Welcome everyone, we're at about eight, so we should probably get started. I'm Catherine Mosier, I'm a pediatric physiatrist from Akron, and I have the privilege of moderating today's session. Before we get started, I want to just call to your attention a couple of things. One is, we do have a pediatric networking dinner tomorrow evening, and we still have spots available, so if anybody's interested, please register. It's free, and it's gonna be a great time. We're gonna present some awards for pediatric abstracts this year, and just have a time of networking and fellowship, so please join us. And then, when we're done with today's talk, we will have time for questions, and for those who are joining us online, please submit questions, we'd be happy to field those as well. So, our talk today is called Navigating Through the Available Therapies for Duchenne, How Do You Choose? Which is really exciting that we have the opportunity to even have this discussion, because eight years ago, we wouldn't have been having this conversation, but in the last eight years, we've seen eight different therapies that are FDA approved specifically for Duchenne, and many more in the pipeline. So, our first speaker is gonna be Nancy Kuntz, who comes to us from Lurie Children's Hospital, where she is the Medical Director of the MOTSA Foundation Neuromuscular Program, and Director of their MDA Care Center. Nancy's been involved in many, many trials over the years, and she's also been a member of the Synergy Group, and she is a Professor of Pediatrics and Neurology at Northwestern University Feinberg School of Medicine. And then we will have Craig Zaidman, who is a Professor of Child and Neuromuscular Neurology at Washington University in St. Louis, and has been actively involved in trials for the Syrupta Gene Therapy and Givenostat. So, I'm gonna give it over to Nancy. Oh, can we, can you guys see the slides okay? Or should we dim the lights a little? That's right, could somebody dim the lights for us? Thank you, and then you just hit play. Yeah, well, we'll be okay, I think, if we dim the lights. Will you guys be okay? Did you have enough coffee? Okay. All right, great. All righty, that would be good, thanks. Yeah, wonderful, we got it, great. So I think we wanted to have someone who was old enough to have really understood how Duchenne was back in the day. It was very, very different. I guess first I'll give you my disclosures, none of which are affecting what I say today. But when I was a fellow, Duchenne muscular dystrophy was one of those muscular dystrophies that affected only boys. And if you found somebody who had really pretty, prominent calves and who had this Gowers maneuver when they stood up, the rule of thumb was that they would stop walking by age 10 and probably die around age 20. And there was not much we could do. We always used muscle biopsies to make sure it was a dystrophic kind of process. And you can kind of see here, on the top, it's a very early stage of Duchenne muscular dystrophy where it's just a little bit of fiber size, a variation in some inflammation, but still very recognizable as muscle. At least that's what the janitors tell me when I'm there late at night trying to make a talk. They say, that looks like steak. But right underneath that is a biopsy. And this is a legacy slide that my mentor gave me from about 50 years ago of a practice he had where there was a family with five boys. And you can see as they age, there's increasing amounts of lordosis that they have to use to even stand. And finally, the oldest one has to throw his hands behind him to keep his center of balance over his feet. But the amazing thing is that this lower muscle biopsy is probably from a child around this age, not a really, really old boy with Duchenne. And that's one of the things I think that we have lost track of since we don't do muscle biopsies anymore. And I think that we need to remember that timing is really of the essence here as we try to come up with therapy. People have finally figured out that dystrophin is this wonderful connector that seems to connect the actin-myosin contractile elements to the basement membrane. But one of the problems people are having in terms of trying to come up with a real solid treatment for Duchenne is that even though we have gene therapy, the DMD, the dystrophin gene is big. It's 79 exons, two and a half megabytes kind of thing in size, and that's three times larger than the largest current viral vector. And we'll talk about that a little bit later. We know that dystrophin affects not only the smooth muscle, skeletal muscle, and cardiac muscle, but also affects the brain, retina, and kidney in ways that we don't always understand. But in terms of knowing what to do, I think it's really important, even in the day with all these disease-specific therapies, to go back to this sort of approach, this multidisciplinary approach, where you have orthopedics, pulmonology, cardiology, rehab, OTPT with rehab, as well as all the case management and GI and neuromuscular people, all looking at the children and adolescents, and then as they become adults now, trying to figure out what things can be done to maximize function and minimize progression. So natural history of DMD has really changed, and you can see a number of the reasons why it's changed. Early on, it was just observation, and the top arrow is basically the way it was when I was a fellow, not much intervention. After that, there was a lot of attention paid to using steroids and watching ventilation, particularly at night, and using BiPAP and support whenever it was necessary, and taking care of the spine. And with all of those things, you can see that both the, a little bit the length of abnulation, but also the lifespan increased. And now, with all of that, and adding to that proactive cardiac management, the boys are living longer. This will just show you a little bit about some of the data that shows corticosteroids make a difference. And I think the basic message to take away from this slide is that the survival curves, the Kaplan-Meier graph, as it were, in the red is from boys who have had significant corticosteroids, and the blue is not. There's still families begging to not use steroids or refusing to use steroids, walking with their feet and just not filling the prescriptions. MDA says they've done some studies and that around the country, maybe only 50% of people with Duchenne are on steroids. And it breaks your heart if you really look at this data, because you can see that really important functions, things like being able to get up from the ground, things like walking are affected, and you can add months and years to life with those things, with that treatment. One of the things I think is very, very important is that we've all participated in natural history studies to try to come up with small increments of progress or change or decline that happen over time in boys with Duchenne, and that's really important, because we don't want to introduce a new treatment and then wait 10 years to see if they're still walking, or 20 years to see if they survive. You want to know in six to 12 months, are you on the right track or not? And what you can see here is from the DORSTAR ambulatory assessment, and I think maybe a number of you are probably familiar with that, but basically, it has 17 major kinds of movements, beginning with standing and going on to climbing, standing on one foot, hopping, so on and so forth, in a very graded fashion, and each of those 17 has a score of zero to two. Zero, they can't do it, one, they can do it but poorly, and two, they do it according to standards that the PTs have validated. And so you can see here the graph of some of the trajectories over time. A typically developing child would obviously start down here and then just go forward and just keep going and not stop, adding on motor milestones all the time. But the boys with Duchenne make progress a bit more slowly, and then they peak, and after they peak, then they begin to decline. But what's important is in this paper by Francesco Muntoni, you can see that the actual height of achievement is different in different boys. Some of them peak here, and some of them peak a little bit better. The rate at which they decline is different in different boys. This is just a mean of a number of boys, but they kind of clustered them together in these different classes. Some declined slowly, and some declined very rapidly. And basically, the bottom line is that without paying adequate attention to this, you can really kind of completely muck up evaluation of treatment. I think that's what happened myself to the early exon skipping studies where, or I mean the gene therapy studies where in the four to seven-year-olds, they stratified it to the four and five-year-olds and the six to seven-year-olds, but didn't realize until they were analyzing all of the data that the six to seven-year-olds weren't evenly matched in terms of all of these parameters. And so the placebo group was much better in terms of their initial NSAA and whatever, and the treatment group was much lower so that although the treatment group improved, they didn't meet the statistical significance that was considered a failure and why the gene therapy was initially only approved for the four and five-year-olds. People have since gone back, and instead of using the control group, used a very, very large natural history cohort and done what I consider magic, but what the statisticians call propensity matching, where they really take many, many individual characteristics and make sure to match that in a natural history cohort to have that serve as placebo. And I think increasingly with most boys with Duchenne having had some kind of prior treatment, and with this being a rare disease, this is becoming, and with there being commercially available treatments, it makes it less ethically reasonable to expect a large placebo group to volunteer. And I think this propensity matching will improve and will prevent errors because of these different kinds of pathways that boys with Duchenne take. There are some prognostic indicators where you can sort of get a sense where some boys may do a little bit better and some a little less well, but I think this is all very, very early. People have been trying to look at some genetic modifiers, things that have to do with connective tissue type and maybe even response to steroids and or inflammatory immune responses. And some of that seems to make a difference in terms of motor outcomes. Certainly, whether the boys have been treated with steroids, whether the boys have had very aggressive preventive intervention in terms of cardiac medication makes a really big difference. And then just in general, some things that you look at, earlier they're frankly symptomatic. It's probably a more severe disease, but some of that has to do with how carefully they're being monitored. And then there are a few DMD mutations that on occasion people will exclude because in general, boys with those mutations, out of the hundreds and hundreds of mutations that can occur at dystrophin, those seem to do a little bit better. So they don't wanna, again, mess up the statistics. I think that as we sit here and try to decide what to do with boys who present with Duchenne muscular dystrophy, we have a very basic question that we still haven't really answered, I think, completely adequately. We have shown that using steroids, corticosteroids, makes a difference. But I don't think that we've really worked out the best age at which to start the steroids or the dosing schedule or even the type of steroids. There are a few attempts to make some comparisons, but they're completely inadequate because by the time they make a tiny little study or a big study, then some new players come on the field. For example, the 4-DMD study, which was a big effort between Europe and the United States, didn't include high-dose, oral pulse, two-day-per-week steroids of any kind. And so that hasn't been compared to the deflazocort and the corticosteroids. Anne Connolly has led several very important trials, another one's ongoing right now, for boys under 30 months of age. I believe strongly, and this is a personal opinion, not something I've got absolute data for, but just common sense in looking at those muscle biopsies that the earlier you start steroids, the better the children would do. And the point is, what can you do to balance and minimize the side effects? This trial that we completed with about five or six sites across the United States used two-day-per-week prednisolone orally. Now, there's another one going on because of some new animal data doing it with one-day-per-week pulse of oral prednisolone, and we'll see how that one comes out, but you can see that there was a clear difference and the boys did better in terms of their overall fine and gross motor scale scores. Personally, I think that now that we're moving toward newborn screening, that this means that we're gonna have a wonderful opportunity to treat and observe the response and the side effects in treating very young children with dystrophinopathies. The youngest I've treated so far is six weeks. Child did very well. Again, there was a study that the Synergy Group with Diana Escalar at Helm did to compare the two-day-per-week to the daily steroids. And people look back and say, well, it was only a year and a half long and it was only one study and things of that nature. But frankly, a lot of centers around the country, or at least a significant number, have taken to doing this oral pulse steroids and find that side effects in terms of mood, in terms of lack of growth, in terms of bone demineralization, a lot of other very important things, even in terms of weight gain, is a lot less in the group that get the oral pulse. But I've had families look at me and say, you know, it's too new. It's not the standard. It's not the usual. I don't wanna do the weird stuff. So, and there are a lot of centers around the country where they only use daily steroids. And so we've gotta still work on that kind of issue. People are making some comparisons and there has been a big discussion. The blogs, the parent blogs have for a long time told us that deflazocort does better than prednisone. People are now finally looking at some data and you can see here that in these curves, the green is the deflazocort boys. And you can see that over the long term, talking way out into the non-ambulatory phase, where the motor milestones we're looking at are things like FVC and percent predicted, ability to bring your hand to your mouth or ability to turn yourself at night, that there was a longer persistence of those functions in individuals who had deflazocort. So it may be that there is a benefit there. I have to say though, that in my experience, a lot of times the families that have over the years sought out deflazocort are the ones that are very committed. Because until the last two, three years, one had to get it from the UK and there was a lot of hassle involved. And I always found that these were the families that had more willingness to kind of push the dose to match the growth and things like that. So I think it's still kind of, there are unanswered questions. To try to get around the issue of all the side effects of steroids that are known, a wonderful scientist with a pharmacology background who had some, I understand, personal interest in Duchenne did a lot of work. And you can see here that these are the, as you remember from chemistry class, the pictures with prednisolone, which is the active form of prednisone, the active form of deflazocort, and then this new synthetic agent, bamoralone. And the difference is here. There's a double bond instead of a single bond. And it changes the propensity to interact with different kinds of pathways in the body. It has less transactivation and doesn't interact with certain of the enzymes and other things. But the bottom line is that with this, there appears to be less bone demineralization and better linear growth. There are still, and it has a partial mineralocorticoid antagonist function that makes it difficult to give in very high doses, particularly if you're on a lot of cardiac medicines like aplerinone and some of the others, a spironolactone and others. So this has to be given daily. It has been approved in the US. It is a new drug. And frankly, most insurance companies don't approve it unless you fail the others because of a problem like multiple bone fractures, complete failure to grow and so forth. So I think there's more study to be done there to really see what's better. The other thing that's difficult is bamoralone was not tested against, it was tested against daily deflazocort and prednisone, but not against high dose oral pulse steroids. And many of us find that the things that are advantages in the bamoralone are advantages to the oral pulse therapy as well. But you can see here, this just demonstrates the changes. On the left is a graph showing the increasing height in the boys treated with bamoralone, whereas those treated with prednisone, their percentile for height declined over time. However, there is weight gain in all groups, including those who take bamoralone. This is again showing that there are fewer vertebral fractures. Again, it was comparing in the 4-DMD study, the average number of vertebral fractures, and then comparing it in the long-term observational studies with bamoralone. And you can see that it's fewer fractures than prednisone or deflazocort. Well, with this, I think we've gone over a lot of the, what people have considered over time, the standard of care or the basic care of Duchenne muscular dystrophy. And now we're gonna consider some recently introduced in the last half decade or decade, disease-targeted therapies for Duchenne. And one of the very, very important things to remember is that it's mutation-dependent. Again, we have over 300 different kinds of mutations. Again, they have classifications of it. They have those stop codon ones, the nonsense, the missense, the duplication, whatever. But even within that, each group, there are many individual kinds of mutation. And many of these therapies that we're gonna talk about either have restrictions where they are not meant to be used in certain kinds of mutations because of either an observation or demonstration scientifically that there are increased side effects, or it only works in certain mutations. And so we'll go through that a little bit. I think one of the very difficult things to talk about is the treatment of stop codon in Duchenne. That was one of the very first big trials that has gone on, and it's gone on in Europe and in the US. And on the next slide, we'll show you some of the outcomes. But then we also have to consider exon skipping, which tries to take the mutations that knock the read-through out of reading frame and put it back into reading frame. And then we've got the issue of dystrophin gene replacement therapy. Right now, we'll be talking about, for exon skipping, the currently available ones, which are the PMOs. Now there are four of them that are FDA approved, and you'll see which mutations they deal with. And the complexity, I guess, on a practical level is that they have to be given IV infusion once weekly. And so for boys with Duchenne, particularly boys who have a little bit of extra body tissue, weekly IV placement is really quite complex. And so most of these boys end up with central venous access ports. And this reminds me of my old days as an intern trying to deal with VP shunts. Some of them work very well and never need any tuning. And other children just seem to have the luck of the Koontzes, which is that they have their port break down every other moment and need more fussing and surgery to keep it going. However, there are efforts, both with the basic PMO by changing the platform with the ASOs, to come up with a way to have the half-life be longer, so it could be once monthly that's still in clinical trial, not yet available for prime time. And there are very active research efforts going on using cell penetrating peptides and antibody PMO conjugates that are trying to, again, come up with ways to get this exon skipping into the cell and have it be more long lasting, so it would have maybe once a month or once every several months as an infusion. And I look forward to that. Everyone does. But not every boy has something amenable to exon skipping, and I'll show you the numbers in a moment. Okay. Adalurin was shown in, I believe, in some studies to improve motor outcomes and delay loss of ambulation. However, it was one of the first studies going through the FDA, and I don't really understand. I can't explain it to you. Perhaps if anyone does, they can teach me as well. But it has not been approved. The FDA sent them, the company, back many times to do bigger studies, to do it differently, to have different controls, so on and so forth. So you can see that reasonable people doing reasonable analyses show that this works, and for a while it was approved in the European Union. My understanding is that for some reason it's been on hold or recently withdrawn. But for individuals, and I've seen some of the boys who were in the trials here in this country, and they really did seem to do well. But it's not available. You can see here from this pie chart an estimate of the kinds of, the fractions of all of the mutations that appear with Duchenne, how many might be amenable to exon skipping of different kinds. So, you know, this, the biggest one down here that says other just means that it's such a few number that it's way less than the one or two percent. And so it would almost be an individualized sort of treatment. But the biggest fraction up here is for exon 51. Now, again, that's not one mutation, but that's the combination of all of the mutations that if you added on deleting exon 51, it would bring it back into reading frame. I can't tell you how many insurance people and government people I talk to that they say only 15 percent of people respond, that you give it to, and it's not that. It's the 13 or 15 percent of all the mutations are the only ones that one would give it to. So I don't have to explain that to you, but that makes me feel better to have you understand immediately. But that was the first one. So exon 51 has been approved. There are actually two commercial agents that serve for exon 53 skipping, and they both work well. Again, right now they're all once a week. Exon 45 has also been approved, and that is another 8 percent. I don't think we have a sense of those fractions of all the children who have mutations, how many of those children have been able to access the therapy or not. But I know some who've had it and who've had exon skipping for five to seven to eight years is my best memory of how long this has taken, and they're doing quite well compared to peers. And you can see down there, exon 44, exon 52, exon 50, 43. Those are all ones that are being worked on and that are in trial right now. So we'll see how that goes. And again, we'll also see if some of these come up with ways of having longer duration. I think this group probably understands the going back into reading frame pretty well, but the cartoon down there is the one that shows you how if you make a slightly bigger deletion it will bring it back into reading frame. One of the interesting things, here we go, and here's just some of the data. There are many selections I could have made. Many of all those things that got approved went through extensive study, including widespread large phase three trials. And so there's a lot of data out there to show that motor outcomes improve. Sometimes they express the motor scores with the total number of seconds it takes to accomplish something, the total number of meters you can walk over a given period of time. But then also sometimes they turn that into velocity, and that's why sometimes the good guys in yellow are going down on the bottom. They have done some animal studies and looked to see if the dystrophin produced by exon skipping in any way interferes with the microdystrophin that would be produced with gene replacement therapy. And apparently it does not. They have these studies that show it just lines up nicely along the sarcolemma, just taking its turn wherever. So as far as we know, there's no theoretical reason why these two can't be used together to improve outcomes. The difficulty would be just that the two of them together would be quite costly. Again, just some more data, and I don't mean to go over it too quickly, but it's just wonderful data that shows improvement in outcomes, improvement in the amount of dystrophin in the muscle biopsy and improvement in the motor outcomes with exon skipping. And in fact, some recent long-term data was actually able to show that there was a lengthening of independent ambulation by several years with long-term exon 51 skipping, which is incredibly important. Well then I'd like to go on to the whole issue of gene therapy, gene replacement therapy. There's so much that we've learned, and there's so much that we do not know. I feel more humble every month that I help these children get this therapy. Gene editing undoubtedly will be available at some point and will be very, very helpful for a number of people for their individual kind of mutation, but it's not in humans with dystrophinopathy at this point. And obviously gene knockout and addition aren't useful here. But what we're talking about is really gene replacement. It's important to recognize that there are three components in any kind of product that will replace genes, like so for dystrophin. The transgene is the microdystrophin or mini-dystrophin, whatever. Obviously we talked about the fact that the full-length dystrophin, which people could synthesize, can't be used because it's three times too big. So what's done is people select out the important parts. And right now, so far there have been five different scientific groups around the world who've been addressing to try to answer the question, what is the most important part by doing preclinical animal trials and things of that nature. They also try to, some of them, model some of their choices on some of the natural human experiment, meaning those individuals with Becker muscular dystrophy, who rather than being just slightly better than boys with typical Duchenne, are the Becker individuals who live until, who walk until 50 or 60 years of age, and then figure out where their mutations are and then model it after that. So that's the transgene. The promoter always serves to direct this toward a certain organ system. Now obviously here we want to be directing it to both skeletal and cardiac muscle. And you'll see each of the scientific groups has a different theory about what promoter to use to accomplish that. And then finally the vector, meaning how do we get 1 or 2 times 10 to the 14th times the number of kilos of an artificial foreign protein into cells in the body and have them tolerate, have us tolerate such a thing. And I think no one knows how to do it. But viruses have for millennia. I mean, all of my ID pictures from college to medical school to residency all had a big honking cold sore right on my upper lip from the herpes simplex that lives somewhere in my body and kept putting it out at times of less sleep, shall we say. And so here is just a cartoon of the dystrophin gene and the idea that you're making it much smaller. Here is an outline of the five different approaches. And you can kind of see all of them have the N terminal and the C terminal. But there are significant differences between the different scientific groups and their approach toward making a micro dystrophin. And frankly, we don't have enough data yet to know if any one of them is superior. There's been a lot more work and in fact enough study to lead to FDA approval for the Alevidis from Sarepta, which will be marketed internationally by Roche. The others are still in trial, but Pfizer has withdrawn their product. And this is basically what's happening. The viral vector in whatever way, oh, and I forgot to mention that in addition to different promoters and different transgenes, they have different viral vectors. The one for Sarepta was AAVRH74 from a rhesus monkey when they isolated it and the others are either AAV8 or AAV9. And you can see here that it's transduced into the cell and then it's translated into protein. And they picked the AAV, the adeno-associated viral vector, because it does not incorporate into the human genome and therefore, like with herpes, there's always a concern about long-term oncogenesis and all. This because it does not incorporate into the human genome, has less of that. And so it creates this episome that then is translated and turns into protein. I mentioned before the modeling on the ambulatory Becker patients and on the very left, there's a cartoon of the exact mutation in someone from the UK who walked until he was 61 and was at his 61st birthday party walking about talking to people. And you can see it's not exactly the same, but it's quite similar to some of the changes people have made. Now, adeno-associated viral vector people have glommed onto because it seems to have a low rate of natural immunity throughout the world, although it's really quite variable. It's anywhere from a couple percent up to 30 percent in children of school age. And it's not logical to me. I mean, I've heard people complain in Barcelona and recently I'm beginning to complain in Chicago that we have quite a few individuals immune. And yet my colleagues in California say they rarely run into boys who are immune to this. Because obviously if someone has existing antibodies against the viral vector, they cannot receive that gene therapy. But one of the questions that everybody always asks is, well, if you're immune to one product or one viral vector, does that mean everything's out of the game or not? And it depends. Because it turns out that about 50 percent of the surface proteins are shared between the different viral vectors. So there are some times, if that's what triggers your immunity, the ones that are shared, you'll probably have cross-immunity to the others, whereas I've got a boy right now who was immune to AAVRH74 but is not immune to AAV9. So he can go into those trials. So you've got to check. There's been a lot of work. It's been very exciting to watch about understanding the immune response to some of these gene therapies. Obviously, one of the things you have to be aware of is that there's a chance for an immediate reaction to the infusion with itching and different kind of rashes and other minor things like you can have with almost any infusion. And so people have taken, I certainly have taken, to giving a dose of Benadryl and Tylenol with the initial dosing to minimize that. Then we notice, as people have been observed, some reactions, primarily complement-mediated that are relatively quick. Just with existing complement, they have some reaction, thrombocytopenia, myocarditis, just nausea and vomiting are some that are very, very prominent. And then there's kind of a lag period of time and then a whole other batch of transaminitis with very high liver enzymes, risk for immune myositis that on rare occasion has actually caused a boy to lose strength in swallowing and speaking strength, immune myocarditis, which can create heart failure. And so people have looked very carefully to try to understand was there anything to predict what might cause some of these larger immune reactions. At the beginning, because of just concern that having or not having certain amounts of recombinant dystrophin present, people were excluding a lot of the early mutations or deletions of the early exons. So it wasn't uncommon, and even so now in some of the ongoing clinical trials, if you have any deletions between exons 1 and 18 or 1 and 17, you're excluded from the trial at this point. And I think that some of the early ones with the now-approved elevatus had 1 to 17 and also a whole batch of later ones, 50 to something. And so they were just trying to stay away from anything that might have been associated in the past, even once, with a reaction. However, people have done really careful studies, and I think in a beautiful example of collaboration between scientists in these different groups, people have looked at those few individuals who've had very significant immune reactions, like immune myositis or immune myocarditis. And they have worked out that with the current product, elevatus, that it was really any component of exon 8 and or 9. That was what seemed to be associated. Now, there have been other children in the early studies who were treated with that and who didn't have a bad reaction. But of the few that had the bad reaction, that seemed to be a hotspot. So right now, that is a contraindication for using it, either elevated antibodies or that one make you ineligible for the currently approved elevatus gene therapy. And you can see here the multi-organ side effects. Dr. Mandel, when he first began this process, ran into children with marked increases in their liver enzymes. And so he started treating them with steroids and it went away. So then he began with the next children in the queue, giving them, starting 24 hours before the first dose, one milligram per kilogram per day of oral prednisone on top of whatever they were taking. So for SMA, it would be just introducing that. For DMD, it would be adding that on top of their existing steroid regimen. And there seems to be much less of the increase in liver transaminases. And that is tapered. The extra stuff is tapered over three months. And I think this is just going over some of the things that we talked about. So what are practical considerations? To know if someone is eligible for any of the disease-modifying, more advanced or newer dystrophin therapies, what you really have to do is know what their mutation is. And it's becoming easier and easier with some of the programs that PPMD and others have put out there. Years ago, we didn't always have the exact mutation, but now I think we're in a place where it's recognized that that's absolutely critical. So you should have the exact mutation of your patient. And then you can look and see what they're eligible for. For DMD gene therapy, you have to screen for the antibody titers and then look for the dystrophin mutation to see if it's disqualified. We do a lot of monitoring. It's incredibly important that families recognize that this is not a once-and-done procedure. This is something where there is one single dose given over one to two hours IV as part of a very intensive three-month journey where there's a lot of monitoring. There's blood tests, examinations, recurrent sometimes echocardiograms, EKGs, and PT assessments over and over. It's important to try to prevent a double hit of immune roiling, I think of it. So some of the children in one of the early trials that had problems were ones who caught norovirus on the way home from the hospital after the infusion. Certainly when I was a fellow and I looked at SSPE, it was very, very clear to me that the children who developed SSPE after a natural measles infection were the ones who had measles one week and then chickenpox the next week. So when you have those multiple hits of major immune reactions, the children are more likely, I think, to have problems with it. So to that end, you want to make sure that the vaccinations are up to date well before you start the gene therapy so that you're not giving anything within a month or two. Want to make sure the pediatrician's on board to not, you know, add something in right after gene therapy. And you don't want to give the vaccine to somebody who's acutely ill and already fighting something off. So you want them to be well for, I like to do for four weeks. Some people try to, if it was a minor illness, kind of truncate that down a little bit. But again, we don't know exactly what the best limit is. Again, oral corticosteroids, usually prednisone, are started at a significant dose, one milligram per kilogram the day before, 24 hours before. And with one of the major side effects being vomiting, it's incredibly important to work with a family and make sure they understand if the child is vomiting to the point where they can't keep fluids down, that's important and you've got to sometimes give them fluids. But also, if they're vomiting up their dose of steroids, that's really critical and they've got to come in and maybe get the IV steroids. And then there's lots and lots of blood drawing. I mean, the label says draw once a week for 12 weeks. And you really benefit from doing that amount of monitoring. And then again, the corticosteroids are up and it takes two to three months to delete those. Well, if we go beyond gene therapy, what are our other, you know, this, it's frozen. So if you feel like I need to go quicker, let me know. Because the time is frozen down there. There are some trials that have been going on of trying to use other things other than steroids. PNF-alpha, TGF-beta, other kind of things that interfere with the immune system to try to decrease the inflammation other than steroids. Most of those have not been overwhelmingly impressive. But more recently, there has been something that is now FDA approved that is an HDAC inhibitor, histone deacetylase inhibitor, that allows regenerative and reparative proteins and other things to be better produced. And you can see the results of a very large trial recently with all of the things on the spider plot or whatever being well on the side of benefit with all of these different motor scale scores. So this is an agent that has some side effects. Lipids have to be monitored because a certain number have some decrease in their platelets that requires adjustment of dose. And also, some individuals have elevation of lipids in response to it. So those are things that have to be monitored. We don't have a lot of experience with this, most of us, because it was only recently approved. I think within the last few months, this was approved. But very promising. There have been a number of drugs that the cardiologists on most of our teams are using proactively, beta blockers, spironolactone, clarinone, different things, at different ages and phases of change in cardiac function, as noted by echocardiogram, to minimize and prolong the function of the heart, minimize the delay onset of heart failure. But this is a completely new approach that's still in trial. And it's very, very interesting. Again, from my point of view as a non-basic scientist, it seems a little magic. They take donated heart cells from heart donors whose hearts didn't match or whatever, and they make cardiosphere-derived cells. And it's allogenic because it's donated from someone else. And they have infusions of these. And these infusions, you can see on this one what their theory is, is that it goes through the body. And it sits and rests throughout the body and actually improves the repair of the heart. And there have been some very nice, I think we have some outcome studies here. On the top, you can see that there's some enhancement with a scar. And the bottom, or the top one, shows none of the same scar over time that you can see on the bottom. And then, again, just looking at the different pull scores. Right now, they're doing this on non-ambulatory patients to see how it benefits them. And you can see that it improves upper extremity function. So having this cell-based therapy is a great potential for the future. Heart transplantation, something that we would have never considered years ago. But currently at Lurie, we've had three boys with Duchenne in this last year who have undergone heart transplants. These tend to be boys who have more involvement of the heart, where the heart function deteriorates earlier in life. One of them I can think of off the top of my head when he was ambulatory. He just presented to the emergency room in flat-out heart failure without any myocarditis or anything else to explain it. And he didn't improve. And he's done very, very well with his heart transplant. But again, every heart transplant with any underlying disease undergoes incredibly careful look because it's a very big investment of time, energy, and resources. And what they want to make sure is that the person would, with their other disease, whatever it is, would survive the average length of the heart transplant, which is usually about 10 years. So I guess what I would say is that this is an exciting time. I have more questions myself than I have answers. I think that initiating treatment as early in life as you can is really the key. Again, I'm very excited about newborn screening and not sure how it will go, but I'm glad that it's on the horizon. Corticosteroids do seem to be very, very helpful, but we have, again, questions about how they should be used. It's incredibly important we know which mutation the boys have because that will determine which of the advanced therapies they may be eligible for. But I also believe that it really is going to require a combination approach, and we haven't even begun really addressing the issue of which agents in which children will make the biggest difference. So thank you very much for your time. I think what I've done is try to provide the fodder, and now we have Dr. Zaidman who will get you thinking about all of this. So thanks. Do you know? I hope you know how to get the next one up, yeah. Hi, everybody. Nancy, that was excellent. Thank you very much for switching orders with me. I'm Craig Zaidman. I'm a child neurologist, and I do neuromuscle medicine nearly exclusively. I'm at Washington University in St. Louis. How many of you all are practitioners, take care of patients? Most of you. How many of you take care of children? Okay. How many of you have given a Levitas before? How many of you are comfortable giving a Levitas? Okay. I mean, neither. These are my disclosures. I have done research and gotten paid from Sarepta, and I will be discussing that. I've done some research with Juvenistat. But really, the disclosure here is that Nancy is perfectly delightful, and I am a curmudgeon. And so I'll try to keep my color commentary to a minimum, but it may come out. We've dosed 23 boys in clinical trials with Levitas through the Sarepta trials, and I've nearly the same amount with Zolgensma over time. So we're not a massively large program. I think we're moderately large. I guess it's all relative. And then I have some videos in here, and I do have consent from all the families to show these videos. But I would ask, please don't record those videos. I just don't need them on social media. I mean, they didn't really consent to being, like, internationally famous, and we tried to obscure their faces, but please don't record that portion of the talk. So I agree with Nancy. It's an exciting time to be taking care of Duchenne muscular dystrophy, but it is also there's a number of challenges, and in terms of the time it takes for me to counsel families regarding their care. So for those of you that are taking care of boys with Duchenne, I'm sure you're experiencing this. It's always been a job of talking, you know, more than treating in a way. But now we have more treatment, and I find I'm doing more talking, and in a way, less treatment maybe. I think I kind of feel like I'm on the transition, you know, of adopting all of these new therapies, which you can see here. Nancy was kind enough to give me her slides, so we are going to cover similar topics, but I have all different graphics. So if you're thinking of leaving, don't, please. I like this Ford DMD trial. I was not an early adopter of Imflaza. I was raised by Ann Connelly, and I do weekend dosing steroids, you know, for $5 a year. And so I did not adopt giving daily Imflaza, and I was pleased, I think, to see the results of the Ford DMD trial, which essentially showed that daily prednisone or prednisone and daily Imflaza or teflazocort, I'm sorry, trying to use the generic terms, were similar over time. And this was a massive effort, as Nancy alluded to, and I think that there is really a lot to dig into here, and I will reference this graphic over time. One thing to point out is I want to talk a little bit about magnitude of effect. All of the studies we're going to be talking about, Juvenistat, Elevitas, all the ASO therapies, all those boys, in order to get into those trials have to be on stable dosing of steroids for at least three months. So everything you're seeing here in this slide in terms of magnitude of effect, these are steroid-naive children who initiate steroids, and then you can see the improvement that they derive. So the data that we'll be discussing is on top of this, so to speak. So this is roughly a 4.3 to 4 point, I can't remember exactly, improvement in the North Star, which Nancy talked about, and then, of course, they run a little faster, and they walk roughly 50 meters further in six minutes over time. For those of you who don't know this, that Aquabar, that's the 10-day on, 10-day off prednisone, intermittent dosing, which didn't work. Don't confuse intermittent dosing with what I call high-dose weekend or twice weekly, which was not included in this trial, and which a large minority of us use in our clinics, including me. I did like this side effect profile, because when I'm talking to families, what I tell them is these drugs are similar in terms of whether your son will do better or not in terms of their function, which I think for DMD, I think it's a reasonable thing to say. So you'll hear slight differences in emphasis between what Nancy and I say, and I agree with everything Nancy said, I'm a curmudgeon, as I already disclosed. But the cataracts are more common with teflazocort, and they really don't grow. They don't get taller. They also don't gain weight, so they look like little boys when they're 13 years old, and if you walk in and accidentally ask them how second grade is, they get really angry. So I don't do that. I ask, how old are you? Because they look eight when they're 13, and for those of you who remember Gary Coleman from different strokes, he was on chronic steroids, and he maintained that juvenile look in his face for life, and that was prednisone. So it's not just inflaza, but really daily steroids make a big impact on your growth. Inflaza particularly on your height. So that brings us to Vimoralone in terms of the side effect profile, and I'm going to frame my discussion, I'm going to go through each of the drugs Nancy talked about too and try to stay on time here, but the question is, does it work, or is it better? Because that's what my families want to know, is it, do I think it's better? And I'll let you decide what you think, but the other question is, if it isn't better, are the side effects better? And then I am telling my patients how much these drugs cost, and they all are aghast at the cost of some of these medications, and I typically don't include that, but I have started doing that now. When I discuss, start going on these medicines, I tell them the cost. Not to frighten them from doing it, because they'll often get it covered, but to inform them. You can see Vimoralone, I pulled these right off the internet, so if they're wrong, forgive me. It's nearly impossible to figure out what things cost. Vimoralone, $100 a milliliter, about a fifth of the price of Deflazocort. Of course, Deflazocort was much more expensive when they first marketed it in the U.S., and none of us prescribed it, and then they dropped the price quite a lot, and some of us did. Prednisolone, it's pennies. Similar to some of the, again, same data, shown differently to what Nancy showed you, but the red dotted line is six months of Prednisolone, compared to the blue line, which is the higher dose of Vimoralone, now the FDA label suggested dose of six mg per kg per day. And these are functional outcomes, I won't go through each one, but there's really no difference here over six months of being on Prednisolone versus Vimoralone and their function. And then when you transition from Prednisolone to Vimoralone, you don't suddenly get an improvement in your function. You sort of maintain the course, which are the solid lines, the solid red line is transitioned to Vimoralone. So function is the same, and everything I've seen would suggest this, Vimoralone better than Placebo, Prednisolone better than Placebo. But your height improves. So if you switch from Prednisolone after six months, daily Prednisolone to daily Vimoralone, you will start to grow taller. And as Nancy pointed out, this isn't just about hubris, all of us men want to be as tall as we can get. This is about fracture risk. And if in fact Vimoralone is not impacting the bone turnover in the way in which it is designed to avoid, then perhaps they won't fracture as easily. And we're hoping that's the case, because they are growing. They are growing taller. Weekend steroids, they also grow. And my personal experience is we have a lot less vertebral fractures than in the daily steroid treated group. So I think that this is likely to bear fruit, that hopefully we'll see less vertebral fractures in patients on daily Vimoralone than we would on daily other steroids. No comparison to the weekend dosing, of course. And then we get to Juvenistat, which is a histone deacetylase inhibitor, approved for boys six years and older, studied in that same population. It's a twice daily oral medicine. It can cause a reduction in platelets in about a third, similarly can bump your triglycerides, and it has some GI side effects with vomiting and discomfort. The QTC prolongation, actually no children in the trial had that. I think that comes from higher dose studies and other models, either adult volunteers or animals. I can't recall exactly. I'm sorry. But it is listed on the label, so I included it here, but no children in the trial actually had that. But because of these very relatively common problems with triglycerides and platelet reduction, it does require pretty intense monitoring, which I have listed up there. And we did definitely see these problems, in my experience, in the clinical trials. And when you drop the dose, these problems go away. So there were actually dose modifications in the clinical trial, and the FDA label has kind of been in response to that. So the initial dosing was higher in the first parts of the clinical trial, had to drop because of the frequency of side effects. And so hopefully you see maybe a little less of this if you use the per-label dosing. So if you're going to prescribe this, you might want to be able to tell your patients whether it works. I think that's a reasonable question. And it not really just does it work, but the boys and parents will want to know if it makes their children get stronger or faster. Or if not those things, will it at least hold me where I am, and I won't continue to decline? And when you think about whether a drug quote works, I think those are reasonable parameters by which one might define works, especially at high cost or high risk. Because this drug is estimated to cost about $700,000 a year, which is not nothing. Does anyone think it works? Does anyone not know? I'm a curmudgeon. This is the primary outcome from the Juvenistat trial, which is the time it took to climb four stairs. Now, to be fair, the average age was almost 10 years old in this trial. So to expect that this medication would reverse the course of the disease and make these boys stronger or faster seems like a very high bar. So I am not criticizing the decision to approve it, but I am emphasizing the way in which it quote works. Because the boys on the red line who were treated with Juvenistat still get slower over the 72 weeks that they were followed. But they did not get as slow as the boys on placebo by P equals 0.035, which some of you might round to 0.04. But this is the way in which it's been presented, and I'll replicate that. Now I don't want to get too far into the stats. But as you may recall, once you test one hypothesis, you can't then just keep testing multiple others because of the risk that you'll make a type one error or say that there is a difference when in fact there is not. Think about looking through the differential on your CBC and ignoring the fact that the neutrophil count is slightly out of the normal range because you've just checked 15 different statistical tests with one CBC with DIF. So we routinely ignore small, high, low values in our CBCs, and these clinical trials run the risk of having a slightly abnormal neutrophil count if you're going to run 15 hypothesis tests on the same data. So that said, these are the additional assessments that were done as part of the Juvenistat study. And there are no p-values associated with this because the p-values would become increasingly smaller in order to achieve statistical significance because of the multiple hypothesis testing. So this is all pre-planned and completely on the up and up. I've highlighted for you here the North Star ambulatory assessment, and what this number is showing you is the number of skills that the children lost the ability to do, think, get up off the floor. The children in the black line lost about 3 to 4, if I'm reading these numbers correctly, and the placebo group lost 7.5. So roughly 2 to 3 skills were preserved over time in the group that was treated compared to the group that was not. And so if you want to tell a family what to expect, and you're going to give them $700,000 worth of medicine over one year, in a year and a half, they will lose skill. But they might not lose two or three skills they otherwise would have. And to me, that's quite compelling. Without any p-value on this data, remember. So we're in the business now, when I've been so critical of what works and what doesn't work, you know, we are in the business, as Nancy said, of trying to treat the children when they are here in front of us, and not using each of them to predict that maybe they'll will or won't be better at the end of my career. And that's not easy. And a lot of credit to the statisticians and scientists that have developed these clinical trials with these sort of early or preliminary outcomes to try to help us take care or decide, as Nancy said, in six months or a year or a year and a half, whether a drug works or not, which is really what we're after here, aren't we? And this is an example from Craig McDonald's work, where he's basically, this is a poster about time to stand velocity. But I like the way it presents the effect of just prednisone, where you can see that if you initiate prednisone, you have an improvement in your velocity of time to stand, and that this is associated with other things we care about. And he has determined these sort of thresholds of if it takes you more than five seconds to get up off the floor, that's when your risk of losing the ability to stand starts to increase over the next two years. Of course, if it takes you seven seconds to get off the floor, your risk of losing the ability to stand is higher than if it takes you five, and it's higher than if it takes you three. A normal is less than two. But there's a little change in the inflection there, and so Dr. McDonald and colleagues have chosen five seconds as sort of a marker. And if it takes you 10 seconds to get off the floor, then you have an even higher risk. And this is what we're talking about here. When we ask whether these drugs work or not, can we tell you now that you'll be able to change the trajectory of your disease, as some of these drugs are claiming? It's based on data like this, where if your time to stand doesn't reach five seconds, you can claim that we've changed the trajectory of the disease, even though we don't really know, because it'd take 10 more years to figure it out. This is the business we're in. And that has led to a desire to get drugs to the market without knowing what's going to happen over the next 15 years of exposure to them. And so here, we have all the exon skipping therapies and Alevidis, all of which were approved on the accelerated approval pathway. And believe it or not, this is a question in your self-assessment from me. You're welcome. So I'm pointing it out. But all these exon skipping therapies have been approved on the accelerated pathway, meaning there's a surrogate endpoint that the FDA has decided is it reasonable to assume that it will change the trajectory of their disease, the surrogate endpoint here making very small amounts of abnormal length dystrophin protein of varying amounts. And in fact, some of these products make a really, really small amount of different than you and I have dystrophin protein. Less than 1%, less than half of 1% improvement in the average dystrophin from baseline. The outlier here being vitilarsan, which happens to be made by a different company than the other three, has a slightly different backbone structure to it. And I've just put the quote here from this article, which maybe I won't read to you. But you can read it here for yourself that we have, you know, it's been, these are unvalidated surrogate measures. They do make sense. We know how Duchenne works. You need dystrophin. You're missing it. But we don't really know whether improving it will, quote, work. And not at no cost. Even though Duchenne is a rare disease, there's been over $800 million increase in spending since these drugs came to market. Without us having really a well-defined understanding of how they, or if they work, or if they work, in what way do they work, and what do I tell someone they can expect for the cost. And as Nancy mentioned, the personal sacrifice of having to have an IV infusion and a port placed and getting once a week treatment. Like Nancy showed you, this is the data from vitilarsan, and this is comparison to a natural history cohort, so not head-to-head comparison. And I have to say, every single natural history cohort comparison I have seen for every single drug shows that all of the drugs work. And that, at least for Elevitus, the natural history comparisons were remarkably different between the Elevitus-treated open-label cohort and the natural history selection done with this propensity weighting that Nancy talked about. And then the head-to-head trial comes out, and we'll go through those results, but much less compelling. So some of this is statistics. Some of this is chants about your placebo group. I think a lot of it is statistics. And some of it is that the natural history cohorts we're comparing people to didn't live in the modern era. Some of those children didn't have phones, believe it or not. How did they get through the day? I don't know. So anyway, here's the North Star for the four-year data for vitilarsan, and you can see it looks pretty stable. And I have, this is age seven at baseline for these children. So they are now 11, and you would expect them to decline, and this group is not. There's 16 children here. So this is the long-term data we have for vitilarsan. Now a Teplerson's been around a lot longer, and, you know, Nancy showed that they walk about three years, two to three years longer than they otherwise would, and here I'm showing you that maybe they live five years longer than they otherwise would. We're comparing to natural history cohorts again, which come from other eras. And so it's hard to know for sure, but, and this is not a criticism, I'm not criticizing Sarepta by the way, I want to be clear about that. It is very, very hard to do a post-marketing study with a placebo group that's going to track your treatment group over a really long period of time when other options come to market. You just cannot do it. So the FDA has sort of set us up for failure because these drugs are on the market based on their accelerated approval, and we will never have the perfect phase three randomized controlled long-term trial for these. It's just not going to come. This is what we get. Which brings me to Alevidis. I've got 15 minutes, so I'm going to speed up just a little bit because everybody here knows what Alevidis is. And I will just remind you that this is where we are at because what you want to know is does it work? Will it make me stronger? Will it make me faster? Will it stop me from getting worse? And what does it cost? It's over $3 million. This is the primary outcome from the randomized controlled phase three trial, and I have it here divided four and five-year-olds, six and seven-year-olds. The primary outcome for this study was the North Star. I have here for reference the Ford DMD trial just so you can see magnitude of effect. Remember all of the children in the Alevidis trial were on steroids, and so this has to be in effect in addition to that. On average they had been on steroids for about a year, but there was a broad range from three months to four years if I remember correctly. So you can sort of put your mind at the 12-month mark on the right there if you want to see that they should be stable on their North Star. They shouldn't be increasing just from steroids. And the bottom line here is that the North Star was not significantly different over the four, five, six, and seven-year-old age group. So this trial failed its primary outcome. Then what? Well, the statistical plan for this trial was what's called hierarchical, which meant that there wasn't a pre-specified way to handle the issue of multiple comparisons. What Sarepta said was we're going to keep checking our hypotheses in a predefined order until we hit one that isn't significant at the 0.05 level, and unfortunately the one they picked, which was the North Star, failed. And that prevented them from testing their secondary hypotheses with a p-value. So they present what are called nominal p-values in their presentations. But the FDA was very persnickety about not using secondary outcome statistical analyses for risk of making a type 1 error because the pre-specified plan didn't allow for that. So it failed its primary outcome. This is the secondary outcome, which is the rise from the floor. And I have removed the p-values from this presentation, so I have modified the way in which Sarepta originally presented this to their investors. I just want to be clear about that because otherwise, all the slides I'm showing you are unmodified. So I've taken those p-values out, and you can see here that the time to rise was faster in the treated boys than it was in the placebo arm, and these six and seven-year-old boys stayed stable, whereas the placebo arm actually declined. And I have for you the rise from the floor velocity for steroids, again, just for comparison for your own sort of visualization in terms of the magnitude of effect. These are the other secondary outcomes from the Elevitas trial. Missing from this is the 10-meter run-walk, which was also favored treatment. I don't have that data to show you just for simplicity. But here are the other outcomes, the 100-meter walk-run, the time to ascend four stairs, and then something called a stride velocity, which is an accelerometer that they measured. So these favored treatment, this is not so dissimilar from the Givenostat study, to be fair. It's just that they picked the North Star as their first outcome, and it failed. So I think this is kind of relatively equivalent to me, in my opinion. But the details do matter here, because the FDA committee recommended that Elevitas actually not be approved. How many of you knew that? Less of you. But Peter Marks, the director, decided that it should. And so the last time I can remember this happening was that Alzheimer's drug, the amyloid Alzheimer's drug, and then Dr. Perlmutter resigned from the committee, and it was all over the news, and it was a big deal, and half the insurance companies wouldn't pay for it. And this thing, I mean, I had to go looking for this. Somebody told me. I didn't know. This kind of snuck by CNN. This is also in your question bank, by the way. I'm not, I'm really not making, I hope I'm not making too much color commentary here. This is what happened, and that's it. This is what happened. All right, I'm going to show you some videos of our personal experience here, and again, I would request that you not copy these. This is a six-year-old. This is eight weeks after treatment. I think that's impressive. Here he is three years later. Here's another child, this is a year after treatment, he's 7, 6 I'm sorry when we dosed him. And here he is age 7 a year later. Now we're getting on the 3 year mark here for him, he's 9. I've got two more to show you, just bear with me here. Six-year-old, one year after treatment, baseline and before. These are all open label. I would never do this in a randomized controlled trial. We just took these videos ourselves. This isn't with the PT there. I just did it myself and my colleague, I should mention my colleague Natalie Gettaker who helped me make some of these slides and we work like hand-in-hand together. I should have said that at the beginning, I had it on the slide, I forgot. She helped me put these videos together and she's been real critical to our success as a program. She takes phenomenal care of these boys. Here, same boy, three years later, age nine. And then lastly here, I'll show you this young man. This is before and four weeks later. We're actually in the hallway right outside where we do our infusion. I mean, this is four weeks. So I don't think this is from increased attention from the clinical trial. We've had all our boys, by the way, on daily steroids. For this trial, we switched them all to daily steroids and they'd been on it for some time. I don't remember exactly how long. We did not like initiate steroids three months ago in this kid. He'd been on daily for a while. Here he is three years later. We have him on Amanda's now, by the way. Not for very long at this three-year point, I can't remember, less than a year. I think it's amazing he's gawking up the stairs at all. So I don't know, I'm not going to say anything. This is what I see. We got a couple other boys I didn't show you, not because they're any different from this, just different reasons. I could talk about CK values. I mean, this fascinates me. So what we're looking at here, this is the CK value in the black and white from the Sarepta study from the EMBARQ trial. I am watching the time. I know I got seven minutes and no time for questions, I don't care. Look at what happens at eight weeks. I mean, the CK just plummets in the boys that are treated. And then it creeps back up. You can note, by the way, that the additional steroids dropped the CKs in the placebo arm as well. So you might say, man, that is, in this drug, it is doing something, even if we can't measure it on the North Star. I mean, look at those CKs. And then even over time, the CK, interesting, it goes up, but stays a little lower than it would have. What is going on with this drug? What makes this thing go that far down and then come back up? I don't get it. If you're wondering, well, maybe the microdisc just stops producing, no. The 57% of the biopsy at the muscle fibers are expressing this microdystrophin at 60 weeks after treatment. And what I'm showing you here on the other side is the same data from the Pfizer study. Look at the CK there. And at a year, 52% of the fibers are expressing this microdystrophin. So the protein is being made, but the CK goes down and then comes right back up again. And the Pfizer trial failed, every outcome. These are the older boys for whom Elevitis is also approved. This is from data that Sarepta submitted to the FDA. And I will, in the interest of time, just summarize for you that the non-ambulatory or older ambulatory cohorts, small numbers of children, all outcomes are declining or worsening over time. And the randomized controlled trial for this is ongoing. So this is open label. So they do not, these small numbers would suggest that they continue to decline and that they are not stable. Whether they decline less or not, we'll have to wait for the randomized controlled trial. But this is, these boys can get this drug. And this slide is from, again, for DMD, the prednisone comparison study. And I have this here just to show you, these are, each line is one individual. So I'm up here pontificating for you based on my experience of roughly 20 boys with Elevitis. And what I'm telling you is that we're in the business of looking at average change over large groups. But we have to talk to each person individually. And you can see the variation here from steroids, which I think we would all agree work. Yeah? This is the trouble. All right. I don't have a long time to go. So I want to at least mention the side effects of Elevitis, and I'll do it real quick. As it is on your questions, a lot of the boys vomit. Most common thing, they vomit. Zofran, very helpful. Second most common thing, their liver enzymes go up. And AST and ALT come from liver and muscle. So if the CK goes down, which it does, and the AST and ALT go up, it's coming from the liver. But I just checked the GGT, because the GGT just comes from the liver. So that's on your question bank. OK? All right. And then we're going to talk about myocarditis and immune myositis too. Myocarditis, troponins will go up when you get myocarditis. But not all troponins are the same. Troponin T comes from muscle and heart. So you've got to know what troponin you're checking. Here's a, I'm going to skip this in the interest of time. But let me just say, here's a boy whose troponin went up at about 12 weeks. Now this looks massive, right, from his baseline of having a normal troponin, which was nearly undetectable to, you know, whatever this is, eight times what it was. But boys with myocarditis get into the 40s, and this boy is at 0.8. This is an asymptomatic troponin leak. This child is asymptomatic with no vomiting. And also this is happening at nearly 12 weeks. And the cases of myocarditis happen in the first week or so. So you need to know sort of the details of this to know how to react to this. Because boys with Duchenne have troponin leaks, because they have cardiomyopathy. So if you start checking troponins routinely in boys with Duchenne, which is what you're going to be doing, you're going to see this thing bounce around. So you have to develop some thresholding about what you're going to do. And it is very burdensome on the boys and the community, and it's hard to know what to do. We bring them in, and we can do ECHOs and EKGs, because you can also have myocarditis that's only symptom is vomiting. And most of these boys will be vomiting a week after getting the therapy. So when their troponin bumps a little bit and they're throwing up, you've got to bring them in. You just don't know. But this boy, 12 weeks out, little bump. You can see we didn't do anything. We did an ECHO and EKG. We sent him home. We didn't bring him to the hospital. And then there's this boy who, after we treated him, his mom sent us a video of him running up and down a hill at a wedding. She was like over the moon with how great he was doing at four weeks. And then she came to see us for her four-week check. And she says, you know, the last three days, he has just been worse. And this is baseline, and this is week four. And this is the child with the 8-9 deletion. And this is a boy who has immune-mediated myositis. And this is the boy, this is the reason why the FDA label excludes deletion 8 and 9. That's it. That's the boy. It can be a lot worse than that with bulbar weakness and swallowing dysfunction and serious and obvious decline. You can see that boy, the decline is subtle. And if you're not totally believing me, then we treated him with steroids. And here is his four-week worsening. And here he is after steroids and IVIG and tacrolimus at the 12-week mark. So he got better. He stayed better, too, for about a year like this. All right. Thanks for your time and your attention. I really am honored to be here with Nancy. It really is a great pleasure for me. Thanks for staying. Okay. So we're going to open this up. I know we're kind of at the end. But if you have time and would like to stick around, we'll take a few questions. All right. Yeah, I think you've got to, I breezed through the side effects, but I emphasize the side effects when I'm talking to patients for whom the benefit isn't clear, because I think the risk benefit for the currently, for the data that we have available, I think the risk benefits out of whack for patients that are too far along in their disorder, in terms of what the cutoff is for that, I don't know. But that's my personal opinion. But- Anybody who's been treated is about 19 so far, and there have been about, a small number, they had one expanded cohort to include some older, larger individuals. I think the largest, I think, was 80 kilos and 19, and the lowest they went in terms of ejection fraction was 48%. So there's just been no experience, very little experience, of people who are older and heavier. They capped the weight increase at 70 kilos, thinking that's probably lean body weight. But there's just so little experience. And then again, the real, it's 600 mLs of infusate or whatever. And so there was one individual who didn't have any of these commercial products, but it was an NIH-sponsored individual thing where a brother was a scientist, and he got a group of people together and made an individual treatment for his brother, and that individual didn't survive, because he had cardiorespiratory failure, and he had pretty bad heart and lung failure as they approached the process of the dosing. So I think, and then again, it's just the issue of how much muscle tissue is left to be rescued. I mean, rescuing the rest of the muscle tissue, even if it's just to bring your hands to your mouth or turn in bed or something like that, is very, very valuable, but it's just, what do you have to do to rescue that? And the gene therapy, there's just not any experience, and the concern that it might be an extra challenge for the heart. And I would emphasize that the available evidence we have suggests that boys or young men will continue to decline after receiving Levitas, and we don't yet know whether the rate of that decline will be substantially different from the placebo group. And that's, I don't think that's color commentary. I think that's the available data that we have. I think there's a hope that we will slow the rate of their decline, but we don't know. I don't... I think there's some small bits of data that suggest that they decline more slowly, but again, the earliest anybody's been treated is eight years ago, so we don't really have a long period of time. And the concern is, as long as we only have this microdystrophin, it's going to continue to leak. You know, it only partially repairs things, so you're going to have a leaky sarcoma, ongoing Worli inflammation, and things like that, but just the hope, again, that it's less rapid of a change in terms of ongoing degeneration and regeneration, and the concern is that if you do that degeneration and repair, that the satellite cells that were around when the gene therapy was given, are we going to use, will the boys use them up, and then they will more rapidly decline, because any other satellite cells they have will be, you know, un-gene-therapied. We had another... There was another question here in front. Yeah. What do you do with the steroids after the gene therapy, the first 60 days? Do you continue the steroids? Do you stop them for a period of time, and then restart it, or do you make it worse? Let me repeat the question. So the question is, what do you do with the steroids after the 60 days? So it's all about the liver, essentially, at that point. So after 60 days, you can taper the steroids over the four weeks, and you continue monitoring the liver therapy every week. If the liver enzymes are still elevated, then that taper has to be delayed. If the liver enzymes bounce, then sometimes the steroids have to be increased. Usually the bounce that we see in the liver is around the six-week mark, roughly. So if you're at eight weeks and the liver has been stable or trending down, then you can... I drop the steroids personally, and you can come up with your own taper over the four-week period. Just do something simple. But you have to continue monitoring every week. I like to stop a week before the last check, you know, because you just want to make sure that when you get done with the steroids, then a week later that it suddenly hasn't flared back up again. The children that have the high liver enzymes, what you're trying to prevent is liver failure. It's not really... You get obsessed over the GGT, you know, which can be 250, and it'll keep you up at night for real. But you can wallop them with steroids all day long, and it's not going to suddenly normalize. You're just trying to make sure that it is not continuing to go up, and that you're going to flip them into liver failure. None of the children in these studies have had liver failure. They've had transaminitis. No, I'm sorry, one person had evidence of liver dysfunction or synthetic dysfunction from the liver, but improved and survived. So that's how I... That doesn't exactly answer your question, but it depends. You know, if the liver enzymes are trending up, you've got to be aggressive about the steroids, and we usually wallop them. We give them a high dose for a few days, and then we try to taper back down to two migs per KG or so. But if you do this incremental increase, it tends to just stay high. I understand also from the original cohorts at Nationwide Children's that there were a few families who said, you know, now we've got this gene therapy and the kids are looking good. You know, you saw the improvement at the eight weeks in your stair climbing and stuff like that. So they trialed stopping steroids. As soon as they got over the liver three months kind of thing, and they stopped it just to say, you know, great, we've got this gene therapy, and so now we don't need the damn steroids kind of thing. And the children did not do as well. So a very small cohort of post-recovery from gene therapy, stopping steroids didn't work well. End of a handful. Are there any other questions? I think after you're communicated by the citation, how long do you want to do it? So the question is how long do we keep tacrolimus going on the two patients I've had with immune mediated myositis? Actually, I've had two. One of them cared for by Susanne Anacone in Texas, because that's where the patient lived, and he was on tacrolimus for years. My patient, still on, now on sirolimus, actually, my patient who I showed you had an unusual event where he had actually a recurrence of his immune mediated myositis and actually had myocarditis associated with that over a year later. So that is new information. And so it's an ongoing, it's ongoing. Years. Was the IVIG only once? No. The question is was the IVIG only once, and the answer is no, we continue the IVIG monthly and then actually, I don't want to get too far in the weeds on him, because that data is not all available yet. Yes. Ongoing tacro, ongoing steroids, ongoing IVIG, and then tapered for various reasons, and then that young man had a recurrence, particularly after tapering the tacrolimus, because he was having complications from the tacrolimus. Some of the other attempts at gene therapy have different kinds of immune modulating therapy, rather than just the addition of one per kilo of prednisone. And I think in response to these reactions of immune myositis and whatever, so some of the other ones have eculizumab and sirolimus or other things like that given transiently during the first part of the dosing procedure. We don't know if that's going to be a better approach. This is all to be determined.

Duchenne Muscular Dystrophy

pediatric physiatrist

current therapies

early diagnosis

corticosteroids

exon skipping

gene therapy

mutation-specific treatments

viral vectors

mini-dystrophin genes

immune responses

therapy side effects

clinical data