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Chapter 1
An Overview of Recent Therapeutics Advances for Duchenne
Muscular Dystrophy
Jean K. Mah
Duchenne muscular dystrophy (DMD) is the most common form of muscular dystrophy in childhood.
Mutations of the DMD gene destabilize the dystrophin associated glycoprotein complex in the sarcolemma.
Ongoing mechanical stress leads to unregulated influx of calcium ions into the sarcoplasm, with activation
of proteases, release of proinflammatory cytokines, and mitochondrial dysfunction. Cumulative damage
and reparative failure leads to progressive muscle necrosis, fibrosis, and fatty replacement. Although there is
presently no cure for DMD, scientific advances have led to many potential disease-modifying treatments,
including dystrophin replacement therapies, upregulation of compensatory proteins, anti-inflammatory
agents, and other cellular targets. Recently approved therapies include ataluren for stop codon readthrough and eteplirsen for exon 51 skipping of eligible individuals. The purpose of this chapter is to
summarize the clinical features of DMD, to describe current outcome measures used in clinical studies, and
to highlight new emerging therapies for affected individuals.
Key words Duchenne muscular dystrophy, Outcome measures, Disease-modifying treatments
Duchenne muscular dystrophy (DMD) is a severe degenerative
muscle disease. It was initially described by Meryon in 1857, and
named after Duchenne de Boulogne based on his report of a young
boy suffering from “congenital hypertrophic paraplegia,” a condition characterized by early onset weakness and muscular hypertrophy [1]. The biological basis was later attributed to mutations of
the DMD gene on Xp21 [2]. DMD is the most common type of
dystrophinopathy, with an incidence of 1 in 3500 live male births
[3], and an estimated prevalence of 4.8 (95% CI 1.9–11.8) per
100,000 males worldwide [4]. Deletions of one or more exons
account for approximately two-thirds of all DMD mutations; the
rest are caused by duplications, small deletions, insertions, point
Camilla Bernardini (ed.), Duchenne Muscular Dystrophy: Methods and Protocols, Methods in Molecular Biology,
vol. 1687, DOI 10.1007/978-1-4939-7374-3_1, © Springer Science+Business Media LLC 2018
Jean K. Mah
mutations, or splicing mutations. Less commonly, in-frame mutations produce a milder and more variable phenotype known as
Becker muscular dystrophy, or X-linked dilated cardiomyopathy
[5, 6].
Clinical Synopsis of Duchenne Muscular Dystrophy
2.1 Clinical Features
of DMD
Affected boys usually present with a history of developmental delay,
including difficulty with walking, climbing stairs, jumping, as well
as running after the first one to 2 years of life [7]. In addition, they
may have associated speech delay, learning disability, or cognitive
impairment. Early clinical signs include calves hypertrophy,
increased lumbar lordosis, and proximal more than distal muscle
weakness, leading to a positive Gowers sign as well as a waddling
gait. The combination of motor developmental delay, weakness,
and muscular hypertrophy in a young boy should trigger the order
of serum creatine kinase (CK) as an initial screening test; the CK is
significantly elevated in boys with DMD due to ongoing muscle
2.2 Diagnosis of
The diagnosis can usually be made after a careful review of the
clinical history, physical examination, and confirmation by molecular genetic testing that interrogate all 79 exons of the DMD gene,
such as multiplex ligation-dependent probe amplification or comparative genomic hybridization microarray [8]. If the initial genetic
test fails to detect a disease-causing deletion or duplication, DMD
gene sequencing can usually confirm the precise mutation. Identification of the specific mutation is important for accurate diagnosis,
prognosis, and individualized treatment for affected males with
DMD, as well as genetic counseling for their families.
2.3 Natural History of
DMD causes predictable decline in motor function, with difficulty
rising from the floor, inability to climb stairs, and eventual loss of
independent ambulation by early adolescence. The age at loss of
independent ambulation is associated with other functional decline,
such as progressive limitation in upper limbs mobility, scoliosis,
joint contractures, respiratory insufficiency, and cardiomyopathy
[9]. Death usually occurs by the third or fourth decade of life due
to cardiorespiratory complications.
Clinical Endpoints in DMD Natural History Study and Clinical Trials
Accurate outcome measures are important for clinical management
and research. They can inform regarding the extent of functional
impairment, provide anticipatory care before further disease progression, and monitor for therapeutic response to new emerging
DMD Therapeutics
Table 1
Common clinical endpoints for Duchenne muscular dystrophy
Outcome measures for ambulatory patients
Strength and endurance
Timed function tests
6 min walk test
Functional ability
North star ambulatory assessment
Other motor function measures
Outcome measures for nonambulatory patients
Strength and endurance
Cardiac function
Respiratory function
Functional ability
Egen Klassification scale
Performance of upper limbs scale
Patient-reported outcomes/health-related quality of life measures
Muscle biopsy
Neuroimaging modalities
Biomarkers exploration studies
treatments. Common clinical endpoints for DMD include quantitative muscle testing, timed function tests, other functional assessments, goniometry, pulmonary function test, cardiac evaluation
(electrocardiogram, echocardiogram, and cardiac MRI), and
patient reported outcomes such as the Pediatric Quality of Life
Inventory™ Neuromuscular Module and the Pediatric Outcomes
Data Collection Instrument (Table 1) [9, 10].
3.1 Motor Outcome
Measures for
Ambulatory Patients
3.1.1 Timed Function
Tests (TFT)
TFT are objective measures of motor performance; examples
include the time to rise from supine (Rise Time), climb four stairs,
walk 10 m (10 MWT), and the 6 min walk test (6MWT, see below).
They reflect important motor milestones and activities of daily
living in patients with DMD. They can also help predict the likelihood of further disease progression. For instance, a Rise Time of
more than 10 s is associated with an increased risk of loss in
independent ambulation over the coming year [9, 11]. TFT are
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recommended by the European Medicines Agency for use as outcome measures for ambulatory patients in DMD clinical trials; they
are also included as part of the North Star Ambulatory Assessment
(see below) [11–13].
3.1.2 6-Min Walk Test
The 6MWT has been used as a primary end point in some of the
recent DMD therapeutic trials [14]. It is an integrated global
measure of ambulatory function and metabolic efficiency; it captures clinically meaningful aspect of health-related quality of life in
ambulatory patients with DMD [11]. The 6MWT showed high
test–retest reliability among boys with DMD; it also demonstrated
strong concurrent validity with TFT [15]. Boys with a baseline
6MWT distance of less than 300 m have a greater likelihood of
losing ambulation within a year, whereas boys with a 6MWT distance greater than 400 m are relatively stable and are more likely to
be unchanged in their ambulatory status within the same period.
Prespecifying a baseline 6MWT distance of 300–400 m thus provides an opportunity to evaluate treatment effect in a 1-year clinical
trial for DMD [14–16].
3.1.3 North Star
Ambulatory Assessment
The NSAA is a composite functional assessment scale for DMD. It
is composed of 17 items, with scores ranging from 0 to 2 per item;
it was validated as a clinical endpoint in 2009 [12], and used
extensively in Europe as an outcome measure for DMD [17]. The
NSAA is sensitive to changes in motor function related to disease
progression in DMD. Boys less than 7 years of age showed a decline
in NSAA earlier than the 6MWT; the NSAA also demonstrated a
moderate correlation (r ¼ 0.52) with the 6WMT in DMD boys
after a 12-month follow-up period [18]. Participants with a baseline NSAA score of more than 18 was associated with a reduced risk
of losing ambulation compared to other DMD boys with lower
NSAA scores within a 2-year observation period [19].
3.2 Outcome
Measures for
Motor endpoints for nonambulatory patients with DMD include
the Egen Klassifikation (EK) and the Performance of Upper Limb
(PUL) scales. The EK scale includes assessment of muscle strength,
joint contractures, forced vital capacity, and wheelchair dependency; scores ranged from 0 to 3, with higher scores indicating
lower level of independent function [20]. The PUL scale is an
observer-based outcome measure to evaluate upper limb performance. It assesses three (proximal, mid, and distal) domains of
upper limb function to reflect disease progression and physical
impairment in DMD [21, 22]. Changes in upper limbs function
were noted early in boys with DMD, and declined further with
increasing muscle weakness; the correlation between the PUL scale
and the 6MWT became more linear (r ¼ 0.49) among boys with a
6WMT distance of less than 400 m [23].
DMD Therapeutics
3.3 Muscle Biopsy,
Biomarkers, and
Recent clinical trials have included muscle biopsy, neuroimaging,
and biomarkers to reflect disease progression and as surrogate
outcome measures to monitor for response to treatment in DMD.
3.3.1 Muscle Biopsy
DMD is characterized by a dystrophic process in the muscle biopsy;
dystrophin immunostaining is usually absent or markedly reduced,
except in rare revertant fibers. Each biopsy requires an invasive
procedure; furthermore, the amount of dystrophin did not necessarily correlate with motor function [24]. However, dystrophin
localization at the membrane remains essential as a proof of concept
for dystrophin restoration therapies, and it was included as one of
the key outcome measures in recent DMD trials (see exon skipping
3.3.2 Biomarkers
The Somalogic Approach (SOMAscan) employed large-scale multiplexed quantitative proteomic studies to identify selective proteins
that are differentially expressed in DMD. In a recent study, 1125
proteins were quantified based on stored serum samples from two
independent longitudinal cohorts (total n ¼ 93) of DMD patients;
44 proteins showed significant differences that were consistent in
both cohorts when compared with healthy volunteers [25].
Changes in protein levels appeared to correlate with increasing
age and disease progression. Further validation studies are planned
to explore potential diagnostic and therapeutic avenues of serum
biomarkers for DMD and other rare diseases.
3.3.3 Muscle MRI
Skeletal muscle MRI is an objective outcome measure that is not
dependent on the participant’s effort; it is noninvasive, reproducible, and appears to be sensitive to disease progression in DMD. In
a recent study of 109 ambulatory boys (age 5–12.9 years) with
DMD who were followed longitudinally for 1 year, subclinical
disease progression was detected by quantitative muscle MRI
within a relatively short (3–6 months) time period. Moderate correlation (r ¼ 0.54) was found between the modified Brooke lower
extremities functional score and the vastus lateralis fat fraction on
MRI [26]. Among boys whose 6MWT performance improved or
remained stable over 1 year, significant increases in MRI–T2 and fat
fraction were found by the authors. As T2 signal was elevated in
DMD even among the younger boys, muscle MRI may offer the
potential to study patients across a wider age range in therapeutic
trials. Validation of MRI as a secondary outcome measures for
DMD is ongoing [26].
Emerging New Treatment for DMD
Recent scientific advances have enabled the discovery of new
emerging treatments for many neuromuscular diseases including
DMD. Regularly updated information about clinical trials for
Jean K. Mah
DMD is available at Current therapeutic strategies include: (a) Gene replacement or other genetic
therapies to restore dystrophin production, such as exon skipping,
gene therapy, and stop-codon read-through; (b) Muscle growth
and regeneration, such as stem cells therapy, upregulation of compensatory proteins, and myostatin inhibition; (c) Reduction of
inflammation and fibrosis, such as corticosteroids and anti-fibrotic
treatments; (d) Other therapies, including calcium balance, blood
flow upregulation, mitochondrial enhancement, plus treatment of
cardiac disease, respiratory complications, bone health, and exercise
program (Table 2).
4.1 Gene
Replacement or Other
Genetic Therapies
4.1.1 Exon Skipping
4.1.2 Stop Codon Readthrough Therapy
Exon skipping uses synthetic antisense oligonucleotide sequences
to induce skipping of prespecified exons during pre-messenger
RNA splicing of the DMD gene. This results in restoration of the
reading frame and production of an internally truncated protein,
similar to the dystrophin protein expression seen in Becker muscular dystrophy. Eteplirsen is a phosphoramidate morpholino oligomer designed specifically for exon 51 skipping. In a double-blind
placebo-controlled trial of eteplirsen for 24 weeks followed by an
open-label extension study of 12 boys with DMD (age 7–12 years
at baseline) at 30 or 50 mg/kg per week, Mendell et al reported
significant improvement in walking ability among the majority of
the subjects, with histological evidence of de novo dystrophin
production and restoration of the dystrophin-associated protein
complex in their muscle biopsies [27]. Ongoing treatment and
longitudinal follow-up of the same participants for up to 3 years
showed continual stabilization in their ambulatory function, with
no significant treatment-related side effects [28]. Eteplirsen
received the USA Food and Drug Administration approval for the
treatment of DMD with mutations amendable to exon 51 skipping
on September 19, 2016. As part of the accelerated approval process, Sarepta Therapeutics is required to conduct a confirmatory
trial (NCT02255552) to substantiate Eteplirsen’s clinical benefit;
the primary endpoint will be the NSAA. Antisense therapies that
induce single or multiple exons skipping could potentially be helpful for the majority of dystrophin mutations [29].
Approximately 10–15% of DMD are caused by point mutations
with inappropriate expression of specific sequences (UAA, UAG
or UGA) leading to premature stop codons. The stop codons in
turn cause an arrest in the synthesis of the dystrophin protein.
Ataluren is an orally bioavailable drug designed to overcome premature stop codon mutations. It binds to the ribosomal RNA
subunits and impairs the recognition of premature stop codon,
thus allowing the translation and production of a modified dystrophin protein. Earlier studies of ataluren showed that it was safe and
well tolerated [30]. Among 174 boys with genetically confirmed
DMD secondary to premature stop codon mutations, a double-
DMD Therapeutics
Table 2
Examples of current clinical trials for Duchenne
muscular dystrophy
Gene replacement and other genetic therapies
Exon skipping
Exon 51: Eteplirsen
Exon 53: SRP-4053, NS-065/NCNP-01
Exon 45: SRP-4045, DS-5141b
Stop codon read-through
Gene transfer
Muscle growth and regeneration
Cell-based therapies
Myoblasts transplant
Cardiosphere-derived cells: CAP-1002
Upregulation of cytoskeleton proteins
Utrophin modulator: SMT C1100
Myostatin inhibition
Reduction of inflammation and fibrosis
Glucocorticoids and analogues
FOR-DMD: Prednisone versus deflazacort
Other NF-kappa B inhibitors
Anti-fibrotic agents
Other cellular targets
Calcium regulation
Jean K. Mah
Table 2
Cardiomyopathy treatment
Ramipril versus Carvedilol
Spironolactone versus eplerenone
Respiratory intervention
Bone health and exercise program
Zoledronic acid
Strength training
blind placebo-controlled study for 48 weeks showed a marginally
significant improvement in 6MWT for those receiving low dose
(40 mg/kg/day) ataluren [31]. Ataluren has received conditional
approval by the European Medicines Agency since August 2014. A
Phase 3 extension study (NCT02090959) and a Phase 2 early
treatment trial (NCT02090959) are ongoing. Clinical trials involving other nonsense mutation suppression agents are also being
4.1.3 Gene Therapies
Gene therapies can potentially be beneficial for many individuals
with DMD, regardless of their underlying gene mutations. Follistatin is a muscle growth stimulating protein. A Phase 1/2 intramuscular gene transfer trial of rAAV1.CMV.huFollistatin344 to
patients with DMD (NCT02354781) is currently enrolling participants. Another therapeutic option includes a Phase 1 gene transfer study for DMD using rAAVrh74.MCK.GALGT2
(NCT02704325). The GALGT2 gene encodes a β1–4-N-acetylD-galactosamine (βGalNAc) glycosyltransferase; it induces the
expression of dystrophin, laminin α2, and other cytoskeletal proteins. GALGT2 glycosylation also strengthens the extracellular
matrix by binding to α-dystroglycan and reduces eccentric
contraction-induced muscle injury [32]. However, the GALGT2
gene transfer trial was recently withdrawn prior to enrollment.
Furthermore, a Phase 1 adeno-associated virus (AAV) delivery of
micro-dystrophin to restore muscle protein expression in DMD
(NCT02376816) is currently being conducted at the Nationwide
Children’s Hospital. Preclinical studies of microdystrophin and
recombinant AAV-mediated gene therapy are also being conducted
by other investigators [33].
DMD Therapeutics
4.2 Muscle Growth
and Regeneration
4.2.1 Cell-Based
Examples in this group include transfer of myoblasts and
cardiosphere-derived cells.
1. Transplantation of Myoblasts to DMD patients is a Phase I/II
clinical trial (NCT02196467) to investigate the safety and
efficacy of normal donor myoblasts transplanted to the extensor carpi radialis (ECR) muscle of patients with DMD. Approximately 30 million myoblasts will be injected per cubic
centimeter in a progressively higher surface of the ECR; the
contralateral muscle will be injected with saline to serve as a
control. Outcome measures including muscle strength will be
determined at 3 and 6 months post transplantation.
2. HOPE-Duchenne (Halt cardiomyOPathy progrEssion in
Duchenne) is a Phase 1/2 clinical trial (NCT02485938)
involving the use of CAP-1002; it is an investigational product
consisting of allogeneic cardiosphere-derived cells (CDC). All
subjects assigned to the active treatment arm will receive an
infusion of CDC into each of the three left ventricle cardiac
territories (anterior, lateral, inferior/posterior). Other progenitor cell populations including inducible pluripotent (iPS) stem
cells are currently at the preclinical or early clinical phase of
research [34].
4.2.2 Compensatory
Upregulation of
Cytoskeletal Proteins
Compensatory upregulation of cytoskeletal proteins, including
utrophin, alpha-7-beta-1 integrin, and biglycan, have been shown
to stabilize the sarcolemma in the absence of dystrophin in mdx
mice, with improvement seen in the muscle biopsies post treatment
[35]. SMT C1100 is an oral bioavailable molecule specifically
designed to target the utrophin-A promoter to increase utrophin
expression. Both SMT C1100 and its related compounds
SMT022357 were shown in preclinical experiments to increase
the production of utrophin and reduce the dystrophic changes in
the skeletal and cardiac muscles [36]. The PhaseOut DMD trial
(NCT02858362) is a Phase 2 open-label study to assess the safety
and utility of utrophin modulation with SMT C1100; up to
2500 mg will be administered as an oral therapy in ambulatory
boys with DMD.
4.2.3 Myostatin
Myostatin is a negative regulator of muscle mass. Inhibition or
blockade of endogenous myostatin offers a potential means to
compensate for the severe muscle wasting that is common in muscular dystrophies [37, 38]. Examples of current anti-myostatin
therapies in DMD include BMS-986089 (NCT02515669); it is a
Phase I/II double-blind, placebo-controlled study to determine
the safety, tolerability, and pharmacokinetics of a novel myostatin
inhibitor in ambulatory boys with DMD. Similarly, the Phase 2 trial
of PF-06252616 (NCT02310763) is a randomized double-blind,
placebo-controlled study to evaluate the safety, efficacy, and
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pharmacokinetics of a novel monoclonal antibody against myostatin, to be given intravenously to ambulatory boys diagnosed with
4.3 AntiInflammatory Agents
4.3.1 FG-3019
FG-3019 is a monoclonal antibody to connective tissue growth
factor (CTGF). The rationale for FG-3019 is based on data
showing that CTGF reduces the ability of damaged muscle cells
to repair and promote muscle fibrosis. In a preclinical study, FG3019 reduced muscle fibrosis and significantly improved muscle
function in mdx mice [39]. It is currently part of a Phase 2 trial in
nonambulatory subjects with DMD (NCT02606136). Each subject will receive FG-3019 by intravenous infusion every 2 weeks for
up to 2 years.
4.3.2 Givinostat
Givinostat is a histone deacetylase (HDAC) inhibitor. HDAC inhibitors stimulate myogenesis in vitro and counteract against muscle
degeneration in mdx mice by promoting the transcription of a
number of factors that are key in muscle regeneration, including
follistatin [40]. Givinostat also has potent anti-inflammatory effects
[41]. It is being studied in an upcoming Phase 2/3 clinical trial for
ambulatory boys with DMD. The combination effects of givinostat
is expected to enhance the reparative process in DMD muscle by
increasing muscle regeneration as well as reducing fatty infiltration
and fibrosis.
4.3.3 Nuclear Factor
Kappa B (NF-κB) Inhibition
NF-κB plays a central role in DMD disease pathophysiology. The
lack dystrophin and mechanical stress leads to NF-κB activation
early in the disease, with muscle inflammation, fibrosis and degeneration [42]. In preclinical models, reduction of NF-κB is protective of disease progression. CAT-1004 (NCT02439216) inhibits
NF-κB and could potentially be used to treat chronic inflammation
as a result of muscle degeneration. Phase 1 data suggest that treatment with CAT-1004 is associated with reduction in NF-κB, plus it
was safe and well tolerated. Phase 2 studies are planned to determine the utility of CAT-1004 as a steroid-sparing therapy among
boys with DMD.
4.3.4 Glucocorticoids
Glucocorticoids are currently the only available medication that
slows the decline in muscle strength and function in DMD; furthermore, treatment delays the progression of scoliosis and stabilizes pulmonary function. Glucocorticoids prolong independent
ambulation on average by 2–3 years [43]. Deflazacort is an oxazoline derivative of prednisone, with similar side effects profile except
for weight gain. The Phase 3 Finding the Optimum Regimen for
Duchenne Muscular Dystrophy (FOR-DMD, NCT01603407)
study will enroll boys aged 4–7 years with DMD. The study will
compare the side effects profile and efficacy of oral prednisone
0.75 mg/kg/day, prednisone 0.75 mg/kg/day switching between
DMD Therapeutics
10 days on and 10 days off treatment, and deflazacort 0.9 mg/kg/
day as disease-modifying treatment for DMD. The results should
help identify the optimal glucocorticoid regimen for DMD. As
well, a novel steroid-like medication known as Vamorolone
(VBP15 compound) was found to be an effective inhibitor of NFkB in myoblasts, but with potentially better side effects profile, as it
does not bind to glucocorticoid receptors [44]. The current Phase
2 (NCT02760264) open-label study will evaluate the safety and
tolerability of vamorolone in boys with DMD between the ages of
4–6.9 years. Enrolled participants will take the study medication
orally for 14 days, followed by a 24-week extension study period.
4.4 Other
4.4.1 Calcium Balance
Maintaining calcium homeostasis can potentially be therapeutic for
boys and young men with DMD.
1. Rimeporide (NCT02710591) Phase 1 trial: In DMD there is
an imbalance between the levels of calcium and sodium in the
muscles cells that is thought to be important in contributing to
ongoing damage [45]. Based on prior safety and efficacy results
in animal and humans, sodium/proton type 1 exchanger
(NHE-1) inhibition with Rimeporide represents an innovative
pathway to reduce the accumulation of muscle damage, including inflammation and fibrosis in animal models of muscular
dystrophies and heart failure.
2. Secondly, ARMGO Pharma has identified a new class of small
molecule therapeutics that restore normal balance of calcium
within muscle cells by correcting the ryanodine receptor (RyR)
calcium channel complex. In mice that lack dystrophin,
ARM210 corrected a calcium leak occurring through the
RyR complex and improved daily activity, strength, and muscle
force [46]. These studies help establish the rationale for
planning a Phase 1 clinical trial with ARM210 for patients
with DMD.
3. Furthermore, as abnormally high levels of calcium in DMD
muscle contribute to loss of function and eventually to muscle
cell death, AT-300 (preclinical study) is a novel modulator of
stretch-activated calcium channels that is intended to help
restore normal levels of calcium in Duchenne skeletal and
cardiac muscle [47].
4.5 Cardiac,
Respiratory, Bone
Health, and Exercise
Current supportive care including respiratory, cardiac, orthopedic,
and rehabilitative interventions have contributed to improvement
in function, health-related quality of life, and life expectancy for
individuals with DMD; those who are diagnosed nowadays have
the potential of surviving longer and leading meaningful lives. The
DMD Care Considerations Working Group provided a comprehensive framework for recognizing the primary manifestations and
Jean K. Mah
possible complications, building consensus on standard of care
recommendations, and planning for optimum treatment across
different specialties within a coordinated multidisciplinary
team [48].
4.5.1 Cardiac Disease
In DMD cardiac manifestations most often present as a progressive
cardiomyopathy with arrhythmia. Echocardiographic evidence of
structural heart disease in DMD patients include left ventricular
hypertrophy and declining systolic dysfunction [49]. Current clinical trials for treatment of DMD-related heart disease include:
1. Nebivolol (NCT01648634): The objective of this Phase 3 trial
is to determine whether nebivolol (a beta-blockade drug) can
delay the development of cardiomyopathy in patients with
DMD between the ages of 10 and 15 years old.
2. Ramipril versus Carvedilol in Duchenne and Becker Patients
(NCT00819845): The aim of this Phase 3 study is to compare
the efficacy of carvedilol and ramipril on myocardial tissue
properties and heart function, as measured by cardiac MRI
and myocardial ultrasound tissue characterisation analysis.
3. Aldosterone Inhibition (NCT02354352): This Phase 4 study
aims to demonstrate noninferiority of spironolactone compared to eplerenone; both are aldosterone antagonists and
potassium-sparing diuretics. The goal of this study is identify
optimum treatment strategy to preserve cardiac and pulmonary
function in DMD patients with initially preserved left ventricular ejection fraction.
4.5.2 Respiratory
Individuals with DMD are at risk of respiratory complications as
their condition deteriorates due to progressive loss of respiratory
muscle strength. These complications include ineffective cough,
nocturnal hypoventilation, sleep disordered breathing, and ultimately daytime respiratory failure. Death is due to respiratory
failure in the majority of cases [50]. A Phase III SIDEROS trial
(NCT02814019) is a randomized, placebo controlled, parallel
group study to determine the safety, efficacy, and tolerability of
idebenone in delaying the decline of respiratory function in
DMD. Approximately 266 DMD patients on stable dose of concomitant glucocorticoid steroids (either deflazacort or prednisone)
will be enrolled. The study treatment period will be 18 months,
with idebenone doses of up to 900 mg/day.
4.5.3 Bone Health and
Individuals with DMD may develop vertebral compression factures
due to chronic glucocorticoids therapy, progressive muscle weakness, as well as prolonged immobilization. Bisphosphonates are
generally reserved for those with symptomatic vertebral compression or recurrent fragility fractures; however, the long-term efficacy
DMD Therapeutics
of bisphosphonate therapy for patients with DMD remains unclear
[51]. Regular physical activity, calcium enriched diet, vitamin D
supplementation, plus periodic assessments of bone density are
recommended as part of bone health management.
1. Zoledronic Acid (NCT00799266): This is a multicenter, randomized, double-blind, placebo controlled trial to determine
the efficacy and safety of intravenous zoledronic acid twice
yearly compared to placebo in children and adolescents with
osteoporosis on chronic glucocorticoids therapy, including
those with DMD. The primary outcome will be the change in
lumbar spine bone mineral density Z-score at month 12 compared to baseline.
2. Strength Training in DMD (NCT02421523): The overall
objective of this pilot study is to assess whether a mild to
moderate-intensity isometric resistance strengthening exercise
program can be safely implemented in boys with DMD. Safety
measures will include skeletal muscle MRI, patient-reported
pain rating scale, clinical examination, and serial serum CK
DMD is a complex and heterogeneous disease, thus no single
endpoint can replicate the impact of disease progression on affected
individuals. Regulatory agencies have accepted the 6MWT as well
as other clinical evaluations such as TFT, NSAA, and patientreported outcome measures as relevant endpoints for DMD clinical
trials. Additional outcome measures are being developed, including
biomarkers and muscle imaging. It is likely that composite endpoints are needed to confirm the clinical responses to new emerging
treatments. Early recognition of the clinical features and precise
genetic diagnosis remains essential for timely access to individualized therapies. Currently multiple interventions targeting different
disease processes are planned in order to slow down the disease
progression and treat secondary complications. Collaboration with
patients, families, clinicians, scientists, and other key stakeholders
remains a key strategy for advancing the health outcomes, clinical
care, and research for the global DMD community.
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