Welcome, everybody. I'm Catherine Mosier from Akron, Ohio. And I have the privilege of chairing today's session on advances in the care and management of Duchenne muscular dystrophy. And I'm just going to take a couple of minutes to introduce our speakers and then let them get started. So first off, we have Craig McDonald. He is a professor of pediatric physical medicine and rehabilitation and also the chair of the Department of Physical Medicine and Rehabilitation at the University of California, Davies. He's an internationally recognized expert in the clinical management, rehabilitation, and precision therapeutics, such as gene therapy, in the clinical management of muscle diseases. He has also been a pioneer in the development of outcome measures in the population of children with disabilities. He leads the Cooperative International Neuromuscular Research Group, known as Synergy, Duchenne Natural History Study, a collaborative effort which has made seminal contributions to the elucidation of the natural history of DMD and the validation of clinical endpoints that are now used in trials for DMD throughout the world. And our second speaker is Emma Ciafaloni, who is a professor of neurology, pediatrics, and OB-GYN at the University of Rochester in Rochester, New York, where she holds the Robert C. And Rosalind H. Griggs Endowed Professorship in Experimental Therapeutics of Neurologic Diseases. And she is the director of the Pediatric Neuromuscular Program. Her current research focus is related to novel gene therapies for Duchenne muscular dystrophy and the implementation of the newborn screen programs for SMA and DMD in different countries around the world. She is passionate about mentoring young neurologists who have an interest in a career in the rapidly changing therapeutic landscape of pediatric muscular diseases. So without further ado, I will welcome Craig McDonald to the stage. Thank you, Dr. Mosher. And these are my disclosures related to this presentation. Duchenne is an X-length, rare, relentlessly progressive, and ultimately fatal. function with initially a proximal right in a Duchenne patient. And then this also is a clinical sign that we see in Duchenne muscular dystrophy. They have hypertrophy of the posterior deltoid in the infraspinatus muscle. So if you abduct and externally rotate them at the shoulder, you essentially get this valley between two peaks of hypertrophied muscle. And we refer to that as the posterior axillary depression sign, which is quite commonly seen in Duchenne patients. Here's a nine-year-old boy showing the very prototypical Gowers maneuver due to hip extensor weakness. Here he's going to tripod, and he needs to push off his knees to get himself into a standing position. And here is the characteristic myopathic gait, lumbar lordosis, Trendelenburg, swaying to the stance phase limb because of abductor weakness, shoulders retracted, and he's up on his toes, a very characteristic myopathic gait. Here is a myopathic run. He doesn't have a double limb flight. There's always one limb on the ground. You can see the tremendous fatigue, this waddling motion that occurs with his attempts to run, and again, a lot of difficulty with endurance here. Sadly, this same patient, here he is at age 17. And you can see the tremendous burden of disease to this patient and to their family. Here, the family in the home environment is needing to do a deadweight lift into the power wheelchair. You can see the tremendous degree of trunk weakness and loss of head control. And then here, you'll see his severe contractures, hip flexion and abduction contractures, knee flexion contractures, and plantar flexion contractures. And then obviously, the need for non-invasive mechanical ventilatory support. So sadly, tremendous burden of disease for the family. The North Star is a well-established and validated measure of global function. And it's a composite measure across 17 items with increasing difficulty. The healthy boys obtained a total score of 34. These items actually go from those that are either never obtained or lost early in the course of the disease. They're the most difficult items to perform, such as hopping, rising from floor, running, and jumping, and then down to other items, such as rising from the chair, walking, and standing, which are lost later in the course of the disease. And the North Star is scored. It's a very gross measure. It's scored as essentially a 0, 1, or 2 inability to perform an item. A 1 is performance with difficulty or with compensation, and a 2 is performance of the item normally without compensation. So with 17 items, a possible of 34 points on the North Star. And here's some of the items. This is the rise from floor item. Here, his tripod demonstrates a compensation to stand. Here is inability to stand from a seated position without the use of the arms. Here, he is attempting to jump. You can see the difficulty there, as well as the difficulty with hopping for this young man. And here is his very characteristic myopathic gait, difficulty with stair climbing and stair descending, as well. And you can see that even a one-point change in the NSA is a very tall order in terms of a therapeutic to show a treatment effect. And on the left, the patient gets up really without difficulty here, as shown before, the prototypical Gowers, which would be scored as a North Star of 1. And then here, painfully, this teenager on the right has a North Star score of 0 on the rise from floor item. You can see the tremendous difficulty that patient has with just rising from the floor and really can't obtain that within the requisite 30-second time period that we use for clinical trials. But you can see that making a change in the North Star is not an easy proposition for a therapeutic in a one-year clinical trial. The studies, interestingly, have shown that higher peak obtained values on the North Star. Usually, the North Star peaks around six to eight years of age after this maturational phase of the disease where patients are gaining function. But if you look at the peak obtained North Star score, it's directly associated with the time to loss of ambulation or the age of loss of ambulation. On the left, a North Star less than 22, North Star 22 to 25, 26 to 28, 29 to 31, and then North Star of 32 to 34. And you can see that these scores, the peak obtained North Star is directly related to the age at loss of ambulation when following these patients out longer term. Obviously, our therapeutic approaches can be geared at replacing dystrophin, increasing muscle mass and regeneration, decreasing inflammation and fibrosis, protecting perturbations and calcium handling, and also focused on bioenergetics or mitochondrial dysfunction. I think many of the therapeutics have focused on decreasing inflammation and fibrosis. And NF-Kappa B is the target there with, we use prednisone and deflazocort. And now, several days ago, we had the first, we had the FDA approval of vomerilone, which is a dissociative steroid with a better side effect profile with regard to bone health. And that was recently approved. Chavinostat is an HDAC inhibitor, which also enhances muscle regeneration and reduces inflammation as well. I wanna just briefly discuss the importance of steroid treatment in Duchenne patients on our Synergy Natural History Studies. This was a global prospective, Natural History Studies obtained for a follow-up of over 10 years from 2016 to 2017. We published the results in 2018 in The Lancet, looking at the long-term benefits of glucocorticoids in Duchenne patients. And here, you can see that the purple is the steroid-treated patients. The blue, Kappa-Meier survival curves, are the non-steroid-treated patients. And the age at loss of ability to stand from the floor, climb four stairs, and age at loss of ambulation is prolonged by periods of about three to three and a half years with steroid treatment. And in the old days, we used to stop steroids when patients lost ambulatory function. But we learned that, actually, steroids have a big impact on preservation of pulmonary function, as well as upper limb function. And here was our survival curves, looking at the effect of steroids on overhead reach, hand-to-mouth function. And really, quite strikingly, on the right, the age at loss of distal hand function, which was a median age of 31 in steroid-treated Duchenne patients, and a median age of 23 in non-steroid-treated, non-ambulatory Duchenne patients. So steroids, if you continue through the non-ambulatory years, can prolong loss of distal hand function by eight years. So we generally continue steroid treatment, really, throughout the lifespan. And that prolongs not just gross motor mobility, but also upper limb function. And I think this brings us to the combination, the potential for combination treatments with some of the dystrophin restoration strategies, such as exon skipping approaches. But I'll focus today mostly on AAV microdystrophin gene therapy, which is an exciting approach. This really involves gene transfer, using an AAV viral vector, essentially with a replacement gene, which can replace the function of the absent dystrophin. There's also gene editing and gene silencing approaches. But in terms of the dystrophin protein itself, there are these key functional domains. There's the actin binding domain, which binds to the actin scaffolding. The sarcolemmal binding domains. The C-terminus, or the carboxy binding domain, which binds to the dystrophin-associated proteins. And then there's these critical hinge regions as well. And it turns out that you probably can get by with perhaps three of these hinge regions, no less than that, in terms of a shortened microdystrophin protein. So again, these are the protein domains in comparison to the 79 exons in the Duchenne gene. It's the largest gene identified to date in the human genome. And this brings us to a famous case reported by the group at Oxford. And this actually demonstrates a patient who was actually ambulating, who actually was in, served in the military, the British Army in his 20s. At age 45, he had walked up cliffs in the United Kingdom with just a walking stick, and was still ambulating at age 60, needing a stick, and had a waddling gait. And the thought was this patient, he had an X-linked pedigree, and thought that he would have a small in-frame deletion. Again, here's the X-linked pedigree, very similar mild phenotypes throughout the family. And this was a case that was described by Kay Davies, who's a geneticist at Oxford in 1990. And this patient, surprisingly, despite being able to ambulate at age 61, was missing 46% of his dystrophin gene, with a large deletion from exon 17 to 48. And so there was a large portion of the central protein, which was completely missing. And this sort of laid the groundwork to the possibility that perhaps a replacement gene that was much smaller, that could be fit inside an AAV viral vector, could maintain functionality. So essentially, the goal here would be, essentially, with an AAV viral vector, to replace the full-length dystrophin protein with a much smaller dystrophin protein. This is the patient there in the middle. You can see that 46% of his gene is missing. So essentially, this is this patient's dystrophin construct. The Becker patient was still ambulating at age 61. And this is an example of the SIREPTA SRP9001 dystrophin construct. So essentially, what we're doing here is replacing a long spring with a short spring. And that would essentially maintain functionality and protect the sarcolemal membrane from contraction-induced injury. But the gene would be small enough to be able to be fit into an AAV viral vector. And so here's the approach with different AAVs have been used. But the AAV delivers the replacement gene, the vector DNA into the nucleus of the cell, transformation of the vector DNA into circular episomal DNA, and then transcription of that episomal DNA into RNA, which is then translated into the shortened spring or the shortened dystrophin protein, which localizes correctly to the sarcolemal membrane. And these are a range of AAV subtypes which are currently under development. AAV 8 and 9 have been used in clinical trials. And the SIREPTA construct uses an AAV RH74 derived from a rhesus macaque monkey, which seems to be associated with less complement activation and immunogenic effects and has a pretty reasonable safety profile. But AAV 8 also is emerging as a viral vector, which phylogenetically is very similar to AAV RH74. So again, the message here, the full-length dystrophin gene is too large to package into an AAV, but the microdystrophin gene actually can be adequately packaged into the AAV. And these are the transgenes for the AAV microdystrophin proteins. From three of the companies, there's a couple more in some other companies as well, but they all really have very good functionality in preclinical animal models. And so far from what we're seeing in the clinical development programs, these do seem to be functionally efficacious. So any type of gene therapy, you generally have a promoter which drives the tissue-specific expression, a transgene which derives the functional impact, and then the vector itself, which actually is important in terms of the safety profile and transduction efficiency of the gene. And in the Sarepta product, SRP9001, there's a promoter, MHCK promoter, a microdystrophin transgene, and then the use of the AAV RH74 viral vector. And this can be, in terms of efficacy, we can look at transduction efficacy with vector genome copy numbers. We can look specifically at the dystrophin expression looking at western blot, dystrophin localization and restoration of the dystrophin-associated protein complex with immunofluorescent intensity and percent dystrophin-positive fibers, and then also normalization of the muscle microenvironment by looking at reduction of CK values, and then we can look at functional benefits to the patient by looking at the NORSTAR or time function tests. So just to show you an example in preclinical work, this is the really robust microdystrophin expression in the MDX mouse in treated animals there at the bottom, you can see robust dystrophin expression localized to the sarcolemal membrane, and then also restoration of one of the sarcoglycans, in this case beta-sarcoglycan, and then co-localization of the dystrophin protein with the sarcoglycans on these merged images, and there in the middle you see the MDX, which essentially has little to no expression. And in the clinical trials that have been run, there's really evidence of robust dystrophin expression, orders of magnitude higher than we see in the exon skipping programs to date, but expression levels on the order of 23 to 70.5 percent. The recent phase three trial results, which were announced two days ago, showed 34 percent expression in the patients in that phase three trial, and also really quite robust immunofluorescent fiber intensity in percent dystrophin positive fibers. And what's really quite striking is this reduction in CK that you see really quite quickly. This is dated 12 weeks, but in the treated patients we see the CKs coming down within weeks, just several weeks after treatment, with CK values sometimes coming from 20,000 down to 5,000, on average a reduction on the order of 11,000 versus the placebo patients treated with peri-infusion steroids. Also reduced collagen deposition shown in the clinical development program with a mean decrease in fibrosis and collagen deposition of 26.7 percent. And there is a relationship between dystrophin expression, microdystrophin expression, and functional changes on North Star scores, and here you see data from the clinical development program really showing a saturable response. So when you get dystrophin levels above 30 percent, there actually doesn't appear to be any incremental additional benefit, and also even fairly low levels of dystrophin on the order of 5 percent are also bestowing benefit to patients. But with some of the patients in the decline phase versus patients in the maturational improving phase, you wouldn't expect to see a strong correlation in terms of a Pearson RR value because with some of the patients who are more severely affected, no change in North Star is actually a win in terms of stabilization of disease progression, whereas in younger patients a positive change on North Star is a win. So there is obviously significant heterogeneity in the course of the disease. On the North Star you see this maturational functional skill gaining phase of the disease, which is usually in four, five, and six-year-olds, and then very predictable and consistent decline, which oftentimes occurs at six, seven, eight years of age and beyond. But we can look at these time function tests, such as time to rise from the floor and the 10-meter walk-run, and those can actually be utilized as prognostic indicators to actually allow us to predict years to loss of ambulation in a Duchenne population, much in the way of a Franingham risk scorecard or stratification there. And so this really shows the prognostic importance of the time function test, which we use in our clinical practice every day. When I walk in the room and see a Duchenne patient, I check their time to rise from the floor, and I have 10 meters mapped out in the hallway with tape and so forth. So I assess those functions all the time. Now this is a really important slide in terms of what our treatment expectations are with gene therapy in a Duchenne population. The maximum score is 34. So if we're treating a patient younger in sort of the skill gaining phase of the disease, what we see with gene therapy is a bump in function beyond that seen in an untreated placebo or natural history population. And then if we treat a patient, again, in the declining phase of the disease, what we see with gene therapy is essentially stabilization of the disease versus the anticipated decline in function that we see in an untreated population with just standard of care steroids. But what we hope long term is that we see long term stabilization of the disease over periods of three, four, and five years and beyond. And if we look at a one year clinical trial, we see a divergence from natural history, hopefully, but again, it's a fairly modest treatment benefit in a short term trial. But as you follow patients longer over time, what you see is the actual treatment benefit increases over time as you get greater and greater divergence from the known natural history of the disease. So again, the peak obtained North Star value is a prognostic indicator for ultimate loss of ambulation and disease trajectory. So if we can treat patients early and actually obtain a higher peak, obtain functional status in that patient, that's going to have a long term impact on disease trajectory. If you treat a patient later during the decline phase of the disease, you may see stabilization, but not as high a peak obtained function as you would see with earlier treatments. So Professor Mandel from Nationwide Children conducted the first study where four patients were treated at periods of four year follow up in terms of the improvement in their North Star score. So what you see is improvement, but then long term stabilization for periods out to year three and year four. I think this is really the power of the North Star ambulatory assessment, is when you can follow patients longer term for periods of out to three to four years, you can really see the tremendous disease modification with a therapy such as gene therapy. And if you look at the age of these patients when they're followed at four years, I hear they're age 10.1, 9.7, so they're actually approaching the second decade when you would definitely expect them to be functionally declining. And then the 102 trial was carried out as a phase two trial, double blind placebo. The patients were treated, half the patients were treated for the first 48 weeks, and then the placebo patients crossed over to treatment during the part two or the second year of treatment. So this has been followed up to five years. These patients were four to seven years of age on steroids and had sufficiently low antibody titers. And initially we saw statistically significant treatment impacts in the four to five year old patients. They were only stratified based on age. But in the six to seven year olds, there was no statistically significant treatment effect, but there was an imbalance that occurred that was pretty significant prognostically. You can see the placebo patients all started much higher in terms of their Northstar scores, 24 versus 20. Both patient groups in the six to seven year old stratum remained stable. But I think what prognostically, if you look at the placebo patients, their time to rise values were 3.6 seconds, whereas the treated patients were over five seconds. So prognostically, the data on the right actually shows that those that have rise times greater than five seconds have a much more severe disease trajectory and lose ambulation sooner. So the treated patients with SRP 9001 were actually destined to show functional deterioration, whereas the placebo patients were actually destined to be stable over the course of the year. So unfortunately, the imbalance actually led to the failure in the six to seven year old age group. One study, 103, has actually used a commercial grade AAV product, AAV gene therapy product, much in the same way as the SMA clinical development programs eventually utilized commercial grade Zolgensma, essentially. And they didn't really obtain FDA approval until actually they could demonstrate safety and efficacy with the commercial grade product. So SREPTA has conducted the 103 study. Patients showed an improvement in their NRSR scores, followed by stability over one year. And so this data was contextualized with external control analyses from both placebo data sets, such as the Lilly-Tadalfil trial and the 4-DMD trial, but also our Synergy Natural History study was used to actually have a robust external control cohort, 131 patients, 90% of whom were drawn from prospective clinical trials. And if you look at the patients, again, treated with a commercial grade product, they show a relative increase relative to their external controls. Again, if you look at the time to rise value, 4.2 seconds, they actually, some of these patients were higher rise times. Many were greater than five seconds at baseline treatment, so a much higher function than in the recent EMBARQ study, where all patients had rise times less than five seconds. So again, in terms of study 102, when we look at the treatment expectations here, again, in the young four- to five-year-olds, you expect this increase in function relative to placebo, and that's indeed what was seen. And in the six- to seven-year-olds, you actually, when you contextualize the data with external control groups, the placebos actually function very similar to an external control cohort, whereas the gene therapy treated patients actually showed stability, whereas the external control patients were showing decline. So again, I think, predictably, we see this improvement in function if we treat patients early, stabilization of function if we treat patients later. And then what's really quite striking, to my mind, which is really the most impressive data, is when you follow these patients out three to four years on the NORSTAR, these are the patients that have been treated by Dr. Mendel from nationwide, you see this bump in function followed by long-term stability, whereas the external control cohort are predictably showing really quite significant declines in their NORSTAR values. And in fact, when you look at each individual treated patient versus their own predicted trajectory using their baseline values on time function tests, each of the patients actually has a really quite impressive stabilization of function over their predicted disease trajectory. And again, I'd like to just show you some videos here. This is, you know, again, prototypical patient attempting to run, eight years of age, six minute walk distance of about 330 meters. And here's some examples of patients I've treated. This is a patient pretreatment from the 103 trial, so we know he actually got the gene therapy product. Here he is walking down the stairs, holding on to the railing with difficulty going down the stairs. Here he is six months after gene therapy treatment, ambulating up the stairs, so really quite impressive. Here's the stair declining, again, six months following gene therapy treatment. And here he is on the playground, climbing up the playground structure. So this stair climbing actually translates to the real world environment of the playground. You literally can't pick this kid out from the remaining kids on the playground in terms of his ability to go downstairs, run. This is during the pandemic, he's dutifully wearing his mask there. And then here he is. Dad is actually a tech savvy person and actually obtained a drone with a video. And here he is actually running in the playground. And I've been taking care of Duchenne kids for 35 years, and I have just never seen a Duchenne kid run like this with this degree of endurance and really normal running function six months after treatment. And here he is riding a bicycle as a newly acquired skill, which is, again, pretty impressive for a Duchenne patient. Here he is two years post gene therapy treatment. And on the left, you remember back to those videos we showed in terms of compensations and the Gowers maneuver. But here is literally two years post gene therapy on the left, essentially hopping up with really no Gowers sign. Here he is actually hopping, which, again, we don't. I only got him a trampoline. And here he is six months after gene therapy. We don't recommend trampolines to the same patients. Yeah, you know, again, I've had patients develop rhabdomyolysis who've actually been on the trampoline. results here. Here's five patients I've treated who I've treated in the 103 program. So this is open label, so we know they actually got gene therapy. And this is their follow-up two years after gene therapy treatment. And on the left is a seven-year, four-month-old, 25 months post-gene therapy. Here's a seven-year, 11-month-old, 24 months post-gene therapy. Here's an eight-year, six-month-old, 28 months post-gene therapy. Here's a nine-year, six-month-old, nine-and-a-half-year-old, two years after gene therapy, you know, still running. And then impressively, on the far right, this is a 13-year-old who actually was treated. He didn't have normal running ability at the outset, but he's actually maintained his running ability in a stable fashion for up to two years post-gene therapy treatment. So pretty impressive stabilization of function in a 13-year-old, still running, not running normally, but still running with stability. And again, we presented the data to an FDA advisory committee. The advisory committee recommended for accelerated approval for the Delon Dyser Gene Moxie Parvovac or the SRP 9001 by a vote of eight to six. And subsequently, the FDA granted accelerated approval specifically for four- to five-year-olds where there was some placebo-controlled data on June 22nd. We actually literally were able to dose a U.S. patient with CCS, Medi-Cal, or Medicaid insurance three days before his sixth birthday in early August. So it's really been quite gratifying. And there's Professor Mendel and Luis Rodino-Kleipak, the two co-inventors of the Delon Dyser Gene Moxie Parvovac gene therapy treatment. I do want to comment, this is publicly available data that SIRREPTA just released two days ago from the EMBARQ study, really showing the top-line results. And this is on the SIRREPTA website, so publicly available information. There you can see again on the North Star a tendency for the four- to five-year-olds to show a greater treatment effect. The study did not reach the primary endpoint, but across all of the time function tests, which were pre-specified in key secondary endpoints, time to rise, 10-meter walk-run, four-stair climb, as well as the community wearable device, the Stride Velocity 95th centile device, there were statistically significant treatment effects that favored the gene therapy-treated patients. So really, I think the investigators are quite encouraged by these data. If you think back to the videos, you know, we tend to show videos of kids rising from the floor, kids running, and kids climbing stairs. And those are the granular levels of function that I think we're able to demonstrate in a one-year trial with time function tests that are just not the NSAA, I think, in a four- to seven-year-old age group, is just not responsive enough. And keep in mind, this trial enrolled patients all with time to rise from the floor less than five seconds, so they were a much healthier group. And I want to just point out, this is data that's been published by Francesco Montoni and Eugenio Macchiri, showing the performance on the time to rise from floor on the left. And these are latent class trajectories. So these are four different trajectories seen in Duchenne patients. And what you find is striking here is that every single trajectory, once you hit a time to rise of five seconds, actually is very steep in the upward pattern. There's no patients that show stability. They all decline. So I use a five-second rise from floor value as really a threshold for the onset of functional decline in Duchenne muscular dystrophy. But every patient in the Sarepta Phase III trial had a rise from floor decline. Those patients, essentially, even at four to five years of age, they all have rice and floor time. in the clinical trials, but look at the North Star item there on the right. This is the same publication. These are curves, incidentally, that were like supplementary materials, so you have to go back and actually pick them out of supplemental materials, but here's the North Star item. It's showing the percentage of patients that actually go to a North Star score of zero on the rice and flour function, and essentially what you see there is that the decline on time to rise or time function tests occurs in all cases prior to age seven, but the North Star value doesn't really, you don't lose North Star values until you get to age eight and beyond, and so the patients, 86% of the patients in the clinical trial had an NSA rice and flour score of one, so they didn't show, it's just too gross a measure to show decline in the course of the clinical trial. They also don't develop in a one-year trial normal function, so I think this just points out the relative degree of greater sensitivity in the time to rise versus the North Star score, and what was really quite striking that Sarepta showed in their publicly available data, if you look at actually every patient in the trial had a rise time less than five seconds, and if you look at the odds ratio for the risk reduction in terms of the risk of progressing to a threshold rise time of five seconds, there was a 91% risk reduction overall, highly statistically significant in risk of progressing to a rise time of greater than five seconds, which I thought is really quite compelling. So just to conclude, AAV gene therapy improves histology, microdistrict quantification has been determined by the FDA to be reasonably likely to predict clinical benefit. For patients in the skill-gaining phase of the disease, usually seven years and younger, microdistrict gene therapy leads to improved function, higher peak obtained function. For patients in the declining phase of the disease, AAV gene therapy stabilizes function but doesn't necessarily improve function, and then the treatment benefit has been shown relative to the natural history data and the propensity match controls to be durable for periods of four years or greater. I'd just like to acknowledge our research team at UC Davis as well as our funding sources over the years. And with this, we will pass the presentation on to Dr. Cefalone. So we're going to change gear a little bit. Having reviewed now the major milestones in terms of gene therapy in Duchenne is obviously this is the end of the beginning in a way, but what are the next milestones and improvement and challenges? So these are my financial disclosures. My topic is really more about bucket concepts about what is the future and the improvement for gene therapy. So nothing specific to a particular product really. And we're going to review a little bit building on this current milestone that we just reviewed. So, you know, addressing preexisting and induced AAV immunity, the ability to redose, the safety. So we have learned very precious lessons and mitigation strategy that is not just for Duchenne but for the whole field of gene therapy. And this has been a very rewarding learning in the field. Also the work that is ongoing in terms of next generation vectors and how can we improve the vectors for better safety and better efficacy. Manufacturing, obviously we need to improve the scale and decrease the cost for these gene therapies. The durability and dilution effect, let's remember the targeting skeletal muscle and the heart is very different than targeting anterior horn cells like in SMA. So the challenges are quite different. And then what is the therapeutic window for dosing and what are the therapeutic expectations, right? This is a more chronic progressive disease. And so what we're targeting in terms of effect and what is really the best therapeutic window for dosing. And then I want to really put it into, okay, the big picture. If we do have novel disease modifying treatments that really come from the bench into the clinic, how can we do the very best job for our families and patients to access this medication in a timely, proper way? We're going to talk a little bit about the role of newborn screening and the fact that we still have major diagnostic delay in Duchenne. So this is obviously a big milestone. And I just want to remind everyone that there are several different constructs out there. All built with a promoter. There is a transgene. So there are difference among the different programs that you can see listed here. Where the transgene product has differences. There are obviously some domain in the gene and the proton that are essential for function. But as you can see, the different transgene have different hinges and different rod repeats. So they do have difference in the transgene. And then of course the AAV serotype is different across the program. But this is obviously one of the major milestones. If you look at the list of option, we have discussed the SRP 9001 just because the program is obviously the one most advanced at this point. But these are coming rapidly. And I'm so glad that Craig showed the case of Kay Davis because I want to remind to the younger crowd is how important outliers are in science and in our rare diseases because the outliers are there to teach you something special if you pay attention. And obviously that patient of Kay Davis really was the brilliant clue to say, okay, we can construct an amine or micro dystrophin gene that still has quite remarkable function. And that's how really the gene therapy field moved forward. So let's talk about why AAV vectors are the most popular right now. They have several advantages. So they have no known human pathology. They're replication incompetent. They can target a range of tissues including crossing the brain barrier. They have a low pre-existing immunity in the general population. We're going to talk a little bit more in details about that. They are quite efficient in transduction and they can obviously use for systemic delivery. So we're talking about IV delivery of these vectors. There are several serotypes available and important for our particular monogenic diseases that they're non-integrating. So they sit as epizome in the nucleus but they don't integrate. And this is important because if you remember in the early ages of gene therapy there was integrating mutagenesis and leukemia and cancers and that was kind of one of those barrier in the gene therapy field. The disadvantages as we have seen is that some patients do have pre-existing antibodies to this AAV. They never had disease. They're not pathogen but they do have antibodies. Therefore, that's clearly an exclusion for using this drug for two reasons. One is that transduction is going to be inhibited by the antibody second to safety obviously. It's very, it's a risk. There is 100% seroconversion after you get dosed. So that's open up the question of need for re-dosing. They do have a relatively small payload capacity of less than 5KB and although the milestone we have overcome that with the mini and micro dystrophin gene that is still a factor. And obviously the manufacturing complexity and the cost and also this is very important to remind everyone that to target skeletal muscle and heart we are using the highest doses in the gene therapy field across not just neuromuscular but in general. So there are extremely high doses. And remember these doses are based on kilograms. So you know Duchenne, they're now babies and you know they grow and they're on corticosteroids. So this is based on weight. So this is important to remember because obviously this is also a challenge to reach enough target tissue. So the pre-existing seropositivity is a lot that the family really worry about this and they ask. And obviously it's an exclusion criteria for dosing either in clinical trials or in real clinical practice because obviously if you have antibodies neutralizing or total antibody there is decreased transduction and a very high risk obviously of immune response. So you don't want to do that. And there is unfortunately cross reactivity that exists among different serotypes but it's not 100%. So obviously every program use different AVV. And it's very interesting because if you look at the data there are geographical variations. So we do start having emerging data in the United States about seropositivity for our programs ongoing. But if you translate that into the world those numbers are much higher and we should pay attention to our global, you know rare diseases, what is the future there. So there is emerging data in literature and it's very important to remember each gene therapy program has their own eligibility and say validation. So if a patient come to me and say I want to be tested for all the antibodies for all the gene therapy now, it doesn't work that way. Because every specific methodology is different. Some use total binding versus neutralizing antibodies. There are different cutoff, say validation and reagents. And really they're very specific to the specific drug and program. And is remember that this phylogenic relationship among the AAV, you know, is determined by clades. So AAVs that belong to the same clades are more similar, less similar. So although there is a large cross reactivity if a patient test positive let's say for an AAV9, there is still pretty good reason to test for AAV9 or AAVRH74. And those numbers we don't have strong data yet but they're accumulating from practice. And so they can still test negative and maybe be able to access in a different program of AAV. So that's very important to remember. Data published now, there was a study specifically for the AAVRH74 vector. And this is the seroprevalence in Duchenne muscular dystrophy patient in the United States. And they test 101 patient between the age of 4 and 18. These were Duchenne just in the States. And they had their own cutoff which is equal or less than 1 to 400. And as you can see the seropositivity was about 14%. So that's at least what we can tell our patient that that's where it stands for that particular gene therapy and antibodies. So people are already thinking, okay, well that takes out about 14% of patients that cannot really access this. So people are already working on that. One strategy is obviously pharmacological agents and immunomodulation including plasmapheresis. And there are studies ongoing on how to overcome that population that already has seropositivity. Other strategies is epitope masking meaning that you can actually try to code the AAV surface with lipid or nanoparticles, cell-derived vesicles or exosome. We're going to talk a little bit about that. And really to kind of decode the AAV to escape the immune response in the antibodies and then reach the target tissues. Directed evolution of AAV, you know, like RH74, we always find tweaked AAV capsid with different epitopes. So that's another strategy with less sensitivity to neutralizing antibodies. And then alternative strategy is this concept of the full to empty ration. And so empty capsid which do occur. So when we inject this dose, it's a high dose of vector. Not all those vectors are actually full. Some are full, some are empty, and some are a mix, not full at the correct dose. And so that can be actually kind of a decoy for the immune system. So people are really thinking about using empty capsid as decoys for the immune system. The other thing the family now are really bringing up and we as providers or clinical trialists and clinicians is the shedding and seroconversion, right? These are usually bio safety one class when we dose this patient either in the clinic or in the clinical research center. But is the vector shedding and what does that really means for family members? Remember, Duchenne family, you know, there are families out there with more than one sibling. Obviously, that's the most crucial, right? If they become seropositive because a sibling has been dosed and that will prevent them from being dosed. So and some families because the data is still not clear, they were going along really extra length in kind of separating siblings for months or, you know, leaving several. Of course, that's obviously not everybody can do that first of all and really will be very important to actually have data to guide our family and say, okay, this is the risk and this is really what you should do. Maybe it's just three days and not three months. There are studies emerging from animal models in humans and I think there's going to be more and more to be learned about this. This is very important. So in naive mice, mice that were actually exposed by topical ocular delivery of even very high titers of vector and this is for the SRP9001. These are, they've been presented at a different meeting. They remain seronegative and there were control as they were exposed intramuscularly and so this data suggests that probably there is the low risk of seroconversion even from exposure of high doses and from shedding. There are also some emerging data in human in some of the patient in the 103 Dandever study and we learned that the vector DNA concentration peaked very rapidly at day one after dosing in saliva and urine and at two weeks in feces. This was measured by digital draw PCR and the mean concentration of all sample declined by more than 99% by week four. So and interestingly in the crossover study of 41 patient the placebo control so you know 50% of patient get placebo or drug and then they switch. None of one does switch seroconverted so those are also some kind of reassuring emerging and we're going to learn more with the data for the phase three are not available yet so there was zero seroconversion in that trial. And so overall it seems like the shedding is less of a concern and the risk of seroconversion following exposure is very, very low. Novel vector so that's the other thing as we're going to talk about safety. So these vectors do are very immunogenic still and they're challenging in terms of you know high dose and really trying to minimize safety and liver exposure. So some of the strategy that are in the works is really to tweak and engineers these vectors to make them less immunogenic, more powerfully targeting the target tissue so that we can use lower doses, less liver toxicity and more efficacy. So one such example is the myo AAV that has been now studied in mice, non-human primates and even in human cell culture and it has demonstrated this is published 25 to 50 times greater gene expression in skeletal muscle. What that means that you can use much lower doses and with 10 to 15 times greater expression in cardiac muscle which obviously for Duchenne is crucially important and with 50% reduced delivery to the liver. So what this means is that these are going to be the future, the next generation vector with less toxicity, lower dose and hopefully you know less costly and complicated manufacturing. Another such example and this is not a comprehensive list, there are many labs working on this is the SGT003 which is really the next generation vector for the solid biosciences program which I show you in that list of the programs and in preclinical in vivo and in vitro study also showed two to three times greater delivery in expression in skeletal and heart muscle with decreased tropism to the liver and this I think that's biosolid is moving back into human trials with the new IND with this engineer version of their AAV9. But there are other ideas that are being studied, non-viral delivery vessels or exosomes, they are not in humans yet but the idea is that exosomes are really natural nanoparticles so they really communicate between cells in several tissues so obviously by definition they are inherently non-immunogenic and the other big advantage is that they can accommodate very large cargo payloads genetically so they're not restricted to the small 5KB and also they can have specific tropism to different tissues so this can be used also for epitope masking so to encapsulate AAVs and so this is in the works, there are already some emerging data for AAV9EV in mice and I think that this is going to be something in the future so obviously gene therapy has still challenges but people are very, very actively working on this other delivery mode especially for muscles. And we have not discussed safety, safety obviously is a major and when we talk about safety for gene therapy is two flavors really. There is an immune reaction against the capsid and the vectors and the immune reaction and safety concern against the transgene. So some of the adverse events are really common to all programs versus other being very specific to the specific construct and capsid and program of different manufacturers. So for example, the most common side effects is nausea, vomiting, decreased appetite and fever. This is really seen across all programs. Asymptomatic laboratory abnormality, especially transaminitis have been seen commonly across programs and then less commonly true liver toxicity in immune hepatitis. This has also been seen across different products and some rhabdo. This is in SRP 9001. There are then complement mediated immune reaction against the capsid, one thrombotic microangiopathy, acute kidney injury and thrombocytopenia. There was one death as you probably are aware of due to acute cardiomyopathy at day seven post-dosing. This was the Pfizer program that was put on hold by FDA. That's the only death so far across all programs for Duchenne up to date. And then systemic inflammatory response and thrombocytopenia, that's the SGT001, that's the biosolid program. So some commonality there. But mitigation strategies of course is screening labs to make sure that people don't have, they're not seropositive. There is a very intense labs monitoring for about 12 weeks post-dosing weekly. Lots of labs, a lot of work when you translate from clinical trials to real life. You really need to have a team to really follow all these. Careful clinical monitoring for symptoms. There is nausea and vomiting and then there is nausea and vomiting. Projectile vomit should really raise that something else is going on like cardiomyositis which we're going to talk next. But obviously we have beautiful medications that work like Zofran and Pepsi and we love them because they really, really help. But you know, in some cases this has required hospitalization and IV, especially for the steroids because these kids need to have additional steroids for 90 days after dosing. And so if they don't keep down those extra steroids, you really put them at higher risk for an immune response. So you really need to pay attention. And the liver toxicity has happened. There's been no death from liver toxicity but has required plasmapheresis, IVIG, hospitalization and other strategies for that. But the other huge learning, and this has been a great lesson to collaboration between industry and academia across different program is really the shared learning because there were these five cases of acute myositis, three with acute cardiac involvement. So these were kids that all of a sudden that had acute weakness, muscle weakness, some bulbar swallowing difficulties and some with cardiomyositis and elevated troponin. And these occur within three and seven weeks post-dosis and all five patients really belong to different drugs constructs. So across companies that were using different AAV vectors, different promoters. So it was, this obviously was a safety signal across the different programs. And so it wasn't really related to the capsid or the promoter or the dystrophin, the mini dystrophin gene. So it's really was concluded that this was an immune reaction against the transgene in patient that were cream negative setting for that particular portion of the transductor gene. And was really a class effect of T cell mediated. So the mitigation plan quickly turned around was the really patient with certain mutation in the prime end one to 17 really have been now excluded across different programs. And you can see the exclusion criteria. And there is more obviously to be learned there about, it seems like there were really large deletion between the one and 17 exon. So in fact, if you look at the label now, for example, for the SRP 9001 that is approved clinically, it's the exclusion is actually smaller than one to 17 is only exon eight and nine, if I'm correct. So, but this year is gonna evolve moving forward. So this is, you know, was already brought out by the, by Craig, what is the therapeutic window? We know the babies are born with extremely high CKs at birth. So we know that the changes of injury muscle necrosis in the muscle are there already way before we can see clinical symptoms, right? So that's obviously one of the many question out there is what is the sweet spot? What is the best therapeutic window for this gene therapy? And we're gonna obviously learn more as more data from clinical trials across broader range of patient will become available. But this bring us to the big problem, which is still a big problem. We have a ginormous diagnostic delay. And this is a work that has been done through surveillance with a long standing collaboration with the CDC through the MDSternet, this is all published. We did a study with boys that were born between 82 and 2000, the mean age of diagnosis was four or five years of age, okay? And this is really because people don't screen for CKs, which is very cheap, universally available, and they just don't do that. And so there is a two and a half years average delay from the first symptoms notice to until someone, the light goes on and they check CK and they realize, okay, this is not just normal growing pains, this is Duchenne. And if you look at black and Hispanic and minority, the delay is even greater at all milestones, CK measurement, DNA confirmation for the diagnosis. So that's a fact. So we did a lot of intervention with the AEP and the CDC to really raise awareness of milestone and really bringing up lower threshold for CKs, you know, delay in ambulation, think muscle and a lot of really tough work. And so we re-evaluated with the more modern cohort of boys born between 2000 and 2015, again, with the same methodology through the MD-STAR-NET. And this is geographical surveillance. So these are not cohort single clinic, they're really public surveillance going to the chart and really abstract the data. And unfortunately, the diagnosis was still stuck at 4.9. So we use this really also to, again, we proved again that if you're Hispanic or black, all of those milestones are much delayed. And remember, so right now we have a product that is approved for four and five years old, but if we don't diagnose them until seven, the window is closed for many of these kids. And really, if you don't diagnose early, you also delay corticosteroids, another standard of care, which have already shown that improve outcome by survival by 10 years. So we're not talking just about gene therapies, really access to care that has a very powerful impact in terms of outcome. So does delaying diagnosis really matter? I hope that as a group like you, I don't have to convince you that this is a genetic disease, obviously genetic counseling and reproductive choices and have a Duchenne kids in the family is dramatic enough, but if you have two or three, that's really an incredible burden. And then also during this diagnostic audits, many kids get liver biopsy because they see their AST, ALT, they're elevated, but nobody checked the CKs and it's really not liver disease. So what we refer to diagnostic audits. And then of course, society has changed. And now that we have so many, not just the gene replacement approaches, but also downstream antifibrotic, anti-inflammatory, there is an array of opportunity also to study early, right? So, but if we don't diagnose you early, you can't really access trials that usually are very strict in terms of age range. So obviously many good reason. And so what's going on with numerous screening? Do we have a case for Duchenne in this stage and age? And there has been since the seventies, large numbers of numerous screening pilots for Duchenne that all eventually ended or failed. Obviously there wasn't really much in terms of treatment. And one of the most important principle for numerous screening is really, okay, do you have a treatment at seven days? What's the difference if you diagnose at birth versus young kids? And so obviously they were doing, but now things are really changing rapidly. So the most recent pilot was not in Ohio State with the CKs, two tiers, so high CK and then DNA testing. New York State is really the most recent pilot. These are some of the results. Many papers published out of this pilot. Obviously the pilot started right when COVID began. So the target number did not reach, but yet again, it was a positive pilot that showed that this is feasible. It also provided incredible data to really, now we have an FDA approved CK-MM kit. So, which is crucially important to really make the case to the RASP. And so, although PPMD submitted a nomination package through the RASP, I think back in February and it was not accepted for full review. We went back in the spring and in June actually, and after elevities was actually approved. It actually passed unanimous. I think there was one absent vote. And so right now the Duchenne case is sitting under a full review, evidence review, and we shall hear the recommendation in a few months. At the same time, though, few states already went their own way and that's how newborn screening works in this country. So in New York State, the governor just signed a bill and so New York State is gonna start newborn screening universal for Duchenne actually this spring. And I think that Ohio has already passed as well. And so, as you know, it's a mixed process for newborn screening and states can make their own decisions. So that's really the learning and opportunity while all these other advancement in therapy, this is gonna be very, very important. And so this really make us think about is the criteria for population screening, the Wilson and Youngdon criteria, which has really been, they stood the test of time since 68, but our society has changed dramatically. So I think that these are all the thing that needs to be checked for newborn screening to be approved and I think we're getting very close for Duchenne, but there are still some challenges, right? Are we really gonna treat these kids in seven days or do we need to wait four, three? So that's still a sticky point. But I think that many people are thinking about this and Europe is might be already exploring other proposition that if you do have the option to be tested for a disease that now has treatment, would you do it? And vastly, population survey says that 80 to 90% of families say, yes, I want my baby tested. And also the data also for Duchenne is really that although there is stress both ways, right? Diagnostic odyssey versus the really few years of honeymoon not knowing in a way, but I think that the balance is really towards yes, we do need to know early, to intervene early. And so family are really thinking that yes, overall the preference is for newborn screening among parents of healthy babies. And also when you talk to Duchenne families that had been identified through pilots newborn screening or that they experienced a diagnostic delay, overwhelmingly I think that the field is moving towards, yeah, we want newborn screening. I'm gonna leave you with some food for thought and I don't have answer for this, but all of us that have experienced the SMA, first gene therapy, we were all inundated by emails of families from around the world say, can you give me gene therapy? Can I come to you? And this was from the world, these are rare diseases. And of course we know that some centers have international centers, this is not new, people come, they pay cash, you know, and they get whatever medication they can afford. But, you know, even in the United States, do we really have equity and access at this point? And even if we have newborn screening, is that really leveling the field or what's the next step? And we know the challenges of approval versus access. So, and I think that from what we have learned for much more common diseases, we have an opportunity here in rare diseases to really say, you know, are we pay attention? Are we trying to prepare to really make access available to all who are good candidate for this? And not just in the States, but in the world. And how do we do this? These people that come maybe, and then they go back to low resource settings, you know, we're not gonna be able to follow them. We don't really know the safety at 20 years for this gene therapy, so we're just sending them back, and then what's the plan? So many issues there. So in conclusion, I think that there is a lot of good work already happening, but that's the future. We definitely need earlier diagnosis, being by doing better as clinician or through newborn screening. We do need to really pay attention to access to novel treatment, approval versus access, and improve that. Improve the cost of new drugs. To really sustain the combination therapy model, nobody is stating that there is a cure for Duchenne. We're not close to that. And so if we're using combination therapy, you know, what is the cost and how is gonna be the access? It's really a sustainable model, and how can we do better as a society? Because this is not a provider problem or a manufacturer problem. It's a society problem. We need to do better and address that. Obviously, institutional readiness and support for specialized multidisciplinary, it takes a team to do this. You cannot just give gene therapy and then see them in three months. And remember, cystic fibrosis, they have almost 130 specialized center around the country. When you talk about SMA and Duchenne, we have 29 states covered with highly specialized clinics, so we're not quite there. So depending where you are geographically, you might have to travel hours and then, you know, weekly labs, and who's in charge if you end up with liver toxicity? Are you gonna go to your pediatrician, you know, 300 miles away that they're not supposed to know a lot about gene therapy, right? So there are practical issues. Obviously, improve equitable access to diagnosis, standard of care, which is huge. You don't just give this costly gene therapy novel. There is still a standard of care that needs to be implemented because all the data from trials is on kids that are on best standard of care. So now, if you translate in real life, not everyone is on corticosteroids, and we have data about that, but that needs to be kept in mind. And then, really, it's a small club. If you go around talks about gene therapy, you're gonna see a lot of the same us. So we really need to bring more train, and so I'm so glad that we were actually invited to this meeting because we need young, neuromuscular, specialized people that are gonna say, this is exploding. This is not just for neuromuscular. This is gonna be for pediatric. It's Batten, it's Rett's disease. It's exploding, and we need the expertise. And this is beside everything else that is exploding in other neurological diseases. So a lot of good, good work, and like I always tell to my friends, none of us is gonna be able to retire anytime soon because this is gonna keep us very, very busy. So thank you for your attention, and I think we're gonna take questions. Thank you. Because they're really a modified Becker, are you still versus exon skipping, but they might have, I mean, one missed the window because of the four to five-year-old age, but they only have like a three deletion mutation, and more likelihood of having more complete gene with exon skipping, whereas where you have micro dystrophin, you only have like a, I think it's like 16 exon mutation, even though all of them are a little bit different in the transgene. How do you decide with that family what's best to go for it? I mean, the gene transfer therapy is really new. Thanks. Yeah, so again, I think, you know, in answer to the first question, I don't think neuromuscular clinicians are feeling that steroids in any way can be discontinued post-gene therapy treatment. I think that there is still active inflammation and damage going on, and I think the children in the trials have all been continued on stable doses of corticosteroids. I think the interesting question is going to be whether gene therapy can perhaps down the road result in perhaps some sort of steroid sparing possibility in terms of, you know, perhaps alternate steroid types or different regiments, perhaps high-dose weakened regiments could still result in efficacy, or perhaps an alternative steroid such as mormelone, you know, might be efficacious on top of gene therapy. So I think those are going to be remaining questions. You know, I think in Becker muscular dystrophy, you've got an in-frame deletion present from the time of fetal development, you know, with different expression in, you know, every skeletal muscle cell in the body. And so I think with any of the exon skipping strategies or gene therapy, you know, to think that we're, you know, necessarily converting a Duchenne patient into a Becker patient, the average life expectancy of Becker dystrophy worldwide is 67 years of age. So obviously, you know, if we could achieve that with some of these dystrophin restoration strategies and cocktail approach, I mean, that would be huge, but we're not there yet. With regard to exon skipping therapies, I think that, and I'll be really curious to see Dr. Cefaloni's thoughts on this as well. I mean, obviously, when you have FDA-approved exon skipping drugs that, you know, are producing meaningful amounts of dystrophin and can be continued long-term, I think that's, you know, pretty compelling. So there's certainly not a reason to withhold exon skipping therapy, you know, prior to consideration of gene therapy treatment. I think some of the next generation exon skipping drugs are going to produce hopefully orders of magnitude higher levels of longer dystrophin constructs. But I think that the data from the gene therapy programs does look, you know, pretty compelling, you know, versus what we see with patients that are perhaps having, you know, one or 2% levels of dystrophin expression. But I think certainly, you know, I don't know of many payers right now that would necessarily pay for both, you know, a gene therapy approach and an exon skipping approach. If you have a one-time treatment that can produce a durable effect for five years or more, that's probably gonna end up being more cost-effective than, you know, years of exon skipping therapy. But I think exon skipping for those percentage, small percentage of patients that have exon skip amenable mutations, you know, still could be a viable additional treatment option, particularly if a child's showing functional decline. But I'd like to get your thoughts, Dr. Sheffaloni. Yeah, no, I agree. The exon skipping as they currently stand, I think that the dystrophin expression is modest. I think the efficacy is modest. And I think it's only include a small portion of patients. Remember, as it stands right now, they're weekly IV infusion for the rest of your life. So those, you know, when you translate that from research to real life, patients and family has, that's, it's part of the decision. There are very exciting next generation PPMO that I think that from preclinical data are showing dramatically improved expression and so if that pans out and also with dosing that is more spread out rather than weekly, maybe once every two months, that's obviously is gonna make that conversation very different. And I think that is all very, very good. I mean, we have learned compared when I trained that even a little bit of dystrophin and we always had that, oh, 30%. Well, that has moved way lower. Yet, you know, it's also the window of opportunity, right? Is when are you gonna treat and then for how long? So it's the complexity of having options. We should embrace and try to do the best and to do our best, we need more data, right? To guide and say, okay, what will be best? But things are happening, definitely moving forward for exome skipping and obviously for gene therapy. And remember also the exclusion, right? Gene therapy that are still mutation exclusion and so forth so we really need to broaden something for everyone. And the steroids because if you have been doing steroids for 30 years like I have, my dream is a world with no steroids, right? For not just this disease, for many other things. They're a cursing and a blessing. It's a wonderful blessing because the efficacy data blow everything else out of the water for better or for worse. But maybe, you know, better alternative to steroids and maybe decreasing the dosing and exposure with less long term side effects. So that's the hope, I don't think we're there yet. But I have to tell you in real practice, for kids that have got the gene therapy and they get up from the floor like, okay, I've never seen a Duchenne doing this. Do I increase the dose of steroids by weight? No, well, let's keep it there. So, you know, people are already, we get that question all the time. So we're cheating already a little bit, but definitely not stop. restriction will shift or change for older patients? For, I'm sorry, older? Older DCM patients. Yeah, I think most definitely in terms of gene therapy. I think we have some data on older ambulatory patients and non-ambulatory patients. I think that the time function test from the phase 3 EMBARQ trial does show that you see similar benefit in terms of the time function tests in the 6 to 7-year-old age group versus the 4 to 5-year-old age group. So there's not really a biologic rationale for the age restriction of 4 to 5. And I think there's a real possibility that the age restriction is going to be expanded, broadened. I think the label will be broadened. And hopefully, we'll see a label that includes all ambulatory children. I still think there's more data that needs to be obtained in terms of broad expansion to a non-ambulatory population. We need more safety data, some more efficacy data, different expression data, and so forth. But I think, certainly, I think initially we'll see, hopefully, broader labeling for the ambulatory population. And the trials are being conducted to also go the other direction. The trials are being conducted down to two years of age. And I think we'll see trials subsequently dosing down to six months of age, which I think the newborn screening is really going to lay the groundwork to potentially treat these patients within the first year of life. Yes, this is a steroids-related question. So I'm an adult neurologist. I take care of young men with Duchenne muscular dystrophy. When they come to me at the age of 18, 19, 20, et cetera, many of them either never were on steroids or haven't been on steroids for 10 years. They usually have pretty strong feelings about steroids. How much should I be pushing them to restart steroids or start steroids for the first time? Well, I think one of the, I think the data does show there is a potential impact in terms of distal upper limb preservation. And in those older patients you mentioned, you're probably talking about preserving distal upper limb function as well as pulmonary function testing. But I think now that we have four, and pathologic fractures are not insignificant in these patients as well as weight gain. And I think that it's going to be very interesting to see the role that Vimoralone will place potentially in that older population with the bone sparing properties of Vimoralone. As well as hopefully we'll have to learn much more about the dosing of Vimoralone. I don't think that you're going to be jumping in and treating an adult or a late teenager with six milligrams per kilogram of Vimoralone. I think we're going to learn over time. But I think probably a lower dose, as most of the adult patients who are on prednisone or deflazocort are on far lower doses, as their muscle fibers are not really increasing over time. You're only really dosing the fatty tissue and connective tissue if you just keep marching the dose up with weight gain on a per kilo basis. So I think it'll be really interesting to see with Vimoralone, dissociative steroids, and perhaps other new regiments. What are your thoughts, Dr. Cefalani? Well, I think that when I see patients, young adults with Duchenne that have not been exposed to steroids, it's a great missed opportunity. Because we now know that the delay in ambulations, less scoliosis surgery, delaying cardiomyopathy, the advantages are numerous. And we know this now by large data sets and long perspective. So I really think it's sad. And we're really, you know, their trajectory is much more rapidly progressing than the one who have been treated on corticosteroids. Having said that, it takes a village to do it right. But from the studies, we know that about 50% of in surveillance data, Duchenne really exposed to corticosteroids. So when we talk about best standard of care, well, is it really implemented? I think we're still far from that. We are improving because we're raising all these. But it's a lost opportunity. So what do I do with these cases? Well, sometimes I convince them maybe the high dose weekends. And really, I'm thinking heart, diaphragm, upper limb function. But is there good data to really push? No. So it really is, it should have been done to begin with. But they are out there. So yeah. Just one other consideration along those lines is that there's increasingly non-ambulatory clinical trials that are being conducted in Duchenne muscular dystrophy. And most of the industry sponsors are designing these trials to require stable dose of steroids. And so if you don't treat these non-ambulatory patients, in many cases, they're not eligible for these clinical trials, such as cell-based therapy, CAP-1002, and some of the gene therapy, non-ambulatory trials, and so forth. So I think that's another important consideration that I have that, in the discussion with my patients, is just the importance in terms of potential for novel therapeutics and clinical trial participation. All right, so I'd just like to thank everybody for coming. I hope you found this a valuable part of your day, and I think it's time for us to adjourn, but I'm sure we can stick around a little bit if anybody didn't get a chance to ask a question. Thank you.

Duchenne muscular dystrophy

clinical management

rehabilitation

precision therapeutics

North Star Ambulatory Assessment

steroid treatment

gene therapy

muscle function

preclinical data

clinical trial data

pre-existing antibodies

viral vectors

manufacturing