Trials For Duchenne Muscular Dystrophy Research Articles

“Watching time tick by…”: Decision making for Duchenne muscular dystrophy trials

ObjectiveThis interview study explored clinicians' perspectives and parents' decision making about children's participation in Duchenne muscular dystrophy (DMD) clinical trials. MethodsData from semi-structured interviews conducted with clinicians and parents in U.S. or Canada were assessed using thematic analysis. ResultsEleven clinicians involved in ten trials and fifteen parents involved in six trials were interviewed. Parents described benefit–risk assessments using information from advocacy, peers, professionals, and sponsors. Strong influence was attributed to the progressive nature of DMD. Most expected direct benefit. Few considered the possibility of trial failure. Most made decisions to participate before the informed consent (IC) process, but none-the-less perceived informed choice with little to lose for potential gain.Clinicians described more influence on parental decisions than attributed by parents. Clinicians felt responsible to facilitate IC while maintaining hope. Both clinicians and parents reported criticisms about the IC process and regulatory barriers. ConclusionsThe majority of parents described undertaking benefit–risk assessments that led to informed choices that offered psychological and potential disease benefits. Parents' high expectations influenced their decisions while also reflecting optimism. Clinicians felt challenged in balancing parents' expectations and likely outcomes. Prognosis-related pressures coupled with decision making prior to IC suggest an obligation to ensure educational materials are understandable and accurate, and to consider an expanded notion of IC timeframes. Anticipatory guidance about potential trial failure might facilitate parents' deliberations while aiding clinicians in moderating overly-optimistic motivations. Regulators and industry should appreciate special challenges in progressive disorders, where doing nothing was equated with doing harm.

MRI quantifies neuromuscular disease progression

MRI quantifies neuromuscular disease progression

Duchenne muscular dystrophy: clinical trials and emerging tribulations.

This article reviewed the most recent clinical trials investigating potential treatments for Duchenne muscular dystrophy (DMD). In the development of these studies, investigators have encountered unexpected challenges that reveal limitations in our understanding of the clinical trial design for this disease. Recent clinical trials for DMD have revealed limitations in our understanding of the natural history of this disease. As a result of these revelations, there has been a significant effort to document the natural history of Duchenne and develop valid outcome measure that could be used in clinical trials in different subsets of patients. Treatment for DMD is a rapidly changing field. Some of the drugs that are currently under investigation will receive Food and Drug Administration approval in the near future. These would become part of clinical practice. This article summarizes the different therapeutic approaches under investigation and illustrates the importance of defining sound research methods that are specific to the disease and population under investigation.

Antisense oligonucleotide drugs for Duchenne muscular dystrophy: how far have we come and what does the future hold?

What is the current status of Duchenne muscular dystrophy therapy? Duchenne muscular dystrophy (DMD) is a devastating disease and the most prevalent lethal genetic disorder worldwide [1]. DMD is an X-linked recessive genetic disorder mostly caused by frame-shift mutations in the DMD gene, which disrupts the translational reading frame, resulting in a lack of dystrophin protein [2]. The lack of dystrophin, a muscle supporting protein, leads to lethal muscle wasting in DMD patients [3]. Due to advances in clinical management, specifically with pulmonary intervention, DMD patient survival has been prolonged, although most patients develop dilated cardiomyopathy eventually, and die from cardiac or respiratory failure by 30 years of age. Currently there is no cure for DMD patients, with treatment strategies being limited to glucocorticoid corticosteroids. DMD trials using corticosteroids found that there was an overall improvement in muscle strength as well as prolonged ambulation in the short term (6 months to 2 years) [4]. However, this treatment strategy also presented various limitations with its use. Presently, glucocorticoids have harsh side effects such as impaired growth and increased susceptibility to infection. Although glucocorticoid treatment has shown potential value in DMD, other treatment options are heavily being explored. Does antisense therapy hold the key? Recently, antisense-mediated exon-skipping therapy has emerged as a promising strategy for the treatment of DMD [5]. Antisense therapy is a strategy that uses short DNAlike molecules called antisense oligonucleotides (AONs) to selectively hybridize to nascent pre-mRNA, in order to correct various genetic diseases via exon skipping, splice modulation or by inhibiting gene expression [5]. In DMD, antisense-mediated exon skipping is currently one of the most promising treatment options. AONs can be used to restore the open reading frame, by establishing expression of a truncated but functional dystrophin, seen similarly in Becker muscular dystrophy, its milder counterpart [5]. Becker muscular dystrophy although commonly arising from mutations in the DMD gene retains its ability to produce partially functional dystrophin protein, due to inframe mutations that maintain the reading frame [5]. Antisense therapy, although currently promising as a treatment option for various disorders, has had slow success. Antisensemediated RNA regulation, which was first observed in nature, has greatly improved since the late 1970s, after Zamecnik et al. demonstrated that a gene expression can be inhibited by transfection of a short antisense (complementary) DNA sequence [6]. Antisense oligonucleotide drugs for Duchenne muscular dystrophy: how far have we come and what does the future hold?

TNF-α-Induced microRNAs Control Dystrophin Expression in Becker Muscular Dystrophy.

The amount and distribution of dystrophin protein in myofibers and muscle is highly variable in Becker muscular dystrophy and in exon-skipping trials for Duchenne muscular dystrophy. Here, we investigate a molecular basis for this variability. In muscle from Becker patients sharing the same exon 45-47 in-frame deletion, dystrophin levels negatively correlate with microRNAs predicted to target dystrophin. Seven microRNAs inhibit dystrophin expression in vitro, and three are validated in vivo (miR-146b/miR-374a/miR-31). microRNAs are expressed in dystrophic myofibers and increase with age and disease severity. In exon-skipping-treated mdx mice, microRNAs are significantly higher in muscles with low dystrophin rescue. TNF-α increases microRNA levels in vitro whereas NFκB inhibition blocks this in vitro and in vivo. Collectively, these data show that microRNAs contribute to variable dystrophin levels in muscular dystrophy. Our findings suggest a model where chronic inflammation in distinct microenvironments induces pathological microRNAs, initiating a self-sustaining feedback loop that exacerbates disease progression.

Respiratory muscle training in children and adults with neuromuscular disease

Respiratory muscle training in children and adults with neuromuscular disease

Outcome reliability in non-ambulatory boys/men with Duchenne muscular dystrophy.

Therapeutic trials in Duchenne muscular dystrophy (DMD) often exclude non-ambulatory individuals. Here we establish optimal and reliable assessments in a multicenter trial. Non-ambulatory boys/men with DMD (N = 91; 16.7 ± 4.5 years of age) were assessed by trained clinical evaluators. Feasibility (percentage completing task) and reliability [intraclass correlation coefficients (ICCs) between morning and afternoon tests] were measured. Forced vital capacity (FVC), assessed in all subjects, showed a mean of 47.8 ± 22% predicted (ICC 0.98). Brooke Upper Extremity Functional Rating (Brooke) and Egen Klassifikation (EK) scales in 100% of subjects showed ICCs ranging from 0.93 to 0.99. Manual muscle testing, range of motion, 9-hole peg test, and Jebsen-Taylor Hand Function Test (JHFT) demonstrated varied feasibility (99% to 70%), with ICCs ranging from 0.99 to 0.64. We found beneficial effects of different forms of corticosteroids for the Brooke scale, percent predicted FVC, and hand and finger strength. Reliable assessment of non-ambulatory boys/men with DMD is possible. Clinical trials will have to consider corticosteroid use.

Splicing modulation therapy in the treatment of genetic diseases.

Antisense-mediated splicing modulation is a tool that can be exploited in several ways to provide a potential therapy for rare genetic diseases. This approach is currently being tested in clinical trials for Duchenne muscular dystrophy and spinal muscular atrophy. The present review outlines the versatility of the approach to correct cryptic splicing, modulate alternative splicing, restore the open reading frame, and induce protein knockdown, providing examples of each. Finally, we outline a possible path forward toward the clinical application of this approach for a wide variety of inherited rare diseases.

It's A First — Parent Advocacy Group Offers FDA Guidance Document on Clinical Trials for Duchenne Muscular Dystrophy

It's A First — Parent Advocacy Group Offers FDA Guidance Document on Clinical Trials for Duchenne Muscular Dystrophy

Magnetic Resonance Imaging and Spectroscopy Assessment of Lower Extremity Skeletal Muscles in Boys with Duchenne Muscular Dystrophy: A Multicenter Cross Sectional Study

IntroductionDuchenne muscular dystrophy (DMD) is an X-linked recessive disorder that results in functional deficits. However, these functional declines are often not able to be quantified in clinical trials for DMD until after age 7. In this study, we hypothesized that 1H2O T2 derived using 1H-MRS and MRI-T2 will be sensitive to muscle involvement at a young age (5–7 years) consistent with increased inflammation and muscle damage in a large cohort of DMD subjects compared to controls.MethodsMR data were acquired from 123 boys with DMD (ages 5–14 years; mean 8.6 SD 2.2 years) and 31 healthy controls (age 9.7 SD 2.3 years) using 3-Tesla MRI instruments at three institutions (University of Florida, Oregon Health & Science University, and Children’s Hospital of Philadelphia). T2-weighted multi-slice spin echo (SE) axial images and single voxel 1H-MRS were acquired from the lower leg and thigh to measure lipid fraction and 1H2O T2.ResultsMRI-T2, 1H2O T2, and lipid fraction were greater (p<0.05) in DMD compared to controls. In the youngest age group, DMD values were different (p<0.05) than controls for the soleus MRI-T2, 1H2O T2 and lipid fraction and vastus lateralis MRI-T2 and 1H2O T2. In the boys with DMD, MRI-T2 and lipid fraction were greater (p<0.05) in the oldest age group (11–14 years) than the youngest age group (5–6.9 years), while 1H2O T2 was lower in the oldest age group compared to the young age group.DiscussionOverall, MR measures of T2 and lipid fraction revealed differences between DMD and Controls. Furthermore, MRI-T2 was greater in the older age group compared to the young age group, which was associated with higher lipid fractions. Overall, MR measures of T2 and lipid fraction show excellent sensitivity to DMD disease pathologies and potential therapeutic interventions in DMD, even in the younger boys.

G.P.116: SCOPE-DMD, an EU FP7 funded consortium for skipping trail across Europe in Duchenne muscular dystrophy

The SCOPE-DMD project builds on results from the TREAT-NMD and BIO-NMD EU projects to investigate a personalised-medicinal product through to market for the treatment of Duchenne Muscular Dystrophy (DMD). The initial goal of the project is to develop a therapy that can restore the expression of a functional dystrophin protein in targeted DMD patients that would potentially benefit from skipping of exon 45 of the DMD gene. The project uses an innovative clinical study design and novel outcome measures to reduce development timelines. The SCOPE-DMD study is an exploratory, open-label, dose-escalation phase IIb clinical trial that will assess the efficacy, safety, pharmacodynamics and pharmacokinetics of weekly subcutaneous doses of PRO045 in subjects with DMD. The study is of seamless design that is driven by the need to maximise the data from an exceptionally small patient population and to provide continuity of care in this rapidly progressing disease – a result of direct feedback from parents. It is made up of two phases: a dose escalation phase with 15 patients and an extended pivotal phase with an additional 55 patients. The consortium consists of 2 SMEs and 3 academic institutes coordinated by Newcastle University. Based on extensive experience from clinical trials of two other AONs in DMD patients, the consortium has worked on a highly innovative development plan that if successful, could be applied to future clinical trials in DMD and other rare diseases. Also magnetic resonance imaging, novel biomarkers and functional outcome measures including accelerometry, myotools and the Performance of Upper Limb (PUL) module will be incorporated into the trial protocol in addition to more established ones. Both expertise and scientific knowledge come together in this consortium to launch an innovative drug product but also to provide a regulatory and pathway-to-market precedence to benefit future patients with rare disorders getting earlier access to treatment.

T.P.6: Six minute walk test: reference values and prediction equation in healthy boys aged 5 to 12 years

This study aimed to (1) generate normative data in healthy boys aged 5–12 years for the 6-min walk test (6MWT), an outcome measure currently used in clinical trials in Duchenne muscular dystrophy (DMD), (2) to describe the relation with anthropometric variables and myometry, and (3) to compare our data with published equations. The 6MWT was conducted in 442 boys according to a standardized protocol. Maximal isometric contractions for knee flexion and extension were recorded with a hand-held myometer. The 6MWT distance increased significantly with age, from 478.0 m ± 44.1 at age 5, to 650.0 m ± 76.8 at age 12, with the steepest increase between 5 and 8 years. Age and height related percentile curves of the 6MWT were developed. Correlations with anthropometric variables were fair to good (age r = 0.60, height r = 0.57, weight r = 0.44). Myometric variables (knee flexors and extensors) showed correlations of 0.46 and 0.50, respectively. When dividing into two age categories (5–8 years, 9–12 years), these magnitude of correlations only applied to the younger age group, while in the older age group correlations were poor. Additionally, predicted values were calculated according to available reference equations (Geiger and Ben Saad), indicating an overestimation by those equations. Finally, the Geiger equation was refitted to our population Conclusion: The percentile curves according to age and height provide a useful tool in the assessment of ambulatory capacity in boys aged 5–12 years with variable diseases and more specifically in Duchenne patients. Significant correlations with anthropometric variables and myometry were only found in the 5–8 years age group. The Geiger prediction equation, currently used to assess ambulatory capacity in DMD was refitted to obtain a more accurate prediction model based on a large sample with a homogenous distribution across the age categories 5–12 years and applying the methodology as currently used in clinical trials in DMD.

T.I.1: The challenge of making therapies happen for neuromuscular diseases

Therapies are finally under way for neuromuscular disorders (NMDs) such as spinal muscular atrophies or muscular dystrophies. However, two pivotal trials for Duchenne muscular dystrophy failed to show significant results and have raised questions of feasibility in this field. This scenario is further complicated by the limited cohort sizes in many NMDs, and by variations in standards of care. In this context appropriate modelling of the preclinical approach is of paramount importance. Considerations have to include equivalence of the animal models, respect interspecies differences, and address disease-specific and method-specific hurdles of translation. Three major criteria eventually decide if a drug can be marketed: safety, efficacy, and mechanism of action. For small cohort sizes determining efficacy is challenging and dependent on selection and quality of outcome criteria. Functional measures, imaging, and biomarkers are constantly evolving. They have to be evaluated against a baseline of placebo or natural history which is lacking or incomplete for most NMDs. In addition, the effect size of an experimental drug is difficult to judge from the preclinical data, in particular from data obtained in mice. In this scenario carefully constructed phase 2 trials can inform on the choice of outcome criteria, cohort size, and trial duration of a pivotal trial. Treatment at a preclinical state, targeted natural history studies or run-in phases without treatment can be valuable alternatives. A conundrum in the field is that timelines of drug developers, academics, regulators, and patients are not the same. This may impact negatively on trial design, outcome criteria, patient selection, and may contribute to failure of drugs which have a valuable mechanism of action and safety profile. Based on examples I will outline problems of previous and ongoing trials, try to formulate what could be teachings to the field, and illustrate points of personal opinion.

G.P.93 : Entry and intracellular trafficking of adeno-associated viral 8 (AAV8) vector in DMD muscular cells

Adeno Associated virus serotype 8 (AAV8) is of particular interest as a vector for pre-clinical and clinical trial for Duchenne Muscular Dystrophy (DMD). In several cell lines, this vector has been shown to enter cells through clathrin-mediated endocytosis followed by a trafficking through the microtubule network in various endosomal compartments toward the nucleus. To efficiently transduce cells, AAV must undergo multiple levels of regulation in these cellular compartments. In DMD, dystrophin deficiency results in disturbed balance of cellular events i.e., fiber centronucleation, disorganized cytoskeleton, presence of fibrosis. We have recently described a loss of virion genomes from both dogs and mice models of DMD treated with therapeutic molecules vectorized in AAV. Indeed, the pathophysiological state of DMD muscle should impact on virions fate and subsequently affect crucial steps for AAV effectiveness as viral uncoating, viral genome maintenance and consequently, the transduction efficiency of AAV. Our project aims to characterize cellular uptake and intracellular transport of AAV8 in DMD muscular cells, with the goal of optimizing AAV vector use to get the best transduction efficiency with the lowest AAV dose. Our first data showed that AAV8-GFP was less efficient to transduce DMD and control primary muscular cells compared to HeLa cells. Moreover, AAV8 traffics through same endosomal compartment in DMD and control myoblasts, but at different rates during early time points of the transduction. These results suggest that in muscle cells, AAV8 uses different entry and trafficking pathways from those previously described in HeLa cells and that dystrophic cellular status could affect subcellular processing of the vector particles. We will specify the relationship between AAV8 vector entry, trafficking, uncoating, and transduction efficiency in vitro in primary myoblasts/myotubes of DMD patients and controls.

T.P.4: Long term natural history data in ambulant boys with Duchenne muscular dystrophy: 36 month changes

The 6 min walk test (6MWT) has been recently chosen as the primary outcome measure in several international multicenter clinical trials in Duchenne muscular dystrophy (DMD) ambulant patients. The aim of the study was to assess the spectrum of changes at 3 years in the individual measures, their correlation with steroid treatment and with age and 6MWT values at baseline. 96 patients from 11 centers were assessed at baseline and 1, 2 and 3 years after baseline. Three boys (3%) lost the ability to perform the test within 12 months, another 13 between 12 and 24 months (14%) and other 11 between 24 and 36 months (12%). The 6MWT showed an average overall decline of −15.8 (SD 77.3) meters in the first year, of −58.9 (SD 125.7) in the second year and −104.22 (SD 146.2) in the third year. The changes were significantly different in the two baseline age groups and according to the baseline 6MWT values (below and above 350 m) (test for interaction, p

G.P.248: Clinical trial readiness of paediatric neuromuscular patients in Ireland

An estimated 85–90% of all paediatric neuromuscular patients in the Republic of Ireland are followed at one neuromuscular centre, located at the Central Remedial Clinic, Dublin, resulting in centralised and coordinated care for the vast majority of Irish paediatric neuromuscular patients. The neuromuscular cohort followed by two neuromuscular specialists at this main centre totals 183 patients (ages 4 months–25 years), and the most common molecularly confirmed diagnoses are: Duchenne muscular dystrophy (n = 61), myotonic dystrophy (n = 16), spinal muscular atrophy (n = 14), merosin deficient congenital muscular dystrophy (n = 8), RYR1-related myopathy (n = 4) and collagen VI-related myopathy (n = 3). Future clinical trials for Duchenne muscular dystrophy, spinal muscular atrophy, merosin deficient congenital muscular dystrophy and collagen VI-related myopathies are presently in planning stages. Given the molecular characterization of these Irish patient cohorts, their close pulmonary and cardiology surveillance and their six monthly neuromuscular clinic assessments, these neuromuscular patient subgroups are clinical trial ready. Furthermore, the Central Remedial Clinic, Dublin, Ireland provides an ideal setting for future clinical trials, with its highly-trained and large-sized physiotherapy and occupational therapy teams, adequate space and facilities for motor function testing and the availability of support and nursing staff. Presently for neuromuscular patients in Ireland, participation in clinical trials would require that they travel to the United Kingdom, which is costly as well as burdensome for neuromuscular patients and their families. Given the availability of neuromuscular clinical expertise, an excellent facility for coordinated neuromuscular care and motor assessments and the commitment of patients and their families to participate in upcoming clinical trials, establishing a neuromuscular clinical trial site in Dublin is an achievable and important goal.

T.P.10: 6 min walk test and Performance of Upper Limb in ambulant DMD boys

The 6min walk test (6MWT) has been recently chosen as the primary outcome measure in several international multicenter clinical trials in Duchenne muscular dystrophy (DMD) patients. In the last few years there has been increasing attention to the assessment of upper limbs. The Performance of Upper Limb (PUL) has been specifically developed for the assessment of upper limbs in DMD providing information of three domains (shoulder, elbow and distal). The first published data have shown that involvement of upper limb is present not only in non ambulant patients and early signs of involvement can also be found in younger ambulant DMD boys. The aim of this longitudinal Italian multicentric study was to evaluate the correlation between the 6MWT and the PUL in ambulant DMD boys. As part of this study all boys are assessed using both measures. The preliminary results in over 100 DMD boys show that early signs of shoulder involvement can already be found after the age of 8 and become increasingly more marked with age. Boys with 6MWT results above 400m generally have full scores or one or two points below the full score. Their scores slightly decrease between 350 and 400m with a more obvious fall in scores below the cut off point of 350 that become increasingly more marked with the decrease in meters on the 6MWT. Our results suggest that upper limb involvement can already be found in DMD boys even in the ambulant phase and the scores on the PUL reflect to some extent the overall impairment observed on the 6MWT.

T.P.1: Pilot study evaluating motivation on the performance of timed walking in boys with Duchenne muscular dystrophy

Current trials in Duchenne muscular dystrophy (DMD) have focused on the distance traveled using the 6-min walk test (6MWT). As a primary efficacy outcome for clinical trials it can be quantified over a continuous scale. Limitations include a self-selected walking speed irrespective of encouragement and weakness predisposing to falls. We predicted that a monetary incentive of $50 could improve same-day 6MWT performance. Nine DMD boys (mean age 7.7) were instructed to walk quickly, not run. Encouragement was permitted throughout the test. Subjects were then stratified into an above or below 350 m group and randomly assigned to either the incentivized (IN) or non-incentivized (non-IN) group. A second 6MWT was completed after a rest period during which the following instructions were provided. The IN was told “If you walk faster on this repeat 6MWT you will receive $50. Remember to walk quickly and safely.” The non-IN were told “You are repeating the 6MWT and remember to walk quickly and safely.” The same evaluator conducted both tests, was blinded to group, and provided the same encouragement during each 6MWT. Current data is available in 9 boys, however data on a cohort of 36 will be presented. The boys in the IN (n = 5, mean age = 7.7) walked an average of 44 m (11%, max: 105 m) farther on the second 6MWT. The non-IN (n = 4, mean age = 7.6) walked an average of 5.1 m (2%, max: 16 m) farther. The increase in distance in IN was most distinct in the above 350 m (75 m or 17%) compared to the below 350 m (24 m or 7%) group. Our pilot data suggest that a financial incentive results in a measurable increase in within-day 6MWT distance in DMD. This variance is more pronounced in the above 350 m group which is the typical target for clinical trials. This data suggests that external motivators have a significant impact on the 6MWT and should be considered in the design and interpretation of clinical trials.

T.P.37: Old measures and new analysis in non ambulant SMA patients

Recent Rasch analysis performed on the most used clinical outcome measures in SMA, including the widely used Hammersmith Motor Functional Scale Expanded (HMFSE), clearly identified issues with current scales. Each scale had good reliability but there were also several issues impacting scale validity, including the extent that items defined clinically meaningful constructs and how well each scale measured performance across the SMA spectrum. Other issues are related to the need for an additional construct that measures motor performance of the upper limb. Furthermore, although natural history data are available, the experience with recent trials in Duchenne muscular dystrophy and in SMA have strongly suggested the need for identifying trajectories of disease course in different subgroups in order to improve stratification criteria and how to power the study in relation to this information. We report on work from an international group to (a) modify the scoring of the HMFSE items based on the Rasch analysis results and on a consensus from experienced physiotherapists and physicians involved in clinical trials. This re-weighting of existing items provides greater linearity of the scale. (b) Critically review the Upper Limb Module and revise a scale suitable for measuring performance of the upper limb in SMA. This will address the floor effect with the existing scale. (c) Provide further analysis of the natural history data available aimed at identifying possible trajectories related to several clinical variables, especially the effect of age and evolving scoliosis and joint contractures. The preliminary results of our effort shows that a new scoring system may help to improve the statistical robustness of the HFMSE and the suitability of a PUL-SMA scale. Furthermore, the analysis of the individual results according to several variables may help to identify subgroups trajectories and to define inclusion and stratification criteria for future clinical trials.

G.O.11: Longitudinal quantitative muscle MRI in 5 Duchenne boys treated with exon 51 skipping – A pilot study

Exon skipping in Duchenne muscular dystrophy (DMD) aims to restore dystrophin expression and maintain muscle function. The largest RCT so far targeting exon 51 failed to reach its primary endpoint despite promising results from preceding studies. It underscores the need for biomarkers. Quantitative MRI (qMRI) is promising as it is a non-invasive method which can be repeated easily. qMRI was used in 5 boys from the 48week RCT (DMD114044) and open label extension (OLE) study (DMD114349) assessing exon 51 skipping with weekly subcutaneous dosing at 6mg/kg drisapersen. T1w, 3-point Dixon and quantitative fat suppressed T2 scans were acquired from the left lower leg at 3T at 3 occasions: n =5), around the start of the OLE phase ( n =5) and n =4). Two boys were on placebo during RCT. Outcome measures were % fatty infiltration, contractile cross-sectional area (cCSA), and mean and standard deviation (SD) of T2 relaxation times in five lower leg muscles. Results were compared to three DMD controls from our natural history study. Interval between scans on treatment varied between 322 and 825days. cCSA and fat% did not show a clear pattern. However, in treated boys, a reduction in mean value and SD of the T2 relaxation time was visible especially in the tibialis anterior muscle. In contrast, T2 values of controls increased. The oldest boy with the highest initial fat% showed a large reduction in fat% and increase in cCSA for all lower leg muscles during 10.5months on treatment. Nonetheless he lost ambulation during the extension phase. The observed shift in T2 values opposite to that of controls may point towards less damaged muscle tissue. Subclinical improvement in muscle structure can provide a base for developing more potent drugs or studying prolonged treatment in younger patients as disease progression may lead to a point of no return regarding ambulation. qMRI should be considered as a biomarker in DMD trials.