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Precision Therapies for the Management of Duchenne Muscular Dystrophy

  • Authors: Crystal Proud, MD
  • CME / ABIM MOC Released: 9/11/2023
  • Valid for credit through: 9/11/2024, 11:59 PM EST
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Target Audience and Goal Statement

This activity is intended for neurologists, pediatricians, primary care physicians (PCPs), and other clinicians who treat patients with DMD.

The goal of this activity is for learners to be better able to optimally use current and learn about emerging gene-targeted therapies for the management of DMD.

Upon completion of this activity, participants will:

  • Have increased knowledge regarding the
    • Nature of genetic mutations responsible for DMD
    • Clinical data for gene-targeted therapies for the management of DMD
  • Demonstrate greater confidence in their ability to
    • Summarize the clinical data for precision therapies used for the treatment of DMD


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  • Crystal Proud, MD

    Pediatric Neuromuscular Neurologist 
    Director of Neurology and Neuromuscular Medicine
    Children’s Hospital of The King’s Daughters
    Assistant Professor of Pediatrics
    Eastern Virginia Medical School
    Norfolk, Virginia


    Crystal Proud, MD, has the following relevant financial relationships:
    Consultant or advisor for: AveXis/Novartis Gene Therapies; Biogen; Genentech/Roche; Sarepta; Scholar Rock
    Speaker or member of speakers bureau for: Biogen
    Research funding from: Astellas Pharma, Inc.; AveXis/Novartis Gene Therapies; Biogen; CSL Behring; FibroGen, Inc.; Pfizer, Inc.; Sarepta; Scholar Rock


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    Senior Medical Education Director, Medscape, LLC


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  • Leigh Schmidt, MSN, RN, CNE, CHCP

    Associate Director, Accreditation and Compliance, Medscape, LLC


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Precision Therapies for the Management of Duchenne Muscular Dystrophy

Authors: Crystal Proud, MDFaculty and Disclosures

CME / ABIM MOC Released: 9/11/2023

Valid for credit through: 9/11/2024, 11:59 PM EST


Activity Transcript

Crystal Proud, MD: Hi, I am Dr Crystal Proud, pediatric neuromuscular neurologist, director of neurology and neuromuscular medicine at the Children's Hospital of the King's Daughters in Norfolk, Virginia. Welcome to this program entitled Precision Therapies for the Management of Duchenne Muscular Dystrophy. Today, we'll discuss the genetic pathophysiology of DMD, review the natural history, discuss genetically based therapies, including exon skipping therapies and gene transfer therapies, and wrap up with some conclusions. Let's begin by discussing the genetic pathophysiology of Duchenne muscular dystrophy. DMD affects approximately one in 3,500 to 5,000 males worldwide. It is a progressive degenerative X-linked fatal genetic disease. The DMD gene is usually responsible for producing a dystrophin protein that helps to keep muscles stable. Unfortunately, with mutations in this DMD gene, we see progressive instability and weakness over time in the boys that this disease affects. As a result of mutations in the DMD gene, which can be from a mutation, a deletion or duplication in any of its exons, leads to insufficient dystrophin protein.

Here, we can see a visual of the dystrophin protein and its structure. It consists of a C terminus, assisting rich domain, various hinges, spectrin repeats. It attaches to the actin cytoskeleton and connects this via a dystrophin associated glycoprotein complex to the muscle cell membrane. The entire structure allows for stability with typical daily movements that the body experiences. Walking, jumping, running, going up and down stairs, the muscles are experiencing force as a result of these activities. It's the job of dystrophin to keep that muscle structure stable during those daily activities. Patients with Duchenne muscular dystrophy are unable to maintain that structural integrity of their muscle with these everyday activities.

The dystrophin gene consists of 7 promoters and 79 exons. It's the largest gene in the body. Here, we see a schematic of each of these exons, which fit together like puzzle pieces. When transcription and translation occurs, the full length dystrophin protein is produced, and this maintains the integrity of the muscle cell membrane that we've just talked about. Most deletions, duplications, or mutations within exons leads to a shift in what's called the reading frame, and this ultimately leads to a non-functional protein. However, some deletions might lead to what is referred to as an in-frame mutation. Here, we see this depicted by the shapes of the exon puzzle pieces, whereby 45 through 47 are deleted, but exon 44 and 48 puzzle pieces still fit together. This leads to some continued translation and some small amounts of functional protein, and thus the phenotype is less severe. This is referred to as Becker muscular dystrophy.

This is a depiction of an out of frame mutation, whereby the reading frame is shifted because exon 45 is deleted. Puzzle pieces 44 and 46 do not fit together. Translation cannot occur; therefore, no protein is produced. This leads to the classic Duchenne muscular dystrophy phenotype. With this phenotype of Duchenne muscular dystrophy, there is a well-established natural history. Most of these boys will not necessarily present to a clinician's office, having had significant delays in motor milestone accomplishments. Although it's not uncommon for them to achieve early motor milestones like walking and running at the later end of what would be typical. But more commonly, they distinguish themselves from their peers in either late preschool or early elementary school. Where maybe the PE teacher observes them as being a little differently appearing in their motor skills compared to their same aged peers. Or their parents observe them in a group of same age children and sees that they are distinguished with regard to their walking, or their running, or going up and down stairs.

They tend to assume a waddling gait in order to compensate for some proximal weakness. Toe walking is quite common as a compensatory maneuver as well. And over time, they demonstrate more significant lower back lumbar lordosis and some excessive arm swing in order to gain some speed as they're attempting to run. Most of them are unable to jump, and this can be a good test to pursue in the clinical office to see if someone might be at risk for a dystrophic process. Over time, their muscles progressively get weaker, and this leads to the more classical goer sign that's depicted here as well. This is a child attempting to arise from a seated position on a floor. Unfortunately, they have significant proximal weakness, which means that they have to assume a wide base and then crawl up their legs in order to assume an upright posture. Traditionally, this occurs much later in elementary school age of a boy with DMD. There are also neurocognitive effects of Duchenne muscular dystrophy. Most of our boys have inattention and features of ADHD, and autism spectrum disorder is not uncommon as well.

Most of our boys with Duchenne muscular dystrophy are identified as having this condition in preschool or elementary school. By elementary ages, there is a more observable difference in their muscle abilities. They may be going one stair at a time instead of alternating their feet. They may be unable to jump, as I've mentioned, have difficulty running, and are slower than their peers. They unfortunately completely lose the ability to walk by their teenage years, and they use power wheelchairs for mobility assistance. We can't forget about the other impacts of neuromuscular dysfunction, including cardiac impacts and neuromuscular restrictive lung mechanics as well. By the time our boys are in their mid-teenage years, most of them will need a support with ventilation overnight, most commonly known as BiPAP. In their twenties, our boys experience cardiorespiratory progressive failure, and unfortunately, this leads to early deaths usually in their late twenties.

The natural history of motor function has been well characterized by Professor Muntoni and his colleagues, who pursued an assessment of boys from diagnosis over their lifespan as they were ambulatory and lost that ambulatory capacity. This test that was performed in each of these individuals is called a north star ambulatory assessment score. You can see here that this has allowed us to be able to create a plot of what is expected for the natural history of this NSAA score. What we see is that most of our boys achieve a peak functional ability on this score at an average age of 6.3 years. They may show some improvements in their motor function up until this point, but most of our boys will subsequently decline on this NSAA score in a predictable fashion. The north star ambulatory assessment score thus is used quite frequently in clinical trials to be able to track progress.

This is a composite endpoint that evaluates physical function across 17 domains, and each of these domains becomes progressively more difficult. The boy is assigned a score of two if they are able to perform a task in typical fashion. They are assigned a score of one if they are able to perform the task with difficulty. They're given a score of zero if they're unable to perform the task. You can see here, that these assessments are as simple as standing all the way up to asking a boy to attempt to jump. Let's talk about genetically based therapies, including exon skipping, as well as gene transfer therapies. Exon skipping technologies are not gene therapies. The ones that we will review are antisense oligonucleotides that bind to pre-mRNA. They allow for a particular exon to be skipped and excised during the pre-mRNA splicing. This restores the downstream breeding frame of dystrophin to permit some protein production. This technology is acting on the patient's own mRNA.

This is in contrast to gene transfer therapy. Gene transfer therapy does not act on the patient's own genetic material. Instead, it serves to deliver a new piece of DNA to the patient's body, through which protein can be produced that the patient's body cannot make on its own. In this case, that would be dystrophin. As you can imagine, these exon skipping technologies are only applicable to a certain population of individuals with Duchenne muscular dystrophy, who have a mutation such that skipping these exons would restore the reading frame.

Here, we see the exon-skipping treatment options for Duchenne muscular dystrophy that are FDA approved. This includes casimersen, which skips exon 45; eteplirsen, which skips exon 51; golodirsen, which skips exon 53; and viltolarsen, which skips exon 53. Here, we see an example of how skipping exon 51 might be efficacious at creating more partial length dystrophin. This is a boy who has Duchenne muscular dystrophy as the result of a deletion of exons 49 and 50. The puzzle pieces of exon 48 and exon 51 do not fit together, meaning this is an out-of-frame mutation, and leads to no functional dystrophin protein being created. If however, we administer eteplirsen, this skips exon 51 and allows for the puzzle piece of exon 48 to fit effectively into the puzzle piece of exon 52. Leading to partial length dystrophin.

Eteplirsen was FDA approved after an initial study of 12 boys demonstrated a primary endpoint of dystrophin protein production. Showing an improvement of 0.93% of dystrophin by western blot in those treated boys. This was after 180 weeks of treatment. This is a weekly IV infusion dosed at 30 milligrams per kilogram per dose. Most of our boys who receive this therapy have a port placed in order for ease of access. Another study with eteplirsen was in 13 boys treated for 48 weeks. Their pre-treatment muscle biopsy showed dystrophin protein of 0.16%, and the post-treatment muscle biopsy showed a dystrophin of 0.44% production. The original 12 boys and others were included in a retrospective 7 year follow-up. We evaluated boys who had received eteplirsen and compared their time of loss of ambulation with other boys who would have been 51 skippable as well. What was demonstrated was that the boys who received eteplirsen actually had a delay in their loss of ambulation time by 2.09 years. They walked for about two years longer than if they had not received eteplirsen. This is quite significant for boys with Duchenne muscular dystrophy.

We know that once our boys lose the ability to walk, they have progressive neuromuscular restrictive lung mechanics as well. The other item that was evaluated in this retrospective study was looking at their pulmonary decline. What was shown, is that they had significant attenuated rates of pulmonary decline if they received eteplirsen. This was in comparison, once again, to natural history patients. Golodirsen is another exon skipping technology that skips exon 53. We see here, an example patient who has Duchenne because of a deletion of exons 46 through 47. This means that the puzzle piece of exon 45 cannot effectively fit into the puzzle piece of 48, meaning it is an out-of-frame mutation leading to no effective dystrophin protein production. This gives the phenotype of Duchenne. However, if we could skip exon 45, like we can with golodirsen, this means that the exon puzzle piece of 44 can fit into the exon puzzle piece of 48. This leads to a partial length dystrophin. This once again is a weekly IV infusion dosed also at 30 milligrams per kilogram per dose.

This medicine was approved in December of 2019, after a 48-week analysis of 25 treated patients showed 0.924% of increased dystrophin production. There's a second option for exon 53 skipping. This is viltolarsen, and this is dosed also intravenously once weekly, at a dose of 80 milligrams per kilogram per dose. In the study utilizing viltolarsen, what was shown was that dystrophin levels increased from 0.6% normal at baseline to 5.9% normal by week 25. That's represented graphically here, with individual patient bars shown. There was a mean change in dystrophin of 5.3% of normal levels, as assessed by Western blot testing. Casimersen is another exon skipping technology that has been FDA approved. It was demonstrated after an interim result from 43 evaluable patients, who had a muscle biopsy after getting casimersen for 48 weeks. We can see that in the placebo group, the main dystrophin percentage was 0.76 at week 48. This was a 0.22% change after that time period. This is in comparison to the casimersen group, who at week 48, had 1.74% dystrophin representing a 0.81% change from baseline. This was statistically significant.

Now that we've reviewed the exon skipping technologies, let's discuss the science of gene transfer therapy. Gene transfer therapy involves a single strand of DNA that is placed into a viral vector. That vector is traditionally administered one time through an intravenous infusion, which carries the vector and the single strand of DNA into the target cells. It enters the cell nucleus, where that single strand of DNA is released, and then it zips itself up to form a double strand of DNA, which subsequently can lead to protein production. That protein production is guided by the DNA components that are included in the vector. Unfortunately, as we've talked about, the dystrophin gene is quite large. In fact, it's too large to fit into an adeno-associated viral vector; therefore, a rationale for transgene selection occurred. Professor Kay Davies and her colleague studied a family whereby this individual, this group of individuals, had a very mild phenotype even though they had quite large deletions of the dystrophin gene.

In fact, in this Letters to Nature paper, there was a patient who was described who had 46% of his dystrophin gene missing but remained ambulatory well into his older ages. This gave rise to the thought that, perhaps if certain critical regions of the dystrophin gene were selected for inclusion in the viral vector, that might be sufficient to change protein production and lead to muscle structural stability. Adeno-associated viral vectors are used most commonly for gene transfer therapies, and they have some advantages and disadvantages. Advantages include that they are non-pathogenic and there are numerous serotypes available. They have low immunogenicity, and they're non integrating, so there is a low risk of insertional mutagenesis. Disadvantages as we've mentioned, include that they have a small packaging capacity, and they cannot fit the entirety of the Duchenne gene. There are some preexisting immunities in some patients, and this would preclude them from receiving treatment as it stands today because it can impact safety, as well as efficacy.

Here, we see the vectors, promoters, and transgenes currently being used in DMD gene transfer therapies. We'll go over each of these individually. Let's start first with some of these clinical trials in gene transfer therapies by discussing SGT001 and the Ignite DMD phase I/II study. This was a randomized, controlled, open-label, single ascending dose study. Boys ages 4 to 17 were eligible for participation, and there were three different arms. There was a low dose of a single IV infusion of SGT001 given to three boys, a high dose given to six boys, and there was an untreated control group. The primary outcomes you can see listed here include change in micro dystrophin protein by western blot, which would be obtained by a muscle biopsy, and then collection of adverse events. Secondary outcomes include some motor function assessments, including that NSAA score that we've discussed.

An update from the SGT-001 trials was shared in October of 2022. Whereby results from biopsies collected 12 months post dosing, showed stable or increased micro dystrophin expression and continued membrane localization. There was another update shared at the MDA conference in 2023. Showing that subjects receiving the high dose maintain stabilization or improvement 3 years after their dosing. In motor function as dictated by the NSAA score and the 6-minute walk test, as well as pulmonary function and inpatient reported outcomes. It's important, when we're doing clinical trials, to consider safety.

The most common related adverse events were nausea, vomiting, and fever. In this clinical trial, thrombocytopenia, anemia, proteinuria, and changes in some of the items you see listed here were also observed. There was also activation of the classical complement system, which led to three serious adverse events. Fortunately, all of which resolved; some other SAEs were observed as well. Safety concerns initially placed this trial on temporary hold. It's now active, but not recruiting. We'll shift gears now to fordadistrogene movaparvovec and the phase 1B study. This also included ambulatory boys with Duchenne muscular dystrophy. These boys were ages 4 to 12 and were on a stable daily glucocorticoid regimen. This included 19 boys, and it was open label, multi-center, and a single ascending dose. Some of the boys, 3, received low dose, and 16 received high dose. The primary outcome in this study was safety, with some secondary outcomes you see listed here, being muscle biopsy results, as well as some functional endpoints.

The one-year analysis of fordadistrogene movaparvovec, showed that 2 and 12 months after treatment, mean levels of dystrophin protein production were 22% and 40% normal respectively in the high dose group. The median age at dosing was 8.8 years, and the median baseline north star score was 27. Follow-up time was up to 18 months. We could see that in this graphic representation, the median change from baseline to one year in north star ambulatory assessment score was an improvement of one point. This is in direct comparison to a loss of four points that we'd expected based on natural history. Adverse events in this clinical trial program included vomiting, nausea, decreased appetite, and fever. Serious adverse events were included as well, such as myocarditis, thrombotic microangiopathy, dehydration, acute kidney injury, and thrombocytopenia. There was one death in this study program that led to a clinical hold for a period of time. That clinical hold has been lifted, and now there is a phase III clinical trial called CIFFREO, which is active but no longer recruiting.

We'll talk next about SRP9001 or delandistrogene moxeparvovec. This is the only FDA approved gene transfer therapy for boys with Duchenne muscular dystrophy ages 4 and 5 years old. This was first studied in the study 101, which is a proof-of-concept study using research grade material. These boys are now more than 4 years out from their dosing. We can see that they have demonstrated an average improvement over time in their north star ambulatory assessment score of 7 points. This is quite significant when we look at the ages of these patients. Now four years out, they range in age between 8 and 10 years old. As we've talked about, north star scores generally decline after age 6.3. The second study was study 102, which also used research grade material. This was a multicenter, randomized, double-blind, placebo controlled, study of 41 patients ages 4 to 7 years old.

These boys were randomized to receive, in part one, the actual delandistrogene moxeparvovec, or a single IV infusion of placebo. Then 48 weeks later, those that were randomized to initially, in part one, receive placebo, ultimately received the active drug in part two, then vice versa for the other group. They were followed over time and underwent muscle biopsy, as well as functional motor assessment testing. We see in this next slide a grouping of outcomes that looks at the 4 to 5-year-old boys, as well as the 6 to 7-year-old boys. What we can see was that as the boys in the 4 to 5-year-old age group were stratified for age, fortunately their baselines also had similar north star ambulatory assessment scores. There is a distinction at week 48 in those scores, whereby the patients that received delandistrogene moxeparvovec did better than the boys that received placebo. This was statistically significant.

Unfortunately, when we look at the 6 to 7-year-old age group, these boys were stratified into receiving either active drug or placebo based simply on age. Their baseline functional status was not taken into account for this stratification. Unfortunately, there was a statistically significant difference in where they started out on their baseline North Star test. Over time, there was not a statistically significant difference between the two groups. This informed later studies, and now we are stratifying based on both age and baseline functional NSAA scores. Study 103 was the next study evaluating commercial-grade material, and this was an open-label study that included various cohorts. One of these cohorts were boys ages 4 to 7 who were ambulatory. Here, we see week 12 results from the gastrocnemius biopsy. This demonstrated that the vector genome copy number effectively shows that the material was delivered to the target tissues; there was a change from baseline of 3.9 copies per cell nucleus.

The next question is, was the dystrophin protein or micro dystrophin protein being effectively made? We can see that there was a change from baseline of 55.4% of normal for this micro dystrophin protein on this muscle biopsy. We can then evaluate the intensity of the muscle biopsy staining. What was demonstrated was a significant change from baseline in the intensity of that staining, showing that that protein is getting to where it needs to be in the muscles. Adverse events were collected in the studies with delandistrogene moxeparvovec and showed that the most common AEs included vomiting, which typically occurred within the first week and resolved with standard antiemetics.

We also saw increases in liver enzymes that were responsive to steroids, but no signs of impaired synthetic liver function. Two SAEs fully resolved, including one patient with increased transaminases treated with IV steroids, and one patient with nausea and vomiting. Importantly, there was no clinically relevant complement activation. The clinical development program continues. There is a study 301, which is a phase III, multinational, randomized, double-blind, placebo-controlled, gene therapy study evaluating the safety and efficacy of delandistrogene moxeparvovec in 4 to 7-year-old ambulatory boys. This is a crossover study as well, that is going to have a primary outcome of change from baseline NSAA score at week 52. It's also evaluating several other secondary outcomes.

Study 303, or the Envision study, is a phase III, multinational, randomized, double-blind, placebo-controlled crossover clinical trial evaluating two cohorts. One of those cohorts is an older non-ambulatory group of boys with Duchenne, and cohort two are older ambulatory boys with Duchenne. The primary outcome will be the change from baseline in total score on performance of upper limb at week 72, as well as some secondary outcomes that will be collected as well.

In conclusion, it's exciting to see that we have opportunities for our boys with Duchenne muscular dystrophy in the clinical trial programs we've reviewed, as well as, with current FDA approved treatments. As you know, DMD is a severe X-linked progressive muscle disease in boys, and early diagnosis and treatment has been shown to improve outcomes. We have precision genetically based therapies that have the potential to restore dystrophin protein expression and modify what we know of the natural history of this disease. Thank you so much for participating in this activity today. Please continue on to answer the questions that follow and complete the evaluation.

This transcript has not been copyedited.

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