Version May 2024
INTRODUCTION — The muscular dystrophies are an inherited group of progressive myopathic disorders resulting from defects in a number of genes required for normal muscle function [1]. The Duchenne and Becker muscular dystrophies are caused by pathogenic variants of the dystrophin (DMD) gene and are therefore named dystrophinopathies. Weakness is the principal symptom as muscle fiber degeneration is the primary pathologic process.
The dystrophinopathies are inherited as X-linked recessive traits and have varying clinical characteristics. Duchenne muscular dystrophy (DMD) is associated with the most severe clinical symptoms. Becker muscular dystrophy (BMD) has a similar presentation to DMD but a relatively milder clinical course [2].
Glucocorticoid treatment and potential disease-modifying therapies for Duchenne muscular dystrophy will be discussed in this review. Other aspects of Duchenne and Becker muscular dystrophy are reviewed separately. (See "Duchenne and Becker muscular dystrophy: Genetics and pathogenesis" and "Duchenne and Becker muscular dystrophy: Clinical features and diagnosis" and "Duchenne and Becker muscular dystrophy: Management and prognosis".)
GLUCOCORTICOID TREATMENT — Glucocorticoids are the mainstay of pharmacologic treatment for DMD [2-6].
Indications — Glucocorticoids are indicated for children with DMD and should be started before there is substantial physical decline (figure 1) [6]. For children with DMD age four years or older whose motor skills have plateaued or have started to decline, we suggest daily treatment with glucocorticoids using either oral prednisone, deflazacort, or vamorolone (where available). (See 'Benefits of glucocorticoid therapy' below.)
We generally prefer deflazacort because it offers a more favorable side effect profile than prednisone regarding weight gain and impact on behavior. Although deflazacort is more likely to cause growth slowing than prednisone, there is some evidence that shorter stature offers a biomechanical advantage in DMD and is associated with slower disease progression [7,8]. In a retrospective study of 70 patients with DMD, those who lost ambulation at a later age had significantly shorter stature than those who lost ambulation earlier [9]. However, insurance coverage for deflazacort in the United States is sometimes limited due to its higher cost. (See 'Adverse effects and monitoring' below.)
Vamorolone is a novel steroid designed to avoid or reduce the adverse effects of glucocorticoid therapy. It acts as a dissociative glucocorticoid ligand to exert anti-inflammatory and immunosuppressive effects. Like prednisone, vamorolone inhibits the NF-kB pathway, but its chemical structure lacks the glucocorticoid receptor binding elements (eg, the 11b-hydroxyl/carbonyl group) believed to be responsible for some of prednisone's side effects. While glucocorticoids are agonists, vamorolone acts as a potent mineralocorticoid antagonist, which prevents negative mineralocorticoid effects [10]. Vamorolone received FDA approval in late 2023 for the treatment of DMD in patients two years of age and older [11]; availability is expected in early 2024.
Glucocorticoid dosing
●Prednisone – The usual starting dose of oral prednisone for treating DMD is 0.75 mg/kg per day [6]. Less well-studied alternative prednisone dosing regimens include 5 mg/kg per day given two times per week on consecutive weekend days or 0.75 mg/kg per day for 10 days on and 10 days off [2,12,13].
●Deflazacort – The usual starting dose of oral deflazacort is 0.9 mg/kg per day [6]. Deflazacort is an oxazoline derivative of prednisone; the relative potency of prednisone compared with deflazacort is 1:1.3 [14]. Thus, 1.3 mg of deflazacort is approximately equivalent to 1 mg of prednisone.
●Vamorolone – The recommended dose of oral vamorolone is 6 mg/kg per day with meals (maximum dose 300 mg for patients who weigh >50 kg) [15]. For patients with mild or moderate hepatic impairment, the recommended dose of vamorolone is 2 mg/kg per day with meals (maximum dose 100 mg for patients who weigh >50 kg).
●Adjustments for patient weight gain during growth – Although practice is variable, many clinicians do not make weight-based dose adjustments of prednisone or deflazacort as patient weight increases over time [16], and the DMD care guidelines do not mandate such adjustments in the absence of functional decline [6]. This strategy may reduce the risk of adverse effects.
The author ordinarily does not make dose adjustments with weight gain unless the patient is rapidly declining, or until the prednisone dose is 0.3 to 0.4 mg/kg per day or the deflazacort dose is 0.4 to 0.5 mg/kg per day. In these situations, it is reasonable to increase the glucocorticoid dose to the starting weight-based target dose (prednisone 0.75 mg/kg per day or deflazacort 0.9 mg/kg per day).
●Dose reduction for intolerable adverse effects – Maintaining the glucocorticoid dose is optimal if side effects are tolerable and manageable. The glucocorticoid dose can be reduced by 25 to 33 percent if the adverse effects are intolerable or unmanageable, with reassessment in one month [6]. The dose can be lowered by an additional 25 percent if intolerable adverse effects persist. A gradual tapering of prednisone to as low as 0.3 mg/kg per day or deflazacort to as low as 0.4 mg/kg per day may give significant but less robust benefit.
●Avoid rapid withdrawal – In patients on long-term glucocorticoid therapy, abrupt cessation or rapid withdrawal of glucocorticoids should be avoided because it can result in adrenal insufficiency (see 'Glucocorticoid tapering' below). In the setting of acute illness, trauma, or surgery, stress-dose glucocorticoid therapy may be needed. (See "Duchenne and Becker muscular dystrophy: Management and prognosis", section on 'Adrenal insufficiency' and 'Indications for stress-dose glucocorticoids' below.)
Benefits of glucocorticoid therapy — Glucocorticoid treatment of DMD with prednisone and deflazacort is beneficial for improving motor function, strength, and pulmonary function; reducing the risk of scoliosis; and delaying the loss of ambulation [4,6]. In addition, some data suggest that glucocorticoids improve survival and delay the onset of cardiomyopathy. The mechanism of the beneficial effect of glucocorticoids in patients with DMD is not clear. Little is known of the effect of glucocorticoids in patients with Becker muscular dystrophy (BMD).
●Motor function – In several small, randomized trials, prednisone treatment led to increased average muscle strength and improvement in standardized timed function testing (eg, time to climb stairs, walk nine meters, or arise from supine to standing). As an example, a six-month trial of 103 boys with DMD found that average muscle strength increased by 11 percent with prednisone treatment compared with placebo. In addition, the average time to climb four stairs was approximately 43 percent faster with prednisone treatment compared with placebo (four versus seven seconds, respectively). In this and other trials, strength increased significantly by 10 days, reached a maximum at three months, and was maintained at six months and 18 months [17-19].
In a trial of 28 patients with DMD, deflazacort treatment for nine months was associated with increased muscle strength and function compared with placebo [20]. Other studies found that deflazacort was associated with improvement in various measures of motor function or delay in loss of ambulation [20-25]. The mean prolongation of ambulation was 13 months [21].
In the multicenter VISION-DMD trial, 121 ambulatory and glucocorticoid-naive male patients (ages four to less than seven years) with DMD were randomly assigned in a 1:1:1:1 ratio to vamorolone 6 mg/kg per day, vamorolone 2 mg/kg per day, prednisone 0.75 mg/kg per day, or placebo [26]. At 24 weeks compared with placebo, high-dose vamorolone treatment (6 mg/kg per day) led to improvement on the Time to Stand Test (TTSTAND) velocity (least-squares mean [LSM] 0.06 meters/second; 95% CI 0.02-0.1 meters/second), the 6-Minute Walk Test (6MWT) distance (LSM 41.6 meters; 95% CI 14.2-68.9 meters), and the Time to Run/Walk 10 meters (TTRW) velocity (LSM 0.24 meters/second; 95% CI 0.09-0.39 meters/second). Compared with placebo, low-dose vamorolone (2 mg/kg per day) showed significant improvement on TTSTAND velocity and 6MWT distance but not TTRW velocity. The differences in TTSTAND velocity and 6MWT distance for vamorolone (both doses) compared with placebo were considered clinically meaningful [26-28].
The duration of most of these studies ranged from 6 to 18 months. One longer-term prospective observational study with up to 10 years of follow-up enrolled 440 males 2 to 28 years of age with DMD [29]. Compared with glucocorticoid treatment for one month or less, glucocorticoid treatment for one year or longer was associated with a delay in disease progression, including an increased median age at loss of mobility milestones (by 2.1 to 4.4 years) and upper limb milestones (by 2.8 to 8 years).
Our clinical experience also supports the benefit of glucocorticoids. When patients are taken off glucocorticoids because of adverse effects, clinicians, families, and/or caregivers usually notice a decline in motor function and energy level, particularly in younger patients.
●Pulmonary function – Several small trials and nonrandomized studies have found that glucocorticoids improve pulmonary function in patients with DMD [4,17,18,23-25,30-33]. As an example, in one trial of 103 boys with DMD, forced vital capacity (FVC) improved significantly (11 percent higher) after six months of daily prednisone treatment compared with placebo [17].
●Orthopedic outcomes – Glucocorticoids may delay the development of scoliosis and reduce the need for surgery to correct scoliosis in patients with DMD [4]. In a prospective nonrandomized study of boys with DMD who were followed for 15 years, the risk of developing scoliosis was significantly lower for the daily deflazacort treatment group compared with the control group (6 of 30 [20 percent] versus 22 of 24 [92 percent]), and the need for spine surgery was also significantly decreased for the deflazacort group [30]. Retrospective data also suggest that long-term therapy with glucocorticoids for DMD reduces the risk of scoliosis and prolongs independent ambulation but increases the risk of osteoporosis and long bone and vertebral compression fractures [34]. However, in a prospective international registry of 340 male subjects with DMD, there were few fractures, and fracture prevalence was similar between patients who were treated with glucocorticoids and those who were not [31].
Measures for assessing and maintaining bone health are described below. (See "Duchenne and Becker muscular dystrophy: Management and prognosis", section on 'Bone health'.)
●Survival – In a 2016 systematic review of glucocorticoid treatment of DMD [4], three studies found that glucocorticoid treatment was associated with improved survival [24,30,35], while a fourth found no clear association with length of survival [32].
●Cardiac function – Data from several nonrandomized studies suggest that treatment with glucocorticoids for DMD reduces new-onset and progressive cardiomyopathy and lowers mortality via a reduction in deaths related to heart failure [35-38]. These findings require confirmation in larger prospective trials.
Studies comparing agents — In most reports, the efficacy of deflazacort for DMD is similar to that of prednisone [4,39-43]. These studies reported comparable improvements in muscle function, pulmonary function, and orthopedic outcomes with prednisone and deflazacort treatment.
The Finding the Optimum Regimen for Duchenne Muscular Dystrophy (FOR-DMD) trial investigated the three most commonly prescribed glucocorticoid regimens and randomly assigned 196 boys with DMD in a 1:1:1 ratio to daily prednisone (0.75 mg/kg), daily deflazacort (0.90 mg/kg), or intermittent prednisone (0.75 mg/kg, alternating 10 days on and 10 days off) [43]. Over three years, the efficacy of daily prednisone and daily deflazacort was similar on a composite outcome that incorporated measures of motor function (rising from the floor velocity), pulmonary function (FVC), and satisfaction with treatment. Both daily regimens were more effective than intermittent prednisone, a difference that was mainly attributable to the rising from the floor velocity component of the composite outcome; the difference in rising from the floor velocity for daily prednisone versus intermittent prednisone was 0.06 rise/second (98.3% CI 0.03-0.08) and for daily deflazacort versus intermittent prednisone was 0.06 rise/second (98.3% CI 0.03-0.09); these were considered clinically important differences. The daily prednisone and daily deflazacort groups were similar for rising from the floor velocity (-0.004 rise/second, 98.3% CI -0.03 to 0.02) and for FVC and treatment satisfaction. In addition, the daily prednisone and daily deflazacort regimens showed similar effectiveness and were more effective than intermittent prednisone for all secondary motor outcomes.
In the FOR-DMD trial, weight gain was greater with prednisone (daily or intermittent) compared with daily deflazacort [43]. More slowing of growth occurred with daily deflazacort compared with daily prednisone, while both daily regimens led to more slowing of growth compared with intermittent prednisone.
In the VISION-DMD trial, the relative efficacy of vamorolone 6 mg/kg per day was similar to that of prednisone 0.75 mg/kg per day for all motor outcomes [26].
Two meta-analyses comparing deflazacort versus prednisone/prednisolone in patients with DMD nonsense or other pathogenic variants who received placebo in multicenter trials of ataluren and tadalafil found that the deflazacort-treated patients exhibited less decline in a series of motor function outcomes over a period of 48 weeks [44,45]. Nevertheless, these studies are limited by the nonrandomized assignment of glucocorticoid treatment. Limited observational data suggest that deflazacort is associated with a lower rate of aggressive behaviors [29,46].
Adverse effects and monitoring — The most common adverse effects after 6 to 36 months of treatment with daily glucocorticoids (prednisone or deflazacort) for boys with DMD are weight gain, decreased linear growth and short stature, hirsutism, and cushingoid appearance [4,17,18,43]. Other adverse effects of glucocorticoids include delayed puberty, long bone and vertebral bone fractures, acne, gastrointestinal symptoms, cataracts, and behavioral changes.
Therefore, growth, endocrine, bone health surveillance, and periodic eye examinations for cataracts are recommended in DMD patients treated with glucocorticoids. (See "Major adverse effects of systemic glucocorticoids", section on 'Monitoring and treatment of adverse effects'.)
●Weight gain – Prednisone may cause greater weight gain than deflazacort. Thus, deflazacort is used in preference to prednisone for patients with DMD who may be predisposed to obesity based on body habitus, dietary habits, or family history. In the FOR-DMD trial, weight gain was greater with prednisone (daily or intermittent) compared with daily deflazacort [43]. The difference in weight gain for the daily prednisone compared with the daily deflazacort group was 2.6 kg (98.3% CI 0.2-5.0 kg) and for daily deflazacort compared with intermittent prednisone was -3.1 kg (98.3% CI -5.5 to -0.7 kg). In an earlier randomized controlled trial of 196 boys with DMD, subjects assigned to prednisone (0.75 mg/kg per day) had greater mean weight gain at 12 and 52 weeks compared with subjects assigned to either of two deflazacort doses (0.9 and 1.2 mg/kg per day) [42].
Weight gain in patients with DMD is an undesirable side effect that may accelerate loss of ambulation, which in turn will lead to more weight gain unless dietary measures are taken to adjust caloric intake. If weight gain is excessive, an obesity management plan should be devised that addresses both diet and physical activity. (See "Clinical evaluation of the child or adolescent with obesity" and "Prevention and management of childhood obesity in the primary care setting".)
If obesity management is not successful, the glucocorticoid dose can be lowered by 20 to 25 percent, and/or patients on prednisone can be switched to deflazacort (but excessive weight gain can sometimes occur on deflazacort). If these measures fail and weight gain is unacceptable for the child or family/caregivers, glucocorticoids can be tapered off. (See 'Glucocorticoid tapering' below.)
●Slowing of growth – In the FOR-DMD trial, there was more slowing of growth with daily deflazacort compared with daily prednisone; the difference in height at three years for daily prednisone versus daily deflazacort was 2.3 cm (98.3% CI 0.7-3.9 cm) [43]. Both daily regimens led to more slowing of growth than intermittent prednisone; the difference for daily deflazacort compared with intermittent prednisone was -8.1 cm (98.3% CI -9.7 to -6.4 cm), while the difference for daily prednisone compared with intermittent prednisone was -5.8 cm (98.3% CI -7.4 to -4.2 cm).
In the VISION-DMD trial, height percentile compared with baseline declined at 24 weeks with prednisone treatment (-1.88) and increased with vamorolone 6 mg/kg day treatment (+3.86); the difference was statistically significant [26]. Earlier open-label extension studies found that vamorolone treatment was associated with normal growth velocity over 18 months [47] and 30 months [48].
●Preventive measures for bone loss – We suggest preventive measures to minimize bone loss for patients with DMD who are receiving prolonged glucocorticoid therapy. Such measures include dietary calcium and vitamin D supplementation, and yearly dual-energy x-ray absorptiometry (DXA) scanning and a 25-hydroxyvitamin D level. (See "Duchenne and Becker muscular dystrophy: Management and prognosis", section on 'Bone health'.)
In the 24-week VISION-DMD trial, serum biomarkers of bone formation (osteocalcin, procollagen 1 intact N-terminal propeptide [P1NP]) and bone turnover (type 1 collagen cross-linked C-telopeptide [CTX1]) declined from baseline with prednisone treatment but not with vamorolone [26].
Indications for stress-dose glucocorticoids — In the setting of severe illness, major trauma, or surgery, most patients taking prednisone or deflazacort dose >12 mg/m2 of body surface area per day will require stress-dose glucocorticoids (hydrocortisone 50 to 100 mg/m2 per day) to prevent acute adrenal insufficiency [6]. Note that the stress doses for glucocorticoids are based upon body surface area, while the DMD treatment doses for prednisone and deflazacort are based upon weight. (See "Duchenne and Becker muscular dystrophy: Management and prognosis", section on 'Adrenal insufficiency'.)
Duration of glucocorticoid therapy — In the absence of significant obesity or other intolerable side effects, glucocorticoids should be continued even for patients who become nonambulatory because treatment may slow or delay the development of scoliosis, pulmonary function decline, and heart failure. Thus, treatment is lifelong in the absence of major adverse effects. Examples of potential reasons for tapering off glucocorticoid therapy include vertebral fractures, development of severe obesity, or recurrent pulmonary infections (if immunosuppression is a concern).
Glucocorticoid tapering — Glucocorticoids should not be stopped abruptly. This is particularly important for patients with a suppressed hypothalamic-pituitary-adrenal (HPA) axis. Expert guidelines recommend implementation of the PJ Nicholoff tapering protocol [49] for patients who wish to discontinue glucocorticoid therapy [6]. The full protocol is available online; the main steps are as follows [49]:
●Decrease the glucocorticoid dose by 20 to 25 percent every two weeks
●Once a physiologic dose is achieved (3 mg/m2 per day of prednisone or deflazacort), switch to hydrocortisone 12 mg/m2 daily divided into three equal doses
●Continue to decrease the glucocorticoid dose by 20 to 25 percent every week until achieving a dose of 2.5 mg hydrocortisone every other day
●After two weeks of dosing every other day, stop hydrocortisone
●Periodically check morning adrenocorticotropic hormone (ACTH)-stimulated cortisol concentration until the HPA axis is normal
Patients who have surgery or develop serious illness or injury during the taper may require stress-dose glucocorticoids (see 'Indications for stress-dose glucocorticoids' above) until the HPA axis has recovered, a process that may take 12 months or longer [6].
GENETIC THERAPIES — Genetic therapies that involve exon skipping (eteplirsen, golodirsen, viltolarsen), read-through of premature termination codon (ataluren), or microdystrophin transgenes delivered by adeno-associated virus (AAV) vectors (delandistrogene moxeparvovec) are approved in some countries for the treatment of DMD. These therapies increase dystrophin expression (figure 2), but clinical benefit has not been established [50,51].
Shared decision-making — While the available genetic therapies for DMD may increase dystrophin levels, it is uncertain if patients benefit from treatment. Nevertheless, some families or guardians of patients with amenable pathogenic gene variants and their clinicians may reasonably choose one of these treatments based upon the potential (but uncertain) benefit and despite the known risks and extraordinary high cost of treatment. Shared decision-making must include discussions of what is known and what is uncertain regarding benefits, risks, burdens, and costs of these therapies.
Exon skipping — Injection of antisense oligonucleotides that induce specific exon skipping during messenger ribonucleic acid (RNA) splicing are designed to correct the open reading frame of the DMD gene in patients with out-of-frame deletions or duplications and thereby restore dystrophin expression (figure 2) [2]. Results from small clinical studies in humans suggest the promise of this approach, including those evaluating eteplirsen, golodirsen, viltolarsen, and casimersen.
Eteplirsen — Eteplirsen is an antisense oligonucleotide designed to skip exon 51 of the DMD gene.
●Patient selection – Eteplirsen may be used to treat children with DMD who have exon 51 amenable pathogenic variants. These deletion variants are present in approximately 13 percent of patients with DMD.
●Efficacy – An open-label study of 19 patients with DMD and eligible DMD deletion variants found that weekly intravenous administration of eteplirsen induced a dose-related increase in dystrophin production without drug-related adverse effects [52].
A subsequent 24-week placebo-controlled trial randomly assigned 12 patients (ages 7 to 13 years and ambulatory) in a 1:1:1 ratio to weekly dosing of intravenous eteplirsen 30 mg/kg, eteplirsen 50 mg/kg, or placebo [53]. This was followed by a 24-week open-label extension phase during which all subjects received eteplirsen. At 48 weeks, those assigned to eteplirsen 50 mg/kg walked a greater distance in the six-minute walk test compared with the placebo/delayed eteplirsen group. However, two patients assigned to eteplirsen 30 mg/kg lost ambulation during the trial. At 24 weeks, muscle biopsy revealed that patients assigned to eteplirsen 30 mg/kg had an increase in dystrophin-positive fibers of 23 percent compared with no increase in the placebo group, and the difference was statistically significant. (Muscle biopsy was not done at 24 weeks for the eteplirsen 50 mg/kg group.) At 48 weeks, the increase in dystrophin-positive fibers for the eteplirsen 30 mg/kg and 50 mg/kg groups was 52 and 43 percent, respectively. Through week 48, there were no adverse events related to eteplirsen treatment. Findings from an open-label extension phase of the study through 36 months suggested that, compared with historical controls, eteplirsen-treated patients had continued benefit on the six-minute walk test and a lower rate of loss of ambulation [54].
Another report, with data from three studies of eteplirsen-treated ambulatory (n = 54) and primarily nonambulatory (n = 20) patients with DMD, found that eteplirsen treatment was associated with a statistically significant and clinically meaningful attenuated annual decline in percent predicted forced vital capacity (FVC%p) values when compared with historical glucocorticoid-treated control patients with DMD [55]. This result supports the use of eteplirsen in nonambulatory DMD patients.
Based upon the finding of increased dystrophin in skeletal muscle observed in patients treated with eteplirsen, the US Food and Drug Administration (FDA) granted accelerated approval of eteplirsen in September 2016 for the treatment of patients with DMD who have a confirmed deletion of the DMD gene amenable to exon 51 skipping [51,56]. The FDA approval of eteplirsen was based on a surrogate outcome (dystrophin increase in muscle biopsy) [57]. As part of the accelerated approval process, the prescribing label states that "continued approval for this indication may be contingent upon verification of a clinical benefit in confirmatory trials" [58].
●Dose and administration – The recommended dose of eteplirsen is 30 mg/kg once a week by intravenous infusion over 35 to 60 minutes [58].
●Adverse effects – In small clinical studies, the most common adverse reactions were balance disorder, vomiting, contact dermatitis, contusion, excoriation, arthralgia, rash, catheter site pain, and upper respiratory tract infection [52-54,58]. Hypersensitivity reactions have occurred, including bronchospasm, chest pain, cough, tachycardia, and urticaria [58].
Golodirsen — Golodirsen is an antisense oligonucleotide that is designed to modify the splicing of exon 53 of dystrophin pre-messenger RNA, resulting in exon 53 skipping of the DMD gene.
●Patient selection – Golodirsen may be used to treat children with DMD who have amenable exon 53 pathogenic variants in the DMD gene. The frequency of this variant among patients with DMD is estimated to be 8 percent.
●Efficacy – In a preliminary trial, 12 children with DMD who had confirmed DMD pathogenic variants amenable to exon 53 skipping were assigned in a 2:1 ratio to weekly intravenous infusions of golodirsen or placebo; this was followed by an open-label study of golodirsen that included the original 12 patients from the randomized trial plus an additional 13 treatment-naïve patients with DMD amenable to exon 53 skipping [59]. The median age of patients at study entry was eight years. After 48 weeks or more of treatment, the mean dystrophin level increased from 0.1 percent of normal at baseline to 1.02 percent of normal. Clinical benefit was not reported. The FDA is requiring the manufacturer to show that golodirsen has clinical benefit (ie, improved motor function) in an ongoing trial [60].
Based upon the surrogate outcome of increased dystrophin production, the FDA granted accelerated approval of golodirsen in December 2019 for the treatment of patients with DMD who have a confirmed deletion pathogenic variant of the dystrophin gene amenable to exon 53 skipping [60].
●Dose and administration – The recommended dose of golodirsen is 30 mg/kg once a week by intravenous infusion over 35 to 60 minutes [61].
Urine dipstick, serum cystatin C, and urine protein-to-creatinine ratio should be measured before starting golodirsen and monitored during treatment, checking urine dipstick every month and serum cystatin C and urine protein-to-creatinine ratio every three months. The glomerular filtration rate should also be measured before starting golodirsen.
●Adverse effects – The most frequent adverse reactions associated with golodirsen in clinical studies were headache, fever, cough, vomiting, abdominal pain, nasopharyngitis, and nausea. Hypersensitivity reactions have also been observed, including rash, fever, itching, hives, dermatitis, and skin exfoliation. Renal toxicity has been observed with other antisense oligonucleotides.
Viltolarsen — Viltolarsen is an antisense oligonucleotide that is designed to bind to exon 53 of dystrophin pre-messenger RNA, resulting in exon 53 skipping during messenger RNA splicing in patients.
●Patient selection – Viltolarsen may be used to treat patients with amenable exon 53 nonsense variants of the DMD gene; this type of pathogenic variant is present in an estimated 8 percent of patients with DMD [62].
●Efficacy – A dose-finding safety trial enrolled 16 boys with DMD gene deletions amenable to exon 53 skipping who were randomly assigned in a 3:1 ratio to intravenous viltolarsen or placebo for four weeks, followed by a 20-week open-label treatment period [63]. Patients assigned to viltolarsen 80 mg/kg once a week showed an increase in dystrophin from a mean level of 0.6 percent of normal at baseline to 5.9 percent of normal at week 25. Among secondary outcomes, all 16 subjects showed improvement on timed function tests compared with historical controls. Continued FDA approval may depend upon confirmation of clinical benefit in further trials.
Based upon the surrogate outcome of increased dystrophin production, the FDA granted accelerated approval of viltolarsen in August 2020 for the treatment of patients with DMD who have a confirmed deletion of the dystrophin gene amenable to exon 53 skipping [62]. In Japan, viltolarsen was approved in March 2020 [64].
●Dosing and administration – The recommended dose of viltolarsen is 80 mg/kg once a week, given by intravenous infusion over 60 minutes [65].
Urine dipstick, serum cystatin C, and urine protein-to-creatinine ratio should be measured before starting viltolarsen, and measuring the glomerular filtration rate should also be considered prior to treatment. The label recommends monitoring for kidney toxicity during treatment by checking urine dipstick every month, and serum cystatin C and urine protein-to-creatinine ratio every three months. Only urine free of excreted viltolarsen should be used for monitoring urine protein; therefore, urine samples should be obtained at least 48 hours after the most recent infusion.
●Adverse effects – The most common adverse reactions with viltolarsen were upper respiratory tract infections, injection site reactions, cough, and pyrexia. Renal toxicity has been observed with other antisense oligonucleotides.
Casimersen — Casimersen is an antisense oligonucleotide that is designed to bind to exon 45 of dystrophin pre-messenger RNA, resulting in exon 45 skipping during messenger RNA processing in patients with amenable deletion pathogenic variants of the DMD gene.
●Patient selection – Casimersen may be used to treat patients who have a confirmed pathogenic variant of DMD that is amenable to exon 45 skipping, which causes approximately 8 percent of DMD cases [66].
●Efficacy – Casimersen treatment increased dystrophin production, as shown in an interim analysis of 43 patients (ages 7 to 20 years) with a deletion in DMD amenable to exon 45 skipping who were randomly assigned in a 2:1 ratio to treatment with casimersen or placebo [66]. At 48 weeks, the mean increase in dystrophin levels from baseline on muscle biopsy for patients assigned to casimersen was 0.81 percent, compared with 0.22 percent for the placebo group [67]. Clinical benefit was not reported in this preliminary analysis. Continued FDA approval may depend upon confirmation of clinical benefit in further trials. Based upon the surrogate outcome of increased dystrophin production, the FDA granted accelerated approval of casimersen in February 2021 for the treatment of patients with DMD and an amenable exon 45 pathogenic variant [66].
●Dose and administration – The dose of casimersen is 30 mg/kg once weekly given by intravenous infusion over 35 to 60 minutes using an in-line 0.2 micron filter [67]. Laboratory studies to include serum cystatin C, urine protein-to-creatinine ratio, and urine dipstick should be measured before starting casimersen and monitored during treatment.
●Adverse effects – The most frequent adverse reactions in clinical trials were respiratory tract infections, cough, fever, headache, joint pain, and oropharyngeal pain [67]. Hypersensitivity reactions, including angioedema and anaphylaxis, have occurred in postmarketing experience. Use is contraindicated in patients with known hypersensitivity to casimersen. Hypersensitivity reactions should be managed with appropriate medical treatment in addition to stopping the infusions.
Stop codon read-through — Some patients with DMD/Becker muscular dystrophy (BMD) harbor a nonsense (stop) pathogenic variant that leads to a premature termination codon (PTC) in the messenger RNA and causes a disruption of dystrophin translation [68]. The strategy of stop codon read-through employs small molecules that promote messenger RNA translation through the PTC to generate a functional protein (figure 2). This approach could benefit the estimated 10 to 15 percent of patients with DMD/BMD who harbor nonsense (stop) pathogenic variants [69].
Ataluren — Ataluren (PTC124) is an orally administered drug being developed for the treatment of genetic defects caused by pathogenic nonsense (stop) variants. Ataluren promotes ribosomal read-through of nonsense (stop) pathogenic variants, allowing bypass of the nonsense variant and continuation of the translation process to production of a functioning protein.
●Patient selection – Where licensed (eg, the European Union and United Kingdom), ataluren is an option to treat patients ages two years and older with DMD caused by nonsense pathogenic variants. This approach could benefit the estimated 10 to 15 percent of patients with DMD who harbor nonsense (stop) variants [69].
●Efficacy – The clinical benefit of ataluren is not yet established.
•In a phase 2 study of 26 boys with nonsense variant-mediated DMD, increased full-length dystrophin expression was observed in vitro and in vivo with PTC124, and serum muscle enzyme levels decreased within 28 days of treatment [70]. However, there were only minimal changes in muscle strength and timed functions with PTC124 treatment.
•A multicenter double-blind trial randomly assigned 174 ambulatory males (median age eight years, range 5 to 20) with DMD/BMD to high-dose ataluren, low-dose ataluren, or placebo [71]. At 48 weeks, the mean decline in the six-minute walk distance was approximately 30 meters less for the low-dose ataluren group compared with the placebo group. However, the mean change in the six-minute walk distance for the high-dose ataluren group was similar to that for placebo group. Based on the low-dose ataluren group results, ataluren received conditional approval by the European Commission in August 2014 to treat DMD caused by a nonsense pathogenic variant in the dystrophin gene. Ataluren is available to patients in 23 countries through either expanded access programs or commercial sales, but it is not approved for treating DMD in the United States.
•In a phase 3, multicenter, 48-week, blinded, placebo-controlled trial (Ataluren Confirmatory Trial in Duchenne Muscular Dystrophy [ACT DMD]) of 228 boys with nonsense variant-mediated DMD, there was no significant benefit of ataluren for the primary endpoint, change from baseline in the six-minute walk test, though there was benefit for some secondary endpoints [72].
●Dose and administration – Ataluren, available in sachets as granules, is administered orally by mixing it into a suspension with liquid or semisolid food [73]. The recommended dose is 10 mg/kg in the morning, 10 mg/kg at midday, and 20 mg/kg in the evening, for a total daily dose of 40 mg/kg. Recommended dosing intervals are six hours between morning and midday doses, six hours between midday and evening doses, and 12 hours between the evening dose and the first dose on the following day.
●Adverse effects – The most common adverse effect of ataluren is vomiting [73]. Others include decreased appetite, weight loss, hypertriglyceridemia, headache, hypertension, cough, epistaxis, nausea, upper abdominal pain, flatulence, abdominal discomfort, constipation, rash, limb pain, musculoskeletal chest pain, hematuria, enuresis, and pyrexia.
Gene transfer via viral vectors — The large size of the DMD gene (2.4 Mb) prevents its packaging into AAV vectors, which can only accommodate up to 4.7 kb genes. The case of a 61-year-old ambulatory patient with BMD and a large deletion of exons 17 to 48 (approximately 46 percent of the DMD gene) led to the design of microdystrophin transgenes, which maintain some of the critical domains of the dystrophin gene and protein (figure 2) [74]. Results from small trials evaluating delandistrogene moxeparvovec suggest the potential benefit of this approach. (See 'Delandistrogene moxeparvovec' below.)
Several earlier studies in mice used a gene-correction strategy employing AAV vectors to deliver the clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 genome engineering system, which cuts the noncoding introns that flank exon 23 [75-78]. This method partially restored dystrophin protein expression in cardiac and skeletal muscle and was associated with enhanced muscle function.
Delandistrogene moxeparvovec — Delandistrogene moxeparvovec is an adeno-associated virus capsid (AAVrh74) containing a transgene encoding a microdystrophin protein under the control of a muscle-specific MHCK7 promoter; it is designed to deliver the microdystrophin transgene to skeletal and cardiac muscles [79,80]. Although it produces microdystrophin protein, the clinical benefit of delandistrogene moxeparvovec is not established.
●Patient selection – Delandistrogene moxeparvovec was approved in the United States by the FDA in June 2023 for the treatment of ambulatory boys with DMD, ages four through five years, who have a proven pathogenic variant in the DMD gene [81].
●Efficacy – FDA approval was based in part upon the surrogate outcome of increased microdystrophin production demonstrated in two small trials; microdystrophin protein expression measured by Western blot of muscle biopsies was significantly increased compared with baseline after 12 weeks of treatment [81,82]. In one trial (n = 41), there was no improvement in functional outcome as measured by the mean change from baseline to week 48 in the North Star Ambulatory Assessment (NSAA), a 17-item rating scale of functional motor abilities in ambulatory children with DMD [83]. The mean change in NSAA score for the delandistrogene moxeparvovec group compared with the placebo group (1.7 versus 0.9) was not statistically significant. In a subgroup analysis, there was a greater improvement in the mean change from baseline in the NSAA score for children in the four- to five-year age group assigned to delandistrogene moxeparvovec compared with placebo (4.3 versus 1.9), while there was no difference between groups for children in the six- to seven-year age group (-0.2 versus 0.5) [82].
●Dose and administration – Delandistrogene moxeparvovec is given as a single intravenous infusion. The recommended dose is 1.33 × 1014 vector genomes/kg of body weight (10 mL/kg body weight) given over one to two hours and infused at a rate of <10 mL/kg per hour [82]. Treatment should be postponed in patients with active infection until the infection has resolved. Testing for liver function, platelet count, troponin-I level, and anti-AAVrh74 antibodies should be done before starting the medication. Glucocorticoid treatment (prednisone, maximum 60 mg daily) is recommended starting one day prior to the infusion and continuing for at least 60 days.
●Adverse effects – The most common adverse effects of delandistrogene moxeparvovec are vomiting, nausea, increased levels of hepatic enzymes and bilirubin, pyrexia, and thrombocytopenia [82]. Warnings and precautions include serious liver injury, immune-mediated myositis, and myocarditis. Delandistrogene moxeparvovec is contraindicated for patients with a deletion in exon 8 and/or exon 9 of the DMD gene, as these patients are at increased risk for severe immune-mediated myositis.
Patients with DMD gene deletions involving exons 1 to 17 and/or exons 59 to 71 could also be at risk for severe immune-mediated myositis; along with glucocorticoids, additional immunosuppressants (eg, a calcineurin inhibitor) may be considered if symptoms of myositis occur [82].
Risk of immune reactions with AAV vectors — The use of recombinant adeno-associated virus (rAAV) vectors to deliver gene therapy is associated with a risk of severe or fatal immune and inflammatory reactions [84-86]. Potent immune responses may be induced because high doses of rAAV are needed to deliver sufficient gene therapy to the sizeable amount of muscle tissue in the body. This risk is illustrated by a report of a 27-year-old patient with advanced DMD and impaired cardiopulmonary function who was treated with high-dose rAAV serotype 9 containing a CRISPR-based transgene designed to upregulate dystrophin [86]. The patient developed worsening cardiac dysfunction a few days after treatment, followed by acute respiratory distress syndrome (ARDS), cardiac arrest, and death on day eight. Evidence from laboratory and postmortem studies suggested that the death was due to an innate immune reaction triggered by the high load of rAAV. Further research to develop safer approaches [87] and identify high-risk patients may help to mitigate the acute toxic effects of rAAV gene therapy. (See "Overview of gene therapy, gene editing, and gene silencing", section on 'Potential concerns with gene therapy'.)
OTHER INVESTIGATIONAL THERAPIES — Other potential approaches for treating DMD include creatine, myostatin inactivation, and skeletal muscle progenitors [50].
●Creatine – Creatine monohydrate has been studied for its potential to increase muscle strength in neuromuscular disorders and muscular dystrophies, but data are limited and suggest that creatine treatment leads only to modest benefit at best [87-91]. Demonstration of clinically important improvement in larger trials is needed before recommending this treatment for patients with DMD.
●Myostatin inactivation – Myostatin is a protein that has an inhibitory effect on muscle growth. Mice that would otherwise express the DMD phenotype but lack myostatin have an increased muscle mass compared with those with a wildtype myostatin gene [92]. Antibodies to myostatin also have a beneficial effect; treated animals have increased muscle mass, strength, lower serum creatine kinase, and less histologic evidence of muscle damage [93]. A myostatin variant was identified in a child with gross muscle hypertrophy [94], suggesting that myostatin inactivation could be a therapeutic target to increase muscle bulk and strength in muscle-wasting diseases such as DMD [95]. However, preliminary trials of myostatin inhibitors in muscular dystrophy have not yet demonstrated clinical benefit [96-98].
●Cell therapy – Treatment with allogeneic cardiosphere-derived cells (CDCs), derived from cardiac progenitor cells, has shown promise for treating DMD; the proposed mechanism is a disease-modifying anti-inflammatory effect [99,100]. The placebo-controlled HOPE-2 trial was stopped early due to funding problems, but in data available for 20 patients with DMD, intravenous administration of CDCs (every three months for four infusions) led to a reduced rate of disease progression at 12 months as measured by a decline from baseline in an upper limb strength score (Performance of Upper Limb [PUL] motor function) of 0.8 points for the treated group and 3.4 points for the placebo group [101]. The between-group difference of 2.6 points was felt to be clinically meaningful. Three patients developed hypersensitivity reactions with infusion of CDCs. Study limitations include small patient numbers and lack of long-term follow-up; larger and longer trials are needed to confirm efficacy.
The use of skeletal muscle progenitors in the treatment of DMD and BMD remains experimental [102-108].
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Muscular dystrophy".)
SUMMARY AND RECOMMENDATIONS
●Glucocorticoids – For children with Duchenne muscular dystrophy (DMD) age four years or older whose motor skills have plateaued or declined, we suggest glucocorticoid treatment with deflazacort, prednisone, or vamorolone (Grade 2C). We generally prefer deflazacort because it offers a more favorable side effect profile than prednisone regarding weight gain and impact on behavior. Treatment with prednisone, deflazacort, or vamorolone may improve motor function, strength, and pulmonary function; reduce the risk of scoliosis; and possibly delay the onset of cardiomyopathy. (See 'Glucocorticoid treatment' above.)
•Dose – The usual starting dose of prednisone for treating DMD is 0.75 mg/kg per day. The usual starting dose of deflazacort is 0.9 mg/kg per day. The recommended dose of oral vamorolone is 6 mg/kg per day with meals (maximum dose 300 mg for patients weighing ≥50 kg).
Although practice is variable, the dose of prednisone or deflazacort is generally not adjusted for weight as patient weight increases over time in the absence of functional decline; this strategy may reduce the risk of adverse effects. (See 'Glucocorticoid dosing' above.)
•Adverse effects – The most common side effects of treatment with glucocorticoids for DMD are weight gain, slowing of growth, hirsutism, and cushingoid appearance. Limited evidence suggests that deflazacort treatment is associated with an increased risk of cataracts and a decreased risk of weight gain compared with prednisone. Limited evidence also suggests that vamorolone treatment reduces the risk of slowing of growth compared with prednisone. (See 'Adverse effects and monitoring' above.)
•Duration – Treatment with glucocorticoids is lifelong in the absence of major adverse effects. (See 'Duration of glucocorticoid therapy' above.)
●Genetic therapies – Genetic therapies that involve exon skipping (eteplirsen, golodirsen, viltolarsen), stop codon read-through (ataluren), or microdystrophin transgene delivery by an adeno-associated virus vector (delandistrogene moxeparvovec) are approved in some countries for the treatment of DMD (figure 2). (See 'Genetic therapies' above.)
•Shared decision-making – While these therapies may modestly increase dystrophin levels, it is uncertain if patients benefit from treatment. Nevertheless, some families or guardians of patients with amenable pathogenic gene variants and their clinicians may reasonably choose one of these treatments based upon the potential but uncertain benefit, despite the known risks, burdens, and extraordinarily high cost of treatment. Shared decision-making must include discussions of these issues. (See 'Shared decision-making' above.)
•Patient selection – Where available, disease-modifying treatments for DMD are:
-Casimersen, for patients with a confirmed pathogenic variant in the DMD gene amenable to exon 45 skipping (see 'Casimersen' above)
-Eteplirsen, for patients with a confirmed pathogenic variant in the DMD gene amenable to exon 51 skipping (see 'Eteplirsen' above)
-Golodirsen and viltolarsen, for patients with a confirmed pathogenic variant in the DMD gene amenable to exon 53 skipping (see 'Golodirsen' above and 'Viltolarsen' above)
-Ataluren, for patients with a nonsense (stop) DMD pathogenic variant that produces a premature termination codon (PTC) in the messenger RNA (see 'Ataluren' above)
-Delandistrogene moxeparvovec, for ambulatory boys ages four through five years who have a proven (nonspecific) pathogenic variant in the DMD gene (see 'Delandistrogene moxeparvovec' above)
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