Good morning. Welcome to this first day of the Academy Assembly. It's wonderful to be here and wonderful to have so many people here. I'm Susan Apcon from University of Colorado and Children's Hospital Colorado, and it's truly a pleasure to be able to present along with some colleagues today. Before I introduce them, I'm going to just read a few housekeeping items. I'm supposed to remind folks and participants and presenters, so I'm going to silence my phone right now and ask that folks silence their phones. This is being a recorded presentation, and so instructions are trying to be at a minimum. Please complete individual session evaluations as they're going to help the Academy with planning future events. The session evaluations are located in the Academy mobile app, the Academy online platform, and online learning portal. I'd also like to remind folks in the audience that the PMR Pavilion offers interactive resources, education and fun throughout the Assembly. There are opportunities including a sponsored hands-on education, educational theaters, a sponsored anatomy and learning lab, and career center sessions. There are more than 130 exhibitors ready to engage with all of us. These are opportunities that are free to all attendees, and there's no advanced registration that is required. Finally, if you walk down the hallway, it was hard to miss the bright yellow T-shirts, and the Academy is encouraging people to pick up your Physiatry Day T-shirt at the member resource center. So having said all that, I'd like to just get us going this morning. You can see from the title on the screen here, we're going to be talking today about decision making in the use of the FDA-approved novel treatments for boys with Duchenne muscular dystrophy. As I was reflecting on this talk, it's pretty wild. Over the last nearly decade of what has happened in the world of neuromuscular medicine for children, while certainly the three FDA-approved drugs for children with spinal muscular atrophy are life-saving and life-changing, we do have multiple medications for boys with Duchenne muscular dystrophy and young adults, and we're going to be talking about those today. I'm joined by three colleagues, and you're going to be hearing from all of them during this panel. Dr. Mindra Laverty is all the way over to the end. She is a child neurologist practicing at Rady Children's Hospital here in San Diego. Welcome. We have Diana Marchese, who is from Children's Mercy Hospital. She is a physical medicine rehabilitation physician who is providing care to kids with neuromuscular conditions. And finally, my colleague, Dr. Ann Stratton, who is also a pediatric rehab physician who is at University of Colorado and Children's Hospital Colorado. These are my disclosures, and I'm going to just jump right into the outline for this next hour and a half presentation. First, I'm just going to describe briefly a natural history of the loss of ambulation in Duchenne. Now, remember, this is a little bit of a higher-level presentation. The Academy has moved us towards a little bit of a different style, so I'm going to expect that people have a basic understanding of Duchenne, so I'm not going to cover the basics, but we'll talk a little bit about the loss of ambulation. We're going to describe some of the commonly used functional outcome measures in clinical trials, and then we're really going to jump into the description of these FDA-approved medications, and each of us will take one on. We're going to be doing it in the order in which the FDA approved it, so that there is no bias involved with that discussion. And finally, and I think most interestingly, we're going to talk about some cases. We've prepared three cases that I'm going to offer up to the panel, and hear how they are approaching these different situations, and how they think about the age and the stage of how to make a decision about what medication to provide a child with Duchenne muscular dystrophy. So we are lucky in pediatric rehab to have an amazing researcher in Craig McDonald out of UC Davis. He really is a leader in the field of neuromuscular medicine, and his work and the work of his colleagues has really informed what we know about the natural history of Duchenne muscular dystrophy. What we do know is that the mean age at loss of ambulation is around 12 and a half years of age. You can see a bit of a spread. This number that he presented comes from an international group of experts, followed between one and three years, with about 270 ambulatory and non-ambulatory boys enrolled in that study. Some were on steroids, some were not on steroids. And what you can see in the bottom few bullets was that the loss of ambulation for those boys who were younger than 12 years of age, there was associations with a lower mean of a force vital capacity, lower mean knee extension strength on handheld myometry, higher rate of planar flexion contractures in the group who lost ambulation sooner. And finally, and maybe not surprising, those who were on daily corticosteroids had a later loss of ambulation. So in other words, those who were not on steroids or who had a shortened exposure to steroids lost ambulation sooner. Those of us who are seeing kids in typically a multidisciplinary clinic know that the physical therapists are instrumental in the care that's provided in these clinics. The therapists are doing outcome measures that help us to inform us in terms of some of our recommendations, whether it be the treatment with a novel medication or the prescription of a mobility device like a manual or a power wheelchair. And these are some examples of the typical outcome measures that are utilized during the clinic sessions, including a forced air climb, time to rise, 10-meter walk run. The last bullet, performance of upper limb, is generally done in boys who are non-ambulatory or those boys who are transitioning from that late ambulatory phase to the early non-ambulatory phase. The 10-meter walk is a test that can be done very easily in the clinical setting, literally walking down a hallway that's 10 meters marked down. And sort of that number 10, that 10 seconds to 12 seconds, if a boy takes longer to walk down 10 to 12 seconds, generally they're going to lose ambulation within the next one to two years. Again, as a rehab physician, that's very helpful in informing what we're going to do next. Again, this comes from Dr. McDonald's work in roughly 270 patients. The North Star, another measure, it's North Star ambulatory assessment, 17 item, things like balancing on one foot, getting up off the ground, stepping over a little platform are examples of that. It's a test that's not as granular, and when you read through some of the trials that failed to meet their endpoints, the North Star sometimes has some criticism because it's not as granular So if you can do it normally, you get a two. If you can't do it at all, it's a zero. And then somewhere in between, if you can do it with compensation, whether it's a little compensation or a lot of compensation, you get a one. And so while some of these treatments may have changed the way, the quality of movement, it may not have captured the true result. And again, the North Star is a way that we can utilize that information in these long-term natural history studies to inform us about the time of loss of ambulation. And those who score a nine or below generally will lose ambulation within that next year. So before I move on and have Dr. Stratton join us, I just want to share a couple quick things. So we have these FDA-approved drugs, and what you're going to hear today is that they work differently. However, Duchenne muscular dystrophy is a result of an absence or near absence of dystrophin. Dystrophin protein helps to connect the intracellular sarcolemma to the extracellular space. When you're missing dystrophin, you have muscle breakdown in that cascade that leads to loss of ambulation, loss of ability to get your hand to your mouth, and then subsequent death now into the fourth decade. When you hear the different speakers talk, you're going to hear about how the mechanism of actions are different. The dystrophin protein is absent, so replacing a dystrophin protein is an example. Or the fibrosis and the fat that infiltrates the anti-inflammatories are a good example of how we might be combating that. So as you're listening to the description, it's helpful, I think, to think about the mechanism of action or the pathophysiology of Duchenne muscular dystrophy and why we might be seeing these benefits. So with that, Anne, I'm going to welcome you up. All right, thank you for that introduction. And so I get to talk about exon skipping in Duchenne muscular dystrophy, and one category of drugs, but I'm going to be touching on four different drugs, so I have no disclosures. So I want to make sure that we all have a basic understanding of the technology behind this. So antisense oligonucleotides are the mechanism that we use to do exon skipping, and they alter messenger RNA splicing to affect the protein expression. Remember, for our residents and potentially med students in the room, you have to go through transcription of the DNA into the messenger RNA, and then that gets translated through to the protein. So antisense oligonucleotides, you may hear or read in the literature some other abbreviations. You may see ASOs, AONs, PMOs, and SSOs. These are all essentially the equivalent thing. I just want you to sort of understand that as you're going through the literature. The way they work, they're engineered snippets that are, you know, you have your base, they have base pairing, and then there's a backbone that is engineered, and they go in and bind at certain sites in the messenger RNA, and they switch the splicing that would normally be coded at that site. So they can either be engineered to encourage an exonic splice enhancer to come and bind, or they can be engineered for an intronic splicing silencer to bind. So basically, they say, hey, come here, splice here, cut here, or nope, keep going, nothing to see here. Keep on translating. All right, so if you remember, Duchenne muscular dystrophy typically means that there is an out-of-frame mutation, and so the transcription translation proceeds along, and then it hits this mutation, and nothing makes sense after that, and you don't have any more protein formed. However, in Becker, in general, they're in-frame mutations, so you have transcription translation moving along, and there's a little hiccup, but the next frame makes sense, and you get resumption, and you have at least a partially functioning protein, right? So the goal of this exon skipping is to restore the reading frame so that things line up again. All right? Challenges with this is getting the construct actually delivered to the nucleus of the muscle cells with a constant supply. So there is a little bit of problem of some endosomal entrapment, and you have to get repeated IV dosing. So there is, I just want you to have in your mind that there are some next-generation drugs being engineered to try and overcome this problem, and I obviously am not talking about those today, but you can keep that in mind. So some of the ways that they will attempt to work to enhance cell delivery will be through something called peptide conjugation, and you'll see those designated as PPMOs, or using an antigen-binding fragment-linked technology as a way to get that backbone and get those nucleotides, oligonucleotides, into the cell and into the nucleus more efficiently for better transcription. So cool technology. Dystrophin is huge, and so fortunately, there are a majority of pathogenic variants that cluster between exons 45 to 55, and we use that to our advantage for people that are very smart in engineering these. So the four drugs that we have available now are eteplersen, goladersen, vitilarsen, and casimirsen. And as you can presume, they are indicated only for very specific skippamenemal genetic mutations, so you have to be able to change the splicing at these specific sites to get things to line up again. And these four drugs put together can treat approximately 30% of our DMD patients. Again, they require weekly IV infusions, and you do have to monitor safety labs, specifically renal function labs. We look at baseline, we get urine, and every four months, blood and urine. So eteplersen is used to skip for exon 51 skipping mutations, skippamenemal mutations. Goladersen is for exon 53. Vitilarsen is also for exon 53, and this is just in order of FDA approval. And then casimirsen is the most recent that was approved, and that is for exon 45 skipping mutations. So diving into eteplersen a little bit, so this exon 51 skipping applies to probably the largest percentage, and again, it's only about 14% of our Duchenne patients, but that's something. And the initial approval was based on increased dystrophin production observed in skeletal muscle in patients that were treated. And so basically, they looked on Western blood analysis, and the amount increased from 0.2% up to 0.5% of normal, which it doesn't sound like much, but that is a two to three-fold increase. And they did not find statistical significance, but there was a trend towards a slowed rate of decline in the six-minute walk test, and follow-up studies have subsequently shown that there is a slowed rate of decline of loss of ambulation and implementary function tests. And the goal is to move things closer, move the phenotype closer to a Becker and away from a Duchenne. And overall, it has had a very favorable safety profile. Goladersen received accelerated approval in 2019, and that is exon 53, as I said, which applies to about 8% of our Duchenne patients. And again, initial approval for this was also accelerated and based solely on increased dystrophin production. And in this cohort, it showed that dystrophin staining increased from 0.1% of a normal production at baseline up to 1% after 48 weeks. Again, slow trend of decline in ambulation, in loss of ambulation and PFTs, and a favorable safety profile. Vitilarsen was approved in 2020, and that is also an exon 53 skipping amenable drug different company, and again, applies to about 8% of our patients. And their initial approval was based on increased dystrophin production, once again, increased from, in their studies, about 0.3% of normal at baseline up to 5.9% of normal. And in their studies, it showed that time function tests, which Sue went over briefly at the introduction, showed significant improvement after 25 weeks of treatment. So and again, favorable safety profile, so very encouraging. And then finally, Casamirsen received accelerated approval in 2021, and this is an exon 45 skip amenable drug, and again, that is another 8% of our patients. So if you add 14 plus 8 plus 8, you get approximately 30% of our patients can be treated with one, or in the case of exon 53, you have two options for drugs. So in Casamirsen, it showed that on immunofluorescent staining, that you increase from 0.9% of normal dystrophin up to 1.74, oh sorry, that's on western blot, and from 6%, 6.5% up to 15% on immunofluorescent staining, which again, encouraging. But there are no functional studies yet that have been reported, so hopefully we'll get that data soon. And again, favorable safety profile, so encouraging. Potential toxicologic risks are that these can potentially be pro-inflammatory, and you could in theory get some vasculitis, and inflammatory infiltrates have not seen that, fortunately, be a problem. Nephrotoxicity is the main thing that all the FDA warnings are about, and that is based on results in a rodent trial with rats. And so hepatotoxicity is also in theory, and thrombocytopenia also a theoretical risk, but fortunately that has not been observed, and the main thing that we look for in our safety labs is we monitor renal function. So these are fortunately dose-dependent transient toxicities, and the backbone that is engineered is the main issue, I suppose, and fortunately newer generations of backbones have gotten much more stable, and have a much better toxicity profile. So overall, very safe, from our experience, technology. So you should know the labs that we get, we get a cystatin C, a urine protein to creatinine ratio, look at renal function, and we have our renal team sort of on call, should these lab results come back funny. I do not fully interpret them myself, and look at the B1 to creatinine ratio. We get monthly urines, and then every four months we get urine and blood, and you should know that these labs, including the urine, need to be obtained in the 48 hours prior to the next dose, because they will be falsely elevated. We've had that multiple times, where the patient gets the infusion at home, they forget to check the labs, so they go pee in a cup after, and sure enough, things are falsely elevated, and then we have to repeat the testing. I just threw in the FDA package inserts, just highlighting some of the things that you'll see for Exondys 51, you have to be Exon 51 skipamentable, and it's 30 mg per kg of body weight once weekly. All of the drugs, except for vitilarsin, which I'll go over next, are 30 mg per kg, and it is an IV infusion over 35 to 60 minutes, and the main side effects that have been seen are some dizziness and some nausea and vomiting. Vitilarsin, you have to, I chose this as a comparative FDA package insert, just because it is a little bit different, different company, different backbone, and they, it's for Exon 53, and this is 80 mg per kg is the dosing, but again, same infusion, IV infusion over 30 to 60 minutes, same lab workup, and same, a similar sort of safety profile and side effect profile, headache, some cough, congestion, injection site reaction, and the like, and nausea. So, logistics for these, this group of drugs, again, you have to think about, these are weekly infusions, most of our kids end up with a central line. We get them, we have a port inserted, and it is weekly dosing, so that requires some logistical finagling sometimes, and patients go out of town, or the like, and so we try and give the dose within three days of that week, and if you are out of the dosing, so your dosing window essentially would be from four to 10 days. If you're out of the window, you just skip that week's dose and start over. So adverse reactions that we have seen tend to be pretty mild, we've had some IV site complications, not too bad with that, headache, dizziness, myalgias, fever, some GI upset, and then the potential for renal toxicity, but I can say that we haven't really seen that at our institution. We've had some false positives that then we've rechecked, and things have been fine. So stay tuned for this technology. These are all of the different potential sites on the Duchenne gene, or the dystrophin gene, sorry, that are skip amenable, so these are all the different exon skipping potential drugs. So the next drug that is likely to come out that we're anticipating will be exon 44 skipping, and that will apply to about 6% of patients, and then potentially others. So if an antisense oligonucleotide is made for each one of these sites, we will be able to, in theory, treat 60 to 80% of Duchenne patients with this technology. So these are my references. Diego and Rady Children's Hospital. I'm a neurologist. It's an honor to be here. Just for starters, I'm a little under the weather. I'm sorry, I will try to project my voice. And I'm gonna talk today about dilandrostrazine moxiparvovac. I, of note, I am a consultant and a PI for Sarepta, who is the manufacturer of this drug. Dilandrostrazine moxiparvovac. The brand name is Alevitus. It was, it got its full approval after initially getting accelerated approval in 2023. It got full approval in June of 2024. It's available for boys four years and older, and it is the first gene therapy for Duchenne muscular dystrophy. It is indeed contraindicated in boys who have deletions of exon eight or nine. And that is because that region is actually corresponding to the hinge region, hinge region one, that actually increases the risk of immune-mediated myositis. That is why those two exons were contraindicated in the final label. Boys who have AVRH74 titers greater than one to 400 are excluded. Those boys have been, their immune system has seen the virus before, and as a result, you cannot give the drug safely. The seroprevalence in a small study of about 101 boys was estimated to be about 14%. And the RH stands for rhesus, meaning it was initially isolated from a rhesus monkey. And that is the prevalence, the seroprevalence of between four to 18-year-olds. As the age goes up, that seroprevalence is thought to actually also go up. Makes sense, we see more viruses as we get older. It is an IV infusion given anywhere from one to four hours, depending on the size of the boy. And it is typically done at an outpatient infusion center. It is a once-in-a-lifetime drug. It is a whopping $3.2 million per dose. And there is premedication that is necessary. So you need to give additional prednisone on top of their standing doses of steroids that they're taking already for their Duchenne muscular dystrophy. And that's dosed at one milligram per kilogram per day. So it's weight-based dosing, and it's 1.33 times 10 to the 14 vector genomes per kilogram, with a maximum dose of 9.31 times 10 to the 15 vector genomes. And it basically tops out at 70 kilograms. I'm going to actually skip that one. And I want to point out that first diagram is the microdystrophin just taking the exons. It is the largest gene in the body, the DMD gene. And the third one is the domains. So you're looking at the different domains, the C-terminal domain, the N-terminal domain, the spectrum repeat domains are in the blue. I want to point out that for the miniature version of the DMD gene that is Delandris gene, that entire midsection is absent. That part was removed in order to miniaturize what's in the transgene cassette. This is a diagram showing what Delandris gene looks like in situ. So you can see that the N-terminal anchors onto the actin-myosin filaments that do the excitation-contraction coupling. And you can see that the cysteine-rich in that turquoise color that anchors onto the beta-distroglycan is anchoring onto the sarcolemma. And it literally acts like a spring, with the hinge domains, which are the squiggly brown lines, actually also giving it some spring and elasticity so that the protein can actually move as the muscle is contracting and relaxing. Here is what it looks like in terms of its transgene cassette. AAV-RH74 is the vector, and that's a recombinant vector. It's an AAV that has been modified and has undergone genetic evolution in the laboratory for it to have tropism to heart and skeletal muscle. The microdystrophin is the actual business section that is in the purple. And then it has a MHCK7 promoter that only transcribes the gene in muscle and heart tissue. And the whole thing is flanked by the inverted terminal repeats in the green. And those are the only portions of the entire transgene cassette that belong to the original wild type virus. This virus does not replicate in our patient once it is given. It is a non-replicating virus. And AAV-RH74 was actually chosen because it doesn't cause disease in humans, but it does infect human tissue. This is what it looks like. It's actually not a bag. It's actually a syringe that slowly pushes down on the plunger over the next one to two hours. You set the rate. And the boy is given through a peripheral IV in the outpatient infusion center. That virus then goes into the bloodstream and the virus knows how to do extracellular trafficking. Enters the target tissues. It enters many tissues, including non-target tissues, but it's not transcribed and not translated in the other tissues that do not have the machinery for attaching onto that promoter, the MHCK7 promoter. Once the virus actually gets to the sarcolemmal membrane, it does endosomal uptake, and then it enters the cell. Once it does endosomal uptake, it actually needs to do something called endosomal escape. And viruses know how to do this, so we don't need to guide it. It's able to do endosomal escape and then attach onto the nucleus. And once it gets to the nucleus, it delivers its transgene, which then forms a circular piece of DNA called an episome. And it is not integrated into the host genome, which is advantageous because then it won't be carcinogenic, and it actually stays as a circle, potentially, hopefully, for multiple decades, but that remains to be seen in terms of the durability of this drug. And it uses its own host innate machinery, the RNA polymerase, in order to make the mRNA, which is then shuttled out into the cytoplasm, which then undergoes translation, and now you have a micro dystrophin protein that is much more stable than what the patient was originally making, which is usually destroyed anyway. This is an overview of what the trial looks like. It's called the EMBARQ trial, and it had 125 boys, I'm sorry, there's a formatting issue here, 125 boys, and there was part one and part two. Half the boys got the gene therapy for part one, and for part two, they got placebo, but it was randomized, double-blinded, controlled, and so the boys who did not get the gene therapy on part one would have gotten it for part two. It's a crossover study. Each part is a year. And boys had to be between four and eight, and a medium North Star, not too strong, not too weak, and all the boys who had one through 17 mutations were actually excluded for this study, but that is different from the label. And you'd need to have been on a stable dose of steroids, and of course, negative titers. The primary endpoint is something called a North Star. I'm sure that you are aware of what that is. And then the time to rise and 10-meter walk run are the secondary endpoints. Sarepta actually designated a specific statistical plan for this study. Only if the primary endpoint was positive could you actually do p-values for the secondary endpoints, but as we know, it failed as primary endpoint. The p-value was 0.2. In the purple are the treated boys, and this is a one-year study, and in the gray are the untreated boys. You can see that the change from baseline in the North Star increased, which is better, which means that the boys are doing better, but both the treated and the untreated arms improved in that one year. So the difference between the two arms was not statistically significant. And this is a diagram showing that if the zero, if you were to set no change as the vertical line, there was an overall favorability, but it still did not meet statistical significance, and the secondary endpoints were favorable, but you can't calculate p-values because it actually failed as primary endpoint. So you can say that the secondary endpoints, which is the time to get up off the floor, time to rise, and the 10-meter walk run were numerically favorable, but you can't claim statistical significance. Same thing with the four-stair climb, the time it took for these boys to climb four stairs, also numerically favorable. So why did the drug fail? Well, I have some ideas. One, obvious one, is that perhaps the drug was not efficacious enough to actually do, to withstand above natural history. Remember, it was never meant to be a full rescue anyway. The second thing is if you do a little bit of analysis in the North Star, perhaps that wasn't the best measure to use in these boys in a one-year study in boys that are, you know, they're quite, they're not that affected. They're medium affected, but they're not very severe, they're not on the tail end of going down. So there's a publication by Dr. Montoni where he classified Duchenne boys into four different classes. If you're a rapid decliner, you are that red boy. And if the boys in the EMBARQ study are the blue. So at six years, which is the average age that they actually entered the EMBARQ study, you can see that the blue line is still, the North Star is still increasing. And then one year later, at seven years, it's still increasing by natural history. So if the natural history of the North Star is increasing, the medicine has to do phenomenally well in order for it to show a statistical significance at the end of one year. So perhaps North Star was not the best measure. Now let's talk about side effects. The most common side effects are nausea, vomiting, and fever, and then those are the initial side effects, especially that first week. You can treat that easily with Tylenol. I definitely recommend Ondansetron and some sort of Pepsid or H2 agent to actually help with protecting the stomach. Increased LFTs are actually the one that actually worries all of us. That typically happens at week four through week six or so. And it can be anything from just a transaminitis that's asymptomatic to full-blown, oh my goodness, my kid is jaundiced and has sclerolicterus, and wow, I really need to bring this boy into the hospital to give them IV methylprednisolone. The first action that you should do is actually increase the standing oral prednisone from one mcg per kg to two mcgs per kg per day, per kilogram per day. And then if that does not work, bring them in for IV methylpred in the hospital. And you can talk to your pharmacy in terms of dosing based on weight. And that works typically very remarkably. Now, the first week is the most tenuous with nausea, vomiting, and complement activation that is not clinically significant, as well as thrombocytopenia, rather, that is also not clinically significant for the vast majority of cases. I personally do not think there have been any reports of that being clinically significant so far. We have been seeing some infusion-related reactions where during the infusion, the boy can have pruritus, flushing, redness, a rash. Stop the infusion, give Benadryl, wait until all the symptoms resolve, and restart the infusion is the way to go for that. And then immune-mediated myositis, which will hopefully not happen because of the exclusion, but we are supposed to watch out for it, typically begins at about week four. Now, thrombotic microangiopathy and hemolytic uremic syndrome does not occur so far, has not occurred with the Levitas, but it's something that we have to definitely look out for in every gene therapy. Everything that I just said, actually, is just written down for you here, so I'm actually gonna skip over it in terms of what to do for the immune-mediated myositis. You do need to give IV methylpred, possibly IVIG, and probably even Imuran or Tacrolimus. And then finally, I do want to tell you that so far, there have been no deaths in this particular DMD microdystrophin program. We all take a huge breath when we give this medicine because of all the risk. The parents need to be on board, they need to follow through with all the aftercare, and we, as a clinical team, need to be very vigilant in order to prevent a death from happening. But only with vigilance and monitoring can we avoid this catastrophic outcome. There have been other DMD microdystrophin programs that have resulted in death, and that is a risk that you need to talk about ahead of time. I'm happy to take questions at the end once all the speakers are done. Thank you. Thank you. Thank you, Shemindra. I'm gonna quickly go through the next medication, which is Vimeralone. So, Vimeralone is in the category of a corticosteroid. It's referred to as a dissociative steroid. It has a different structural entity with a lack of a 11-beta-hydroxycarbonyl group, and what that does is it changes that structure, and ultimately, potentially, some of the comorbidities that are associated with, or the morbidities associated with chronic corticosteroid use. In particular, it's not a substrate for a particular enzyme which is involved with bone health, and so one of the outcome measures I'll talk about is bone markers of bone breakdown and the impact it had. And finally, and importantly, it's an antagonist to mineralcorticoid receptor, which is different if you think about with prednisone or deflazocort. It is an agonist of mineralcorticoid, so it causes a higher blood pressure, and this is an antagonist, which is relevant, again, as we talk about management. Most importantly, it has the same anti-inflammatory effect as the current corticosteroids, so in clinical practice, the use of prednisone, prednisolone, and deflazocort is common. So in October of 2023, the FDA approved this. It is a daily medication dosed at six mg per kg, and it is an oral suspension that the boys take. There are adjustments for hepatic impairment, although there's not really any guidance for that. It was approved for boys two years of age and older, and as opposed to exon skipping, in which Minder talked about with gene therapy, this is agnostic to the genetic mutation. So any boys over two are eligible for this medication. So the design was a phase 2B study, and this was the design that, or the study that led to the FDA approval. It was two parts. Each part was 24 weeks, so a total of 48 weeks. Boys four through under seven were included. None of the boys had ever been exposed to steroids for any length of time. They were all ambulatory, and the time to stand was less than 10. I didn't mention the time to stand as one of those predictors, but typically over 30, a boy will be losing ambulation that next year. So these, again, similar to the gene therapy, these are younger boys who were quite active. So this is the design. Interesting design. The phase, or the period one, there were actually four groups. A placebo group, a prednisone group, which was typical dosing at .75 milligrams per kilogram, and then there was a low dose and high dose of vimeralone. At the end of the 24 weeks, the boys were moved into the second period, and so those who received placebo or prednisone were moved into a low dose or a high dose of vimeralone. Those boys who were already on it continued at that current dose. It was blinded, so families or clinicians did not know. The outcome measures that were used included the time to stand, six-minute walk test, NorStar, and you can see the others. And the safety, so phase two studies are really safety. I should have put that on the left side of the screen instead of put it on the right. Safety was the primary outcome measure looking at any of the corticosteroid-related side effects that we see. Height and BMI were measured, and then serum bone markers. I talked about the fact that this is a different, this disassociated property because of the change in the structure, hopefully less impact on bone. So I just picked a couple of different results to share with you, and what you can see here is a little hard for me to see here. So the top line is the high dose vimeralone group. The lighter blue is the two milligram per kilogram, and then that group that only received over 24 weeks was the placebo group, or the prednisone group, excuse me. And what you can see is those receiving vimeralone at six milligram per kilogram had, this is the, the figure on the left is the change in the Stan from Supine measure, and what you can see is that there was a significant difference with the group who received the high dose steroids, high dose vimeralone. On the right side, again, what you can see is this is the North Star, change in North Star, and those boys receiving the high dose vimeralone did the best compared to those receiving prednisone or even the lower dose group. So safety, obviously, so basically what this study showed was it was equivalent in terms of its efficacy at the 24 weeks to the boys who received the prednisone, and better than those received the placebo. Most importantly, though, was the safety profile. There were three SAEs, all thought unrelated, unrelated to the vimeralone. There were no deaths associated with it. In the group of boys who took the six milligram per kilogram in that first phase, they had a decreased cushionoid face, obviously one of those things that we see in boys on prednisone or deflazocort, and interestingly, the height. So those boys who were on the vimeralone maintained a normal height trajectory. So if you walk into our clinic on an even day, you know who's on steroids and who's not. You have the cushionoid face, you have a very short stature, and you have delayed puberty. The boys on the vimeralone did not have that short stature. Interestingly, the boys who received the prednisone had a slowing in their growth trajectory, but as soon as they crossed over to the vimeralone, their linear growth picked up, which was nice to see, and weight increased in all groups. The BMI in period one, and then stabilized over time. Bone health markers. So this was a significant improvement. So the markers of bone turnover, bone breakdown, leading to fracture risk, was seen in the prednisone group only. And interestingly, again, when they crossed over to the vimeralone, that reversed. And that group who received the vimeralone did not have the increase in the bone breakdown markers. And finally, and very importantly, all groups, vimeralone as well as prednisone, did show evidence of adrenal suppression. So a couple things to think about. If you are prescribing vimeralone to one of your patients, you need to assume that they will be adrenally suppressed, and all that goes along with that. So family education is critical, making sure the family understands stress dosing. And one important point, if you could take home anything from the vimeralone conversation, is you cannot stress dose with vimeralone. Remember I said it's an antagonist to mineral corticoids. It will not give you the bump in blood pressure if someone is stressed and needs that bump in blood pressure. So if you're prescribing vimeralone, it's critical that they also have a prescription for prednisone to be used in case of stress dosing needs. The dose is six milligram per kilogram, and if you're converting someone from either deflazocort or prednisone, and they're on a standard dose of that, you should just go right to six milligram per kilogram. Like you would do with prednisone or deflazocort, if someone wants to come off it, critical that you have a very slow wean. Anne talked about having our nephrologist on call. We utilize our endocrinologist to help us with the weans for someone who's been on any of our corticosteroids for long periods of time. I put this question mark in the last bullet about a plurinone. We don't know what to do. A plurinone also is an agonist, sorry, an antagonist to mineral corticoids, so lowers blood pressure, can change your potassium level. So if you're on a plurinone and you wanna be on vimeralone, you probably have to do a little bit more monitoring. Again, this is corticosteroid. You wanna make sure kids are immunized, especially against those live, especially getting their live vaccines before they start, and then adjusting dosing if they're also on other medications, such as a strong CYP4, sorry, CYP3A for inhibitor. And then finally, and interesting, the package insert just sort of had a general recommendation for monitoring of any type of corticosteroid, including all of the corticosteroid-associated issues like bone health, like puberty, growth, blood pressure, electrolytes, and also cataracts. So I added that to the list as well. So I know I jumped right through, went through that very quickly, but I'm gonna hand this over now to Dr. Marchese. Thank you. Okay, thank you. So I'm Diana Marchese. I'm a pediatric physiatrist at Children's Mercy in Kansas City, and I'm talking about Juvenistat. So in a way, this is a lot simpler than the other drugs that have been talked about thus far. I have no disclosures. So Juvenistat, it's a histone deacetylase inhibitor. That's pretty much what we know. The exact mechanism of action is still somewhat of a mystery, but it helps with the translating of genes, depending on the turning and the unfolding of DNA. It's an oral medication that is given twice a day, and this was just FDA approved in March of this year. It's for boys ages six and up with Duchenne. It's novel because it's the first non-steroidal medication approved to reduce inflammation in boys with Duchenne, and it's not limited by that genetic variant or their ambulatory status. Epidus was the trial that helped get this medication approved. It was randomized, double-blind, placebo-controlled phase three study. It took place over 18 months and included 179 boys. Now they were all on their baseline steroid dose and were either given placebo or Juvenistat. The primary end point was the forced air climb. So this is the chart of the change in their forced air climb over the course of the trial. Juvenistat is the green line and placebo's gray. While both groups had an increase in the time it took them to go up those forced stairs, Juvenistat had a 1.25 second increase in time versus placebo, which was over three seconds. This was statistically significant. They also measured key secondary end points over those 72 weeks. You can see that that North Star score is on there. They also looked at knee extension, elbow flexion strength, and then fat fraction of the vastus lateralis muscle. While these were not considered statistically significant, they all still did favor Juvenistat over placebo. Adverse events, you can pretty much summarize them under three categories. You have the GI adverse events, so diarrhea and vomiting initially, and most of these side effects are worse within those first three months while you're still figuring out that dose. There is a risk of thrombocytopenia, so we monitor platelets frequently in the beginning. And hypertriglyceridemia. The remaining side effects on here are pretty similar between the two groups. And vital signs, EKGs, pulmonary function, all of those remain similar between groups. This is not the EPIDIS trial. This was one that was done prior to that trial, but it looked at the muscle histology of the patients at baseline, and then after 12 months of receiving Juvenistat. So you can see at the top that those baseline muscle fibers have a decrease in muscle size. You can see the muscle fibrosis in place, the fatty infiltration, and then after 12 months, the fibers have increased and there's a lot less fibrosis than was present initially. So it appears that not only Juvenistat can slow down that fibrotic process, but there could potentially be some reversal as well. And this was taken from a poster, and it just compares the age of loss of ambulation in Juvenistat versus that natural history progression. I will point out this tends to be older than when we typically see that loss of ambulation in either group, but again, it still did favor Juvenistat. So how do we prescribe and monitor? In the trial, all the boys were on a stable steroid dose. You're not going to see any trials just looking at Juvenistat in this population. You have to get baseline platelets and triglycerides fasting. There is a risk of that QT interval on EKG getting increased over time. The FDA label recommends that you get a baseline EKG, and then they leave it up to individual clinics and cardiology to continue monitoring that or not. There is an increased risk with that QT prolongation if you're on other QT prolongating medications, but it's rare that our patients are. Platelets you get every two weeks for those first two months. Eventually it settles out to just every three months. For triglycerides, you're getting it monthly, and then that settles to just twice a year. I had mentioned those GI disturbances. Again, the diarrhea can be rather bothersome. There are instructions in the FDA label to reduce the dose. If you've done it at least twice, and they're still having those issues, then they recommend discontinuing the medication. However, I will say that within the Epidus trial, even if side effects did occur, none of the boys had to withdraw or discontinue the medication. All right. Thank you. fun now. So we're going to go ahead and just jump into a couple of cases. We have about 20 minutes left. So I'm going to go ahead and start. And, Shamindra, I'm going to ask you the first case. And then what we'll do is, after she presents, I'll ask the other two to maybe add a few other comments. And then I'd love to open it up to the audience for questions or comments as well. So, Shamindra, Dr. Laverty, the first case is a four-year-old little boy who's amenable to Exxon-53 skipping. His family meets you for the first time and is interested in understanding all of their options and want to help making the decision. So can you talk a little bit about your approach in a four-year-old who has a possibility of Exxon skipping, plus all of these potential other treatments and how you think about that? Thank you, Dr. Avakhan. So as a principal, I always tell my parents all the medications that they're eligible for, for that age group. So if it's a four-year-old, first of all, because the patient is absolutely new, steroids, which unfortunately is the mainstay of treatment and does a remarkable job, despite its side effect profile, should be introduced. And patients, boys on steroids, by the way, ahead of time, actually perform or they have less risk when they, if they were to choose dilandrostra gene, the elevators drug, the gene therapy. So I layer on the different drugs. Me, as a physician, I would probably do steroids first because of its broad effect and long-lasting and over 25 years of data for Duchenne. Then I would actually, did you say he was amenable for? He's amenable to 53. 53 skipping, that's right. I will tell them about the two drugs that are 53 skippers, the Viltepso and the Vitrolarsin. And so, no, no, sorry. No. Golodursin. And, but you as a physician need to understand that oftentimes when you do a 53 skip, your insurance may actually not let you do dilandrostra gene. So you have to weigh the pros and cons of doing one drug versus the other. But perhaps after introducing, if the parents are willing to take that risk with dilandrostra gene, perhaps dilandrostra gene might be the first drug that you could consider. If the parents are amenable, this is an age group that actually is enrolling in second generation gene therapies as well that might have a better efficacy than dilandrostra gene, but that is a risk. Those are not proven yet. It is an experiment. It's going to require a full-blown clinical trial. So there's a lot of options for a four-year-old that's naive right now. I'll stop there. Great. Thank you for kicking us off. Dr. Marchese, anything to add to that four-year-old? Yes. I agree with a lot of what you're saying. I think families can also feel overwhelmed with all of the options that are out there, and it definitely just takes time even as practitioners to really lay out the risks and the benefits of all of these medications. We didn't really harp on insurance, but I feel like that's something I run into a lot. They do like to see whatever clinical trial was done, whatever those parameters were, to be replicated in the patient that is then trying to get approval for another drug. So say if prednisone was the steroid they were on, I guess we're going to start with prednisone if you want to go on and try this gene therapy later on instead of automatically out of the gates going with vimrolone, even though there's that favorable side effect profile there. You could always try to do vimrolone first. Insurance will likely deny it, and then you still have to do the PRED trial. But it's just kind of a game that we do have to play, and families are understanding. It is in the nuances of this case that you have to think. So we've talked about in our clinic also getting some baseline bone marker labs to be able to look at that, anticipating that insurance may dictate that you have to start with PRED. But actually, we've had really good success in our clinic with getting vimrolone approved initially in these young patients. That being said, if the family does choose the LAM-distributed gene, you have to do PRED anyway. So we have to discuss that. So yeah, and another consideration, obviously, if the family chooses to move forward with the gene therapy, that's it in a young child. And so we have to make sure that the family truly understands that this would be their one shot at gene therapy. There's no going back and getting a second gene therapy at this point. And so the informed consent process is really important, really, really important. And we actually have built in sort of a way to document that in the patient's chart in our clinic, just to make sure that we have everything laid out and that the family, to their best understanding, that we have achieved informed consent. Yeah, it's complicated. I think you all brought up really good points. It's everything from insurance to a one-time infusion of gene therapy. I love the fact, Dr. Laverty, that you brought up the fact that there's clinical trials going on, right? So we're on second-generation exon skipping. We're on second-generation gene therapy. And while we can't redose right now, there's a lot of work being done in terms of how one could get redosed, everything from plasmapheresis to novel vectors that may allow repeat dosing. So before I go to the second case, I would love to open it up if anyone has any questions or comments, if you've had experience you'd like to share. Yes? I have a couple of questions in regards to the eliminus. One of my questions was... Yes, thank you. We have an online audience, so I appreciate that. Thank you. Hello. Sorry. I had a few questions in regards to the eliminus. One of the questions I had was in terms of the actual penetration of the virus into the skeletal muscle, how widespread it is. It's actually quieter now than you... Okay. It's on now. Is that good? You're on. Yeah. Okay. All right. In regards to the eliminus, what's the actual penetration of that virus into the skeletal muscle? Is there any data saying what percentage of skeletal muscle cells are affected in general? The transduction efficiency done for the phase one study demonstrated that the amount of dystrophin made in the original four boys was actually upwards of 50% microdystrophin formation. We do not have biopsy data on the EMBARQ phase three study. It was a non-biopsy study. The number of episomes per nucleus ranged from two to three. That gives you an idea of how many viral particles were actually able to deliver a episome, the transgene, to each nucleus in the muscle syncytial cell. The transduction efficiency was actually quite decent. Thank you very much. Thank you. The second question I had is just in terms of clinical indications for when to consider a levitas. You have a patient who is genotypically Duchenne's, but kind of blurs that line phenotypically between your Becker versus Duchenne's. At what point do you start considering whether a levitas would be an option? This is a good question. We all have Becker boys that look like a Duchenne boy. I do not want to take the risk of giving a genotypic Becker a levitas. First of all, it's not FDA indicated. Second, there is another platform that had a little boy that died, and we don't know the circumstances of that boy's death. There are some questions about his genotype. I stick to the label just because I don't know what risk I'm going to get my patient into if I go outside the label, just because it is a high-risk drug. I do not give my genotypic Beckers that look like a phenotypic Duchenne boys a levitas. I only give it to the out-of-frame boys. Thank you very much. And I would add, so if you reverse it and you say that this is a genotypically Duchenne, so it's an out-of-frame mutation, yet is acting like a more mild phenotype, I would wait, right? Because as you heard, there's second-generation treatments, and to expose a child who's actually doing really well and looks like they're going to continue to do well for the near future, for me, I might do one of the non-gene therapy options in that situation to buy a little bit of time to see what else might be available. And I wouldn't be surprised if a family that is a very low-risk family, like they don't want to take any risks. If they don't want to do steroids, they don't want to do dilandrostra gene, but they want to do one of the 51 skips. Like, we are not used to just giving 51 skip because it was always done in the trial with the steroids, but I have a few patients who just want to be on, sorry, 53 skip, rather. So that is also an option. We just don't know what type of efficacy we'll get because this trial was with steroids. And moving back to your initial point about how much of the virus gets into the muscle cell. Anecdotally, we actually have encouraged our patients that have gotten it to run around a little bit, get their circulation pumping. I don't know whether it's doing, you know, what we're hoping it to do, but a thought. I'm going to go ahead and ask a second, or present a second case. And I think Dr. Stratton, you want to take this one. So the second case is an 11-year-old who, again, is amenable to exon skipping, in this case 51, and has actually been on a Teplishin for three years. He's ambulatory, but his 10-meter walk run is getting close to that 10 seconds. It's about nine and a half seconds. Family's interested in their options. How would you counsel them in terms of potential other treatments? Yeah, so this patient, you know, this is an exon 51 skip amenable patient. So there is unfortunately no other skipping option for this patient. They've been on Pretnisid. So we could always discuss switching to a different corticosteroid, either Deflaskort or Vemoralone. But I would probably also advocate in this patient, you know, our other two options are adding Givenostat or potentially treating with Elevitas. And so having that discussion with the family would be our next, would be my next step approach. So understanding that an older boy with, you know, who's already starting to show signs that they're going to lose walking, we don't have a lot of data from that age group yet for the gene therapy. And so, you know, full disclosure, they might be at a little higher risk of complications. It's going to be a higher vector load dose that they're going to receive. And we don't know if they will make improvements or just achieve stability or what exactly. So we'd have that discussion about all those options. Dr. Labradi? That isn't, the older boy is definitely a risk in terms of the Elevitas. I have actually done an over 70 kilogram older boy that's 19 through the ENVISION study, which is the older study that hasn't published out yet. And he did remarkably well. So I think it's a hit or miss, just like the younger boy. So just because it's an older boy, yes, you're given a whole lot more viral particles. Doesn't necessarily always translate, but you need to be fully lights on. Transparency. Yeah. I just wanted to add on there and ask you, were there any cardiac, did the trial have documented cardiomyopathy? Yes, he had an ejection fraction of 45% at the time of entry and baseline screening for the trial that was sufficient to actually enter the study. There were no myocarditis after receiving the drug. He's over a year out from having received the drug, doing well from a cardiac perspective so far. Okay. A couple of things that I think about in that scenario, that child who might be losing ambulation, we don't have a lot of control over how insurance companies are going to, whether they're going to approve or not. And the early study, the EMBARQ study, were all ambulatory boys. And sometimes, as one of you commented, the insurance company will approve if it's within that narrow range. Now, he is outside of the age range, but would he be still within that ambulatory? So we've talked a little bit about thinking about if a child's at risk for losing ambulation in that next year or so, if the family's interested in gene therapy, that we may want to sort of consider that one as a possibility. You talked in a little bit about the changing into steroids. And when I think about changing from prednisone, now we have vimeralone, I think about the height. And so I'm going to be looking, I look at growth charts all the time in this clinic, because if I see the child started on steroids, whether it was prednisone or deflazocort, and it's so predictable, as soon as you start them, within six months, they start to flatten out their height and their weight goes up. So if we're starting to see that flattening out, the boy is at 10, still not yet hit puberty, so it has the potential for additional growth, then I might think about vimeralone as an option to minimize some of the side effects. And maybe you do two things, right? So you, you know, if you're considering elevitous, which is a very, very valid point, that if the child is about to lose ambulation, we might push for that while they're still in that ambulatory window, to hopefully seek insurance approval. And then they need to be on prednisone, they need to continue their prednisone rate while they're being treated in that first two months after treatment. And then switching and adding vimeralones. Okay, thank you. I'd like to open it up to questions. Does anybody have a question about that particular case, or the case before, before we go on? I think we may have time for a third case. Any questions or any experiences that someone wants to share? Yes, if you want to use the mic. Thank you. Sally Evans from CHOP. Sue, you were talking about vimeralone and the change in height and how you see height increase. Do you have enough experience yet to comment on the change in scoliosis in patients who are on vimeralone? Because the shorter height may not be worth the tradeoff, but the patients who are really short have fewer problems with scoliosis. Yeah. I'm not aware of any literature out there. I mean, this, this was recently approved. I don't think we have the numbers to comment on the scoliosis. It's a great question. I don't know if any of the three of you have anything to add. What do you think is going to happen, and do you think it's worth the tradeoff? Yeah. I don't, you know, I guess I don't think about height and the scoliosis. I just, that being a predictor of bad scoliosis, and I may just be missing the literature on that, and please help me if I'm wrong. So, you know, for me, in many of the boys, the height is just not an issue. I mean, for them, it's not an issue. For the parents, it's distressing. I think it's distressing for the parents when they have kids who are 14 and 15 who look like they're 6 and 7 height-wise, but also puberty-wise. I think it's more distressing to them. If a boy is distressed by their height, and so it's sort of the psychosocial impact, then I would be very comfortable with close monitoring. Just, you know, I think, you know, most of you are aware that there's some good literature suggesting that if you are on steroids long-term, you are going to have less of a chance of needing a surgery for scoliosis in the future. So I think corticosteroids, I think this group, we're big fans of it, and I'm not sure that we're ever going to go away from corticosteroids, whether or not we use something like Vimrolone instead of PrET or Deflazocort, I think it's still early. I'd be curious to find out. Hi, thank you for your presentation. I'm Kyle Menzi from PD Rehab in Kaiser Oakland. For the Givenostat, were there any secondary outcomes, especially for non-ambulatory patients? Oh, yes, good question. Sorry, were you done? Yes, so Givenostat, they are currently looking at upper limb testing in the non-ambulatory patients, so that data is coming. The original study that they based it on was all ambulatory little boys looking at the forced air climb, and so I think that we have a lot to learn in the non-ambulatory. Dr. Omura, I think you have the last question before we wrap up. Hi, Jacqueline Omura, Seattle Children's. Thanks for the great talk. Such an exciting time in this population and setting, and I think that maybe more of a comment than a question. Something that strikes me is that we study all of these very high-cost medicines and their efficacy, and there's these really great rehabby outcomes that we look at, and we have no data about how to support these kids with rehab interventions and what optimization looks like. Anecdotally, I can say a lot of boys who get in the pool every week or get outside more often or physically go to school tend to be my patients who do better, and yet I have zero evidence to help me justify the insurance that they should pay for aquatic therapy or that they should, I don't know, should we have these kids weightlifting? There's so many questions I have in the era of these medicines that we don't have answers to. How do we do that? I appreciate that last comment, and I'm going to just sort of let that sit with everybody because I think that this room has an unbelievable opportunity to be able to help answer the question that Dr. Omura is asking. We are so well-poised to support the neuromuscular team. There are many in this room that may not be part of a neuromuscular team, and there's others like the three of us and you, Jacqueline, who are part of a neuromuscular team. We've got amazing neurology colleagues like Dr. Laverty, and I think leveraging our expertise as rehab physicians, working with our physical therapy colleagues, we should be able to help answer these questions. So novel treatment plus pool-based therapy, novel treatment plus a weightlifting program. I'd encourage you, actually, Dr. Omura, Dr. Stratton, I apologize for forgetting the third author, but rehab, a wonderful rehab piece in the Muscle and Nerve Journal from this month, last month, talking about how we can't forget rehab as a core sort of principle to help support these kids who are receiving these treatments. As a neurologist who often administers these drugs, I tell my kids, you can get the medicine, but you have to do the work afterwards. This is especially true for the SMA population, where you gave medicine and they just expected everything to just magically happen, and that's not the case. Same thing applies for Duchenne. The boys do actually have to take care of themselves. They have to take care of their muscles. I have learned that doing excess activity, like when I tell them not to do a bounce house or a trampoline, that even after a Levitas can unfortunately cause a rhabdo. So there is still a upper limit on what these boys should do. I think it's us. We are going to be the game changers, actually, because we have access to the data. We should actually collaborate with each other, with the other institutions to post-market, basically collect the data and figure out, look, the kids that did the aqua therapy actually had better range of motion, better overall manual muscle strength testing five years down the line, three years down the line. We are the ones that actually are going to make the full difference after these medicines come out on the market. I think we've learned that with SMA. Same thing, I think, is going to happen with Duchenne. Yes. Thank you. And thank you, Jacqueline, for that comment. And thank you to the audience for participating in this session. And a very special thanks to Dr. Stratton, Dr. Marchese, Dr. Laverty, for sharing your expertise in the use of these novel drugs. And I hope everyone has a great rest of your day and assembly meeting. Thank you.

Duchenne Muscular Dystrophy

FDA-approved treatments

exon skipping therapies

gene therapy

delandistrogene moxaparvovec

Vimoralone

Givenistat

multidisciplinary care

rehabilitation strategies

insurance reimbursements

neuromuscular degenerative conditions