Duchenne muscular dystrophy (DMD) is an inherited X-linked recessive severe progressive muscle disease affecting 1 in 5,000 boys. Mutations in the dystrophin gene on the X chromosome cause a lack of functional dystrophin, which results in progressive replacement of muscle fibers with fat and fibrotic tissue. Boys who have DMD often have delayed ambulation and develop progressive weakness and loss of muscle that is typically noticed in the first 2 to 3 years of life. Most boys lose the ability to walk by age 12 years, which is followed by progressive restrictive lung disease and cardiomyopathy. Eventually, assisted ventilation is needed and death often occurs in the second to third decade of life. Multidisciplinary care is required as needs change throughout the lifespan (Table 1).1
The dystrophin gene is the largest known human gene, encompassing 2.4Mb at loci Xp21.2. Isoforms of the dystrophin protein are expressed in skeletal and cardiac muscle, the brain, and the retina. The skeletal muscle-specific isoform is a 427 kDa protein that spans the cell membrane and has 4 distinct domains. The C-terminus binds extracellular proteins, the central helical coiled rod region confers flexibility and elasticity, the WW domain binds intracellular signal transduction proteins, and the N-terminus binds to F-actin, one of the major components of the internal scaffolding cytoskeleton.2 Loss of dystrophin function impairs several key structural elements that are required for muscle fiber function. Muscle cell membrane stability is lost, resulting in damage to the muscle membrane from mechanical stress, abnormal signaling pathways cause chronic inflammatory changes, and loss of the nitric oxide-signaling (NOS) pathways results in functional muscle ischemia. The final common pathway is muscle fibrosis, replacement of muscle fibers by fat, and muscle weakness. Primary therapeutic targets aim to correct or improve the production of functional dystrophin. Secondary therapeutic targets aim to improve downstream effects of inflammatory and antioxidant pathways, muscle blood flow, calcium homeostasis, muscle fiber size and function, and connective tissue and fibrosis.
Corticosteroid Efficacy. Corticosteroids are the most commonly used therapy for therapy for DMD (Table 2) since it was shown in 1974 that 13 of 14 boys treated with prednisone daily had improvements.3 Widespread use of prednisone followed after the first placebo-controlled trial in 103 boys with DMD. This trial confirmed efficacy for improving strength and function at doses of 0.75 or 1.5 mg / kg / day without clear additive benefit at the higher dose.4 A later trial confirmed maximal efficacy of 0.75 mg / kg / day compared with the higher dose.5 The largest study of corticosteroids for DMD (5,345 participants) showed continuous corticosteroid use prolonged ambulation by 3 years, reduced scoliosis surgery, and delayed use of assisted ventilation.6 Corticosteroids maintain pulmonary function and upper extremity function even after loss of ambulation,7-9 and in infants and young children, may also reduce gross motor delay.10
Deflazacort is a corticosteroid approved for DMD by the Food and Drug Administration (FDA). Several comparison studies demonstrated slightly greater efficacy of deflazacort compared with prednisone, although side effects are still present, and some are increased. In a 52-week trial of deflazacort at 0.9 or 1.2 mg / kg / day compared with prednisone at 0.75 mg / kg / day, boys treated with deflazacort had slightly higher muscle strength than boys treated with prednisone with no difference between the high vs low dose of deflazacort.11 A large natural history study (n=340) reaffirmed that treatment over more than 1 year with corticosteroids, including deflazacort, delays ambulation loss by 3 years,12 and in a prospective cohort study of 440 participants, deflazacort treatment delayed loss of ambulation by 2 years more than prednisone treatment.13 A recent meta-analysis also identified a functional advantage of deflazacort with slower disease progression over 48 weeks compared with prednisone/prednisolone treatment. A single center retrospective study also found a 2-year benefit on maintained ambulation with deflazacort.14 Importantly, about one-third of participants in these comparison studies who were treated with prednisone were treated with an intermittent dosing regimen, whereas more than 90% of the boys treated with deflazacort had daily dosing.
Corticosteroid Side Effects. Chronic corticosteroid use is associated with numerous side effects in children including delayed puberty, reduced height velocity, weight gain, osteoporosis and fractures, adrenal suppression, cataracts, and behavior changes (Table 2). Alternatives to daily dosing of prednisone have been studied in an effort to mitigate these side effects while maintaining functional gains. Twice weekly dosing of prednisone (10 mg / kg divided Saturday and Sunday) results in greater linear growth with equivalent improvements in strength compared with 0.75 mg / kg given daily over 12 months.15 Other intermittent treatment regimens are less well established or effective. A trial of intermittent treatment of prednisone 0.75 mg / kg / day for the first 10 days of every month is superior to placebo over 6 months in 17 boys.16 Alternate-day prednisone dosing, however, does not maintain the same benefits for strength seen with daily dosing over 6 months.4 The American Academy of Neurology (AAN) practice parameter recommends 0.75 mg / kg / day prednisone as the preferred dosing regimen but recognizes that 10 mg / kg / weekend is equally effective over 1 year with insufficient data for comparison of long term outcomes.17
Deflazacort causes less sodium retention and interference with carbohydrate metabolism compared with prednisone. There is less weight gain with deflazacort than with prednisone (5% vs 18%) and more frequent behavior abnormalities with prednisone.11 Increased side effects of deflazacort include growth retardation, cushingoid appearance, and cataracts.12,14 Although deflazacort may be associated with functional gains compared with prednisone, benefits are tempered by increased growth retardation, cataracts, and significantly higher cost.
Vamorolone is a synthetic “dissociative” steroid that binds to the corticosteroid receptor but does not have the unwanted downstream side effects. Preliminary results from studies of vamorolone show that daily treatment over 6 months improved muscle function without most of the glucocorticoid related side effects,18 and a phase 2b study comparing treatment with vamorolone with daily prednisone is underway.a
Coenzyme Q10 has been studied in small cohort of boys with DMD who are also being treated with corticosteroids treated patients. Escalating doses beginning at 400 mg / day and ranging from between 8.7 to 48.4 mg / kg / day thereafter are being used to achieve the targeted serum concentrations. There are 12 children who completed this 6-month trial and had marginal gains in quantitative motor strength (~1 pound) but no improvements in timed-walk, stair-climb, or cardiac measures.19 In a randomized placebo-controlled phase 3 trial in 64 boys with DMD aged 10 to 18 years, treatment for 1 year with idebenone, a synthetic coenzyme Q10 analog, improved respiratory function. Idebenone attenuated the decline in the percent predicted peak expiratory flow by 6% and in the percent predicted forced vital capacity (FVC) by 3% compared with placebo.20 An open-label extension study showed continued use of idebenone was associated with a 50% reduction in the expected annual decline in percent predicted FVC that was sustained for up to 6 years.21 A phase 3 study of idebenone is underway.b
Vitamin D and Calcium
Reduced bone mineral density and increased risk of vertebral and long bone fractures ae associated with DMD. These risks are exacerbated by exposure to chronic corticosteroids. Supplementation with 25-hydroxy-vitamin D3 (calcifediol) increased bone mineral density in boys with DMD.22 Practice parameters support routine monitoring of bone health with lateral spine X-rays and dual-energy X-ray absorptiometry (DEXA) scans, and monitoring levels of calcium, and levels of 25-hydroxy-vitamin D (ideal level of 30 ng / mL). Vitamin D3 supplementation is suggested at 1,000-4,000 IU daily depending on the degree of insufficiency. Calcium supplementation is recommended if daily dietary intake is lower than the 1,000-1,300 mg recommended daily allowance.
Angiotensin-Converting Enzyme Inhibitors and Cardiac Protection
Progressive cardiomyopathy is a leading cause of mortality in DMD. Early treatment with angiotensin-converting enzyme (ACE) inhibitors before onset of cardiac dysfunction improves long-term mortality in DMD. In a study of boys age 9 to 13 years who did not have cardiac dysfunction (ejection fraction [EF] >55%), those treated with perindopril (n=28) for 3 years longer than boys initially treated with placebo (n=29) had higher 10-year survival rates (93% vs 65.5% survival).24 Based on this finding, initiation of an ACE inhibitor or angiotensin receptor blocker before age 10 years is recommended in DMD.
Nonsense Mutation Read Through. In 10% to 15% of boys with DMD, the mutation in dystrophin results in a nonsense codon that shorten the resulting protein, rendering it nonfunctional. Gentamicin is thought to promote a “read-through” of the nonsense mutation during transcription to produce more full-length dystrophin mRNA, and thus more functional protein. In a 2-week trial, 10 boys with DMD treated with gentamicin had a 50% reduction in creatine kinase (CK) levels. Subsequently, 16 boys treated with gentamicin for 6 months had a 0% to 15% increase in dystrophin from baseline.25 Ataluren also promotes read-through of nonsense mutations but has had disappointing results in clinical trials. In a randomized clinical trial, those treated with ataluren for 48 weeks at 40 mg / kg / day were able to walk 31.3 feet further than those treated with placebo on a 6-minute timed walk test (6MWT), but there was no difference in walking distance with 80 mg / kg / day vs placebo.26 Ataluren was conditionally approved in the European Union. In a subsequent study of 6 months of treatment with 40 mg / kg / day of ataluren vs placebo (n=230), preplanned subgroup analysis showed treatment with ataluren vs placebo resulted in improvement on the 6MWT only for those who had a baseline 6MWT distances of 300 to 400 m,27 although other functional outcomes trended toward improvement. Open-label long-term extension studies are continuing. A recent comparison of boys taking ataluren showed prolonged ambulation compared with matched natural history controls.28
Exon Skipping. Most mutations in the dystrophin gene are frameshift deletions, leading to prematurely truncated mRNA and nonfunctional dystrophin. Exon skipping is a therapeutic intervention that targets pre-mRNA splicing to restore the reading frame. Exon skipping can produce a modified but stable and functional dystrophin protein, missing some internal domains but containing the critical binding domains, similar to what is seen in Becker muscular dystrophy. Antisense oligonucleotides (ASO) are small (8-50 base) nucleic acid chains designed to join with corresponding bases in the pre-mRNA to induce removal of 1 or more targeted exons by DNA ligase and thus restore the reading frame. Of known DMD genotypes, 60% to 80% are amenable to exon skipping; the most common are exons 51 (13%), 45 (8%), and 53 (8%). Candidate therapies have thus far targeted these more common genotypes.
Eteplirsen is an intravenously administered ASO (30 mg / kg weekly) that induces exon 51 skipping and could potentially treat 13% of people with DMD. Eteplirsen is a first-in-class drug, approved by the FDA based primarily on a modest 0.9% increase in dystrophin in 11 boys after 180 weeks of therapy.28 Extensions studies showed improved 6MWT distances over 3 years compared with historic controls matched for age and genotype,29 and stabilization of pulmonary function.30 The FDA has requested additional clinical studies to demonstrate clinical benefits as part of its conditional approval. The European Medicines Agency has not approved eteplirsen. A clinical trialc is comparing high and low doses of eteplirsen, and a phase 2 triald is testing a similar ASO with an added small peptide modifier in the oligomer backbone.
Golodirsen and casimersen are ASOs similar in structure to eteplirsen that induce skipping exons 45 and 53, respectively, potentially treating 8% of DMD each. Golodirsen (30 mg / kg weekly intravenous infusion) was approved by the US FDA in 2019 based on a modest 1.0% improvement in dystrophin levels after 48 weeks of treatment.31 Viltolarsen is an exon 45-targeting ASO that has a different structure from golodirsen.32 After 20 to 24 weeks of viltolarsen treatment, average dystrophin level increased to 5.7% of normal and all 16 participants had improved timed functional testing. Viltolarsene,f and casimersen are inclinical trials.g,h
The large size of the dystrophin gene prevents packaging into a viral vector as is typically done for gene replacement. Instead, a microdystrophin transgene has been designed to produce a modified dystrophin with the essential components for function. In a nonrandomized cohort trial, 4 boys received a single intravenous infusion of the microdystrophin.33 After 12 weeks, the mean microdystrophin expression was 95.8% of normal dystrophin levels after adjusting for fat or fibrosis; at 1 year functional improvements were seen and CK levels were reduced compared with baseline. A phase 3 clinical triali is underway.
Corticosteroid therapy, with either daily or weekend prednisone or daily deflazacort, is the most well-established therapy for DMD. Steroid-related side effects are common and require routine monitoring. Recent advances in exon-skipping treatments show promise, although FDA approved exon-skipping therapies only marginally improve dystrophin production. Other therapeutic avenues to restore dystrophin, including adenovirus vector delivery of microdystrophin, are in clinical trials and hold promise for improving the lives of boys and young men with DMD.
a A Study to Assess the Efficacy and Safety of Vamorolone in Boys With Duchenne Muscular Dystrophy (DMD)(NCT03439670).
b A Phase III Double-blind Study With Idebenone in Patients With Duchenne Muscular Dystrophy (DMD) Taking Glucocorticoid Steroids (SIDEROS)(NCT02814019)
c A Study to Compare Safety and Efficacy of a High Dose of Eteplirsen in Duchenne Muscular Dystrophy (DMD) Patients (MIS51ON)(NCT03992430)
d Study for Dose Determination of SRP-5051, Then Dose Expansion in Patients With Duchenne Muscular Dystrophy Amenable to Exon 51-Skipping Treatment (MOMENTUM)(NCT04004065)
e The Expanded Access Use of Viltolarsen in Duchenne Muscular Dystrophy With Confirmed Exon 53 Amenable Mutation (NCT04337112)
f Study to Assess the Efficacy and Safety of Viltolarsen in Ambulant Boys With DMD (RACER53)(NCT04060199)
g A 48-Week, Open Label, Study to Evaluate the Efficacy and Safety of Casimersen, Eteplirsen and Golodirsen in Subjects With Duchenne Muscular Dystrophy Carrying Eligible DMD Duplications (NCT04179409)
h An Extension Study to Evaluate Casimersen or Golodirsen in Patients With Duchenne Muscular Dystrophy (NCT03532542)
i A Randomized, Double-blind, Placebo-controlled Study of SRP-9001 for Duchenne Muscular Dystrophy (DMD)(NCT03769116)
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CZ has received funding from Biogen and served as a paid advisor to Biogen and Optum