the rare neuromuscular space. So there is significant synergy from one program to the other as we tap into multiple patient populations with a significant unmet need. We're building an incredible team and also understand deeply our responsibility around engaging with the broader community, be that patients, clinicians and others as we rapidly execute our go-to-market strategy. All of this brings us further towards our vision to profoundly improve people's lives by revolutionizing the delivery of RNA therapeutics. We'll now move into the Q&A portion of this morning's presentation, and I would like to introduce to you Dr. Kevin Flanigan. Dr. Flanigan is Director, Center for Gene Therapy at the Robert F. and Edgar T. Wolfe Foundation Endowed Chair in Neuromuscular Research at Nationwide Children's Hospital. Professor of Pediatrics and Neurology at Ohio State University College of Medicine, Dr. Flanigan leads the world-class neuromuscular disorders program at Nationwide Children's, which provides coordinated care with pediatric experts from dozens of specialties, and he is a leading expert in neuromuscular disorders. His primary research interest is in genetic and molecular characterization of inherited neuromuscular diseases and the development of therapies directed towards these diseases. Dr. Flanigan is an experienced clinical trialist. He has sponsored 3 investigator-initiated IND applications for first-in-human gene therapies for Duchenne muscular dystrophy and Sanfilippo syndrome. In addition, Dr. Flanigan is a trial investigator in Avidity's EXPLORE44 study. And his role on this call will be to provide context for this data. With that, I would like to invite my colleagues to join me on screen for our Q&A portion of this morning's call.

Good morning, everyone. We have a lot of questions. We have a lot of participants who have joined us here this morning. And I want to start with you, Dr. Flanigan. We have a question from Josh and Eric from Cantor. And they said, congrats on the very impressive and highly consistent results. Dr. Flanigan, how do you think about CK elevations as a biomarker for disease activity in DMD? And can you put del-zota's impact on CK into context with other DMD data sets?

I'm happy to do that. CK is a marker of muscle membrane [Technical Difficulty]. And quite frankly, it's considered in many ways and imperfect -- in other settings, an imperfect biomarker in that it's activity dependent. So a boy with Duchenne muscular dystrophy out in the community might come in with a CK of 5,000 and he might go to his cousin's birthday party and have a CK of 10,000 or 12,000 the following day, and we see a lot of variability in it. That's what's particularly impressive about this data, is that ad lib activity in these voice is diminished, sustained, in some cases reaching within the normal range. In this setting with that profound suppression of CK activity, it's really a marker of restoration of muscle -- intactness of the muscle membrane. As you -- as everyone on this call is aware, our first diagnostic marker we often see is the elevation of CK. Children with normal CK would not come to the attention of a physician, and we have to take it as a marker of sustained protection of muscle and a marker. In this case, correlating with the [Technical Difficulty] functional improvement in muscle.

Thank you, Dr. Flanigan. Our next question comes from Joe Schwartz of Leerink. And this question is for you, Husam. How do you think about the translatability of the effect of del-zota for -- that the effect is driving for exon 44 patients, to what extent could you see from your other next-generation exon skippers and other exon subsets such as 51, which seems to have a different biology and chemistry coefficient of activity based on what we've seen from the exon skippers to date. And then the second part of the question is -- it's a related question, what is the status of your plans on other subsets beyond exon 44?

Thanks, Mike. Happy to take the question. Well, what we've seen here today is the remarkable delivery of the AOC platform of getting oligonucleotides to muscle tissue. So we believe that with that platform, potentially going after other genotypes, including 51, for example, that was referenced, we should be able to substantially deliver oligonucleotides to skeletal muscle and hence forth, achieve the type of activity that we're seeing to some degree here with del-zota. We're looking to profoundly improve people's lives, as Sarah mentioned, and we think from that perspective, that getting to 10% of normal dystrophin is really where we want to target. In terms of the second question around the other genotypes that we're looking at, certainly, this data has allowed us to accelerate our efforts looking at other genotypes. The most advanced one is AOC 1045. This is an AOC that is targeting DMD patients that are amenable to exon 45 skipping. We're progressing that one as quickly as we can. At this point, it's at the IND-enabling stage. And we look forward to sharing more information on that program in the future.

Thank you, Husam. The next question is from Ritu at Cowen. And this one, Steve, is for you. What are the functional endpoints that will be reported that will be at the end of the year from these patients? What time point and from what number of patients?

Yes. Thanks, Ritu. So we haven't given any guidance at the moment on the exact functional end points in the EXPLORE44 and EXPLORE open-label extension study. We are measuring a range of functional endpoints, both looking at ambulatory function muscle strength, upper limb function and patient-reported outcomes, including quality of life outcomes. So there's a range of data that we'll be able to pull for that disclosure. The time point most patients should be through 1 year of continuous treatment by that time as they've gone out through the open-label extension study. And obviously, that longer duration of treatment allowing for better maturation of the clinical data. That said, we have seen encouraging signs of clinical improvement. And even within the 4- to 5-month duration of the EXPLORE44 study is just not quite at the level of maturity that we feel we're sharing at this point in time.

Thank you, Steve. Our next question is for Sarah, and it comes from Geoff Meacham of Citi. Supported by the data today, could you add additional color to your launch strategy for del-zota and the upcoming transition into a commercial stage company part 1. Part 2 is given the unmet need in this space, could you comment on the responses seen today for both safety and efficacy and how that could be impactful to the treatment paradigm?

Yes. Thanks so much for the question, Geoff, and great to hear from you again. So in terms of our launch preparations, really, that's in full swing, both in terms of the 2 core elements. One is building our patient services organization and then also our market access team. Subsequently, we'll see a sales team come on board later in the launch cycle, so to speak. From an aspect of the data that we have observed for del-zota, we really believe this sets a new standard for four DMD44. And we really look forward to both submitting our first BLA at the end of the year, working with the agency to facilitate a rapid review and then being able to get del-zota to patients who need it as quickly as possible.

Thank you, Sarah. The next question comes from Gena Wang at Barclays, and it's a question for Steve. Understanding that 10 mg per kg was less frequent dose at 8 weeks dosing, but still should be higher dose than the 5 mg at 6-week dosing. 10 mg per kg cohort also had a higher exon skipping rate. So what could be the reason that we didn't see higher protein expression, that's the first part. And then there's a piece on safety. Regarding the safety, what was the follow-up period for the 5 mg and the 10 mg per kg?

Okay. So first of all, turning to the question of muscle tissue concentrations. When you map out the exposure, which is really a factor of both the dose and the time over a period of time, there's only really about a 33% difference. So the 5 mg per kg dose in terms of exposure, it was only about 33% less than the 10 mg per kg. And so 33% difference isn't really large. And so it's not really surprising that the tissue concentrations are very similar. In terms of the exon skipping, actually, although they're numerically different, those differences in exon skipping aren't really significant. And not sufficient to drive differences in dystrophin changes over time. So really, the take home here is that we've seen unprecedented levels, unprecedented increases in dystrophin levels. So really, these levels haven't been seen with any other exon skipping therapy. We haven't adjusted for muscle content. And if we did that, they would probably double. And we're seeing very large improvements in CK reflecting underlying improvements in muscle damage. So these are all really important signs for the patients, and we've seen that at each of the doses and also in the placebo patients when they switched over. Mike, could you just remind me what the second part of the question was? On, it's follow-up, wasn't it? So the patients in the -- if so looking just at the EXPLORE44 study, the patients in the 5 mg per kg cohort that had 4 months of follow-up. And the patients in the 10 mg per kg cohort had 5 months of follow-up. The difference being due to the difference in dose interval. When we look out through the open-label extension study, when we included that data to be really transparent with all of the data that we have at this point from safety, we've got a data cut of the 22nd of January of this year. And in that data cut, obviously, patients rolled over into the open-label extensions at different time points, but we do have patients in that set that have been out for a year of continuous therapy.

Okay. Thank you, Steve. Now we're coming back to you, Dr. Flanigan. The question is, how do you think about choosing between gene therapy, including next-generation microdystrophin constructs and next-generation skippers such as del-zota?

I appreciate the question, and it's one that we'll face in the clinic quite a bit. It's important to note that del-zota will be treating only one set of patients, those who are amenable exon 44 skipping. And we -- I'll point out as well that some of the profound success of this is undoubtedly due to the fact that the protein that it makes, the result of skipping 44. Those are very favorable versions of the isoforms of protein. We know this from observations in large sets of patients for long-standing projects of ours and others have shown for example, deletions of 44 and 45 are underrepresented in all of the databases because they are so asymptomatic presumably. I think that's what the data here shows. So for patients who are amenable to exon 44 skipping, I anticipate that the choice will be made primarily on the availability of such an effective drug like this. We note that as your diagram showed earlier, the result in protein skipping only a small portion of the central rod domain, contains all of the -- all of critical domains that are lacking from current versions of microdystrophins that are approved including the C-terminal functions of the protein as well. So the decision process will undoubtedly be dependent largely on the genotype in the first place. There will be the consideration of whether we could treat patients previously treated with this drug as well that we will be facing in the clinic. And there's no reason based on the science of it so far that we think we couldn't do that as well. So that's a long answer to your question, but I think the choice will be largely driven by genotype. Those amenable to this therapy have the prospect of making a really highly functional version of the protein that we know from patient-derived observations is one that is really consistent with a long-standing meaningful impact from men who are born with the equivalent versions of those rotations.

Thank you, Dr. Flanigan. Our next question is for you, Sarah, and it's from Louise Chen at Scotiabank. How quickly and effectively can you reach the 900 boys in the U.S., if your drug is approved? That's part one. Can you give me more color on the build-out of your commercial infrastructure? How many people will you need to support the infrastructure? And what will be the cost that start layering in as you reach your potential approval?

Thank you. Great set of questions. So firstly, I would say, consistent with our vision around making a profound improvement in people's lives, we'll be looking to get del-zota to patients who need it as quickly as possible post approval. What I would say on the size of our commercial organization. Look, pull back a bit. There's about 500 pediatric neuromuscular specialists in the U.S. So I think that gives you a sense of when we look at a potential prescribing physician base, but it's pretty small. So we would anticipate building a very efficient commercial organization for del-zota, but also it's important to note that this is an organization that we're then looking to layer on to other launches. So as we build our patient services team, and it is our goal to build the best patient services organization in the industry, that's a team that we're building for 3 successive launches. That's the same with our market access team as well. In the case for del-zota, out build will be in the U.S. But also, we're looking to build a global organization in particular, as we layer on programs in myotonic dystrophy and FSHD. And ultimately, conduct a confirmatory study for del-zota with regards to then gaining global approval. One of the other areas from our cost base is obviously, we're making drug right now and making large quantities of drug, both in preparing for launches in FSHD and myotonic dystrophy as well as also making sure [Technical Difficulty] I don't know why I went on mute, but I seem to have gone on mute. So I don't know how much of my answer that you saw at the end. But I would say, look, it's a really exciting time. We deeply, deeply understand the responsibility that we have around getting drug to patients as quickly as possible. We're building an organization to do that. And we're also building an organization to make sure that we do it right, and we do it really well.

Thank you, Sarah. And I do think we caught all of your answer in the end. The next question comes from Gavin at Evercore, and Steve, this one is for you. As we look ahead to functional data for this program coming later this year, what endpoint or end points do you believe we should be most focused on, specifically wondering what you think about SV95C compared to North Star.

Thanks for the question. So as I said earlier, I don't give too much away on the endpoints that we'll be disclosing at the end of the year. We do discuss endpoints with our investigators as to what we want to disclose in order to choose the most relevant clinical data that's going to be impactful with the audience of clinicians. In terms of the walking velocity 95th centile, actually, that's not something that we've measured in this particular clinical trial. We did measure the North Star Ambulatory Assessment along with a number of other measures of lower limb function and measures of upper limb function as well. Of course, the North Star until recently has -- I guess people could say that it was the gold standard assessment, but it hasn't played out so well in some of the recent confirmatory studies for a number of reasons. I think at a high level, we've got a lot of different endpoints that we're measuring and we'll be showing a mixture of both motor function and ambulatory function and upper limb function at the end of the year.

Thank you, Steve. Our next question comes from Ananda Ghosh at H.C. Wainwright. And Husam, this question is for you. What are the key learnings from exon 44 program with respect to PK/PD and safety characteristics of the AOC platform as you think about your future pipeline programs?

Thanks, Mike. I mean the remarkable data that we've been able to share here with del-zota really has translated from our preclinical data through the clinical data set. And we've seen that very consistently, not just with del-zota, but across our platform with the other 2 development molecules as well for FSHD and DM1. So we're really confident that as we progress additional AOCs across the DMD franchise that we're really going to be able to achieve the same delivery of PMO to muscle tissue. And we're also utilizing the same platform to target the heart as well, and so really excited about that. From a safety perspective, as Steve mentioned, I think the safety profile has been very consistent across the platform as well. So from that perspective, I don't see any challenges moving forward with additional programs.

Thank you, Husam. Dr. Flanigan, I'm coming back to you. This is Yanan from Wells Fargo. Can you talk about the CK, AST, ALT, myoglobin post treatment? Have the levels of improvement been seen with other DMD studies? And how do you think that, that could translate into functional improvements? That's a lot. Let me now come back to you.

The sustained -- I would rephrase it slightly that it's AST, ALT, CK during treatment, right? It's not an individual one treatment. And I think that's one of the important facts about this that it really implies that as long as this treatment occurs, the durability will exist of providing long-standing correction of those values. Just a reminder that everyone, I think, on this call will know, that the AST and ALT in this case does not reflect liver injury, but those are values that are -- those are transaminases that are released by muscle as well and they correlate directly with CK levels. So the theoretical boy I mentioned going through his cousin's birthday party running it down, his AST and ALT go up with the CK the day after his activity. So the fact that they stay down and are sustained down over the period of treatment is remarkable and is a measure of continued activity. These levels of drops have not been seen in any of the approved therapies. They have -- or in any of the other studies that have been in save for one special case of our investigator-initiated study for a very unusual genotype. But -- so it's -- this decrease is really quite striking. It is important to note that the exon 44 skip outcome proteins are particularly favorable and that the CK, they seem very protective versions of the proteins as well. So this may not be seen with other exons to the same degree and it may or may not be seen with this dramatic event -- this dramatic amount. But it certainly signals that there's sustained benefit and uptake, the functional -- the basic function of this system, delivering with the transferrin receptor antibody that will hold up for a long time -- for long-term treatment.

Thank you, Dr. Flanigan. Our next question comes from Luca Issi at RBC and Steve, this one's for you. How should we think about safety at 10 mg per kg compared to the prior cut last August, it looks like AEs related drug went from 1 to 4. I appreciate none of them were serious, but any additional color on what were the other three AEs?

Thanks for the question. So the way that -- related AEs are obviously a subset of the overall adverse event. Within clinical trials, particularly for these sort of diseases, it's often more informative to look at the overall adverse events because that tells you all of the experiences of the patient, and they're very similar whether you look at the patients in the treated cohorts or the placebo cohort. For the related AEs, we ask the investigators to report anything that could be possibly related to the drug. And of course, tempo relationship forms part of that. So things that occur in proximal to dosing have a tendency to get classed as related, and there's not necessarily plausible relationships for all of the related events. At this point in time, we haven't really drilled down on the nature of individual events other than ones that occur as more than anecdotal. So what we see in the clinical trials of lots of -- with a lot -- or most of the events occurring in one patient here and there, but different event terms. So what we focused on is events that are reported in 3 or more patients, and those were really pretty benign headache and procedural pain. So nothing really of note there.

Thank you, Steve. Sarah, we have another question for you. This is from Kostas Biliouris at BMO. What peak penetration would you expect from del-zota in eligible DMD patients? And how likely would it be for insurance to reimburse del-zota in patients who may already have received ELEVIDYS?

Yes, that's a great question regarding reimbursement in patients who've already received a gene therapy. As we look at this, I think there's a really good analog, which is the SMA space, where there is both the gene therapy and an RNA therapeutic available. As our patient services team builds out and our market access team really go deep in our understanding of the reimbursement pathways, it's really going to be on an individual patient-by-patient basis, and we're building a team to make sure that we can facilitate that as rapid as possible. With regards to comments on peak penetration rates, it's probably a little too early for us to be guiding on that at this point. Although what I would say is it is our goal to get and facilitate, getting del-zota to patients as quickly as possible, and to the boys and young men who need it as quickly as possible. And we're building an organization and a team to do that.

Okay. Thank you, Sarah. So we're coming to time. We have time for a couple more questions. The next one, Steve, is for you. It's from Bank of America. What specifically did the FDA share to give you confidence on their alignment on the accelerated approval path? And is there any additional data they were looking to see following these top line results?

Okay. Great question. The short answer is the additional data that's required for filing the BLA just relates to longer-term safety follow-up. So as I mentioned earlier, the EXPLORE44 study was relatively short. It was just 4 to 5 months in duration. And so we needed some additional exposures. So we added 16 patients to the open-label extension study to bring the total exposure database into the range of other approved drugs for treating DMD. So with 39 patients overall. And then we need to follow those new patients and the existing patients up for a little bit longer. So we have some more patients through 1 year of follow-up and more patients through 6 months of total follow-up. In terms of the other things that are important, the dystrophin levels, those we already had sufficient data with the exposures that we had in order to file. So the additional patients that we enrolled into the open-label extension study didn't require biopsies, which is great news for those because the biopsies can be quite painful, and the rest of the data set is exactly what we need for filing.

Thank you, Steve. And our last question, which is actually 2 questions is from Yanan at Wells Fargo. I think the first part is for you, Steve, and the second part is for you Sarah. So the first question is, could you talk about any early signs of functional improvements you've seen in the study as for you Steve. And then Sarah, the second part, the EXPLORE44 study enrollment criteria was 7 to 27 years old. Would you seek approval for patients 4 to 6 age? How do you think about the breadth of the label? Go ahead, Steve.

Thanks, Mike. So not really wanting to go into specifics ahead of when we actually disclose the data next year. What I can say is that with the levels of CK reduction that we're seeing, that really is consistent with prevention of muscle damage. It's not surprising that we are seeing some encouraging signs in the data this early on at the 4- to 5-month time point. We are evaluating a lot of different endpoints, and we have seen encouraging signs across several of those endpoints at this point in time. And as we go out through Q4, we'll be able to give more guidance around that.

And then with regards to commenting on potential label and indication statements. As we look at other analogs in the DMD space, it's our expectation that -- well, we plan to seek and it's our expectation of having a broad label that does not necessarily have age restrictions. One of the other aspects, and this is in particular why -- and some okay, why we showed the breakdown of ambulatory and non-ambulatory patients. When it comes to reimbursement, and we all know that approval and reimbursement are often 2 different things. When it comes to reimbursement, it's also important to show a consistent data set as we look at potential benefits in ambulatory and non-ambulatory patients. And what we shared today, looking at the biomarkers was basically consistent and reproducible data sets regardless of ambulatory status. So we are looking for a broad label and then also looking to seek a broad reimbursement and to be able to move as quickly as possible to get drug to patients who need it.

Thank you, Sarah. And that concludes the question-and-answer period of our webcast, and Sarah, I'll turn it back over to you.

Thank you, and thank you, everyone, for joining us this morning, as we move further along our journey in realizing our vision to make a profound impact in people's lives by revolutionizing the delivery of RNA therapeutics.