scholarly journals First Regulatory Qualification of a Novel Digital Endpoint in Duchenne Muscular Dystrophy: A Multi-Stakeholder Perspective on the Impact for Patients and for Drug Development in Neuromuscular Diseases

2021 ◽  
pp. 183-190
Author(s):  
Laurent Servais ◽  
Eric Camino ◽  
Aude Clement ◽  
Craig M. McDonald ◽  
Jacek Lukawy ◽  
...  
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Drug Development ◽  
Neuromuscular Diseases ◽  
European Medicines Agency ◽  
Motor Abilities ◽  
Stakeholder Perspective ◽  
Functional Outcome Measures ◽  
Multi Stakeholder ◽  
The Impact

<b><i>Background:</i></b> Functional outcome measures used to assess efficacy in clinical trials of investigational treatments for rare neuromuscular diseases like Duchenne muscular dystrophy (DMD) are performance-based tasks completed by the patient during hospital visits. These are prone to bias and may not reflect motor abilities in real-world settings. Digital tools, such as wearable devices and other remote sensors, provide the opportunity for continuous, objective, and sensitive measurements of functional ability during daily life. Maintaining ambulation is of key importance to individuals with DMD. Stride velocity 95th centile (SV95C) is the first wearable acquired digital endpoint to receive qualification from the European Medicines Agency (EMA) to quantify the ambulation ability of ambulant DMD patients aged ≥5 years in drug therapeutic studies; it is also currently under review for the US Food and Drug Administration (FDA) qualification. <b><i>Summary:</i></b> Focusing on SV95C as a key example, we describe perspectives of multiple stakeholders on the promise of novel digital endpoints in neuromuscular disease drug development.

scholarly journals New Perspectives on the Diagnosis and Management of Duchenne Muscular Dystrophy

2015 ◽  
Vol 10 (01) ◽  
pp. 73 ◽  
Author(s):  
Francesco Muntoni ◽  
Annemieke Aartsma-Rus ◽  
Eugenio Mercuri ◽  
Hanns Lochmüller ◽  
◽  
...  
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Patient Care ◽  
Neuromuscular Diseases ◽  
Test Reliability ◽  
Standards Of Care ◽  
Specialist Care ◽  
6Mwt Distance ◽  
Care And Treatment ◽  
The Impact

Duchenne muscular dystrophy (DMD) is a rare X-linked recessive disorder that occurs in around one in 5,000 male births. The prevalence of DMD is expected to rise due to improved standards of care and implementation of guidelines, leading to longer survival. Specialist genetic confirmation of a DMD diagnosis is typically followed by access to specialist care and treatment: the exact DMD-causing mutation should be identified because it can influence prognosis and identify patients eligible for treatment. Since the majority of patients has a deletion or duplication of one or more exons (~70 %), generally multiplex ligation-dependent probe amplification suffices to identify the mutation. Exon sequencing is performed to pick up small mutations (~30 %). Greater awareness of DMD is needed among healthcare professionals to enable earlier diagnosis, which would facilitate family planning, as well as patient care and treatment. In DMD patients who are still able to walk, the 6-minute walk test (6MWT) has been shown to be a valid measure of physical functioning and a predictor of disease progression, with high inter-test reliability. In a study of the natural history of DMD, change in 6MWT of around 30 metres has been indicated to be clinically relevant and clinically meaningful. DMD patients responded to treatment as shown by the improvement in the 6MWT score in the large multinational trial of the nonsense mutation readthrough agent, ataluren (Translarna™) 40 mg/kg/day, where treatment was associated with a 31.3 metres improvement on the 6MWT distance, after 48 weeks, compared with placebo. The Translational Research in Europe–Assessment & Treatment of Neuromuscular Diseases (TREAT-NMD) network was launched to provide an infrastructure to accelerate research and therapy development, increasing collaboration, improving patient care and helping to support ‘clinical trial readiness’. As such, the TREAT-NMD registry network is well placed to support further understanding of DMD and the impact of therapies that may be used over the long term, permitting a host of research questions to be explored.

Duchenne muscular dystrophy: Drug development and regulatory considerations

2010 ◽  
Vol 41 (6) ◽  
pp. 740-745 ◽  
Author(s):  
D. Elizabeth McNeil ◽  
Carole Davis ◽  
Devanand Jillapalli ◽  
Shari Targum ◽  
Anthony Durmowicz ◽  
...  
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Drug Development

Differential diagnosis of Duchenne muscular dystrophy

2021 ◽  
Vol 2 (3) ◽  
pp. 159-166
Author(s):  
Alexey L. Kurenkov ◽  
Lyudmila M. Kuzenkova ◽  
Lale A. Pak ◽  
Bella I. Bursagova ◽  
Tatyana V. Podkletnova ◽  
...  
Keyword(s):  
Differential Diagnosis ◽  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Muscle Damage ◽  
Genetic Diagnosis ◽  
Clinical Manifestations ◽  
Neuromuscular Diseases ◽  
Muscular Dystrophies ◽  
Juvenile Form ◽  
Pathogenic Variants

Duchenne muscular dystrophy (DMD) is a disease with an X-linked recessive type of inheritance, belonging to a group of disorders with primary muscle damage, caused by pathogenic variants in the DMD gene and associated with dysfunction of the dystrophin protein. Since DMD is manifested by the gradual development of progressive, mainly proximal muscle weakness, the differential diagnosis is primarily carried out in the group of diseases with muscle damage - myopathies. Among these diseases, the leading candidates for differential diagnosis are hereditary myopathies (limb-girdle muscular dystrophies, facioscapulohumeral dystrophy, congenital muscular dystrophies, glycogenoses - the most common juvenile form of glycogenosis type II (Pompe disease)) and, much less often, congenital myopathies and other conditions of neuromuscular diseases). When conducting a differential diagnosis in a child with suspected DMD, the age of the onset of the disease, early initial clinical manifestations and the development of symptoms as they grow, genealogical analysis, laboratory tests (the level of creatine kinase, aspartate aminotransferase, alanine aminotransferase in blood serum), instrumental (electromyography, magnetic resonance imaging of the brain and muscles) and molecular genetics (polymerase chain reaction, multiplex ligation-dependent probe amplification, next-generation sequencing, Sanger sequencing, etc.) of studies, and in some cases, muscle biopsy data. Knowledge of the nuances of the differential diagnosis allows establishing a genetic diagnosis of DMD as early as possible, which is extremely important for the formation of the prognosis of the disease and the implementation of all available treatment methods, including pathogenetic therapy, and is also necessary for medical and genetic counselling of families with DMD patients.

scholarly journals Comparison of Serum Pharmacodynamic Biomarkers in Prednisone-Versus Deflazacort-Treated Duchenne Muscular Dystrophy Boys

2020 ◽  
Vol 10 (4) ◽  
pp. 164
Author(s):  
Shefa Tawalbeh ◽  
Alison Samsel ◽  
Heather Gordish-Dressman ◽  
Yetrib Hathout ◽  
CINRG-DNHS Investigators ◽  
...  
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Natural History Study ◽  
Motor Abilities ◽  
Igf I ◽  
Comparative Safety ◽  
Pharmacodynamic Biomarkers ◽  
Larger Sample ◽  
Insight Into

Prednisone (Pred) and Deflazacort (Dfz) are commonly used glucocorticoids (GCs) for Duchenne muscular dystrophy (DMD) treatment and management. While GCs are known to delay the loss of ambulation and motor abilities, chronic use can result in onerous side effects, e.g., weight gain, growth stunting, loss of bone density, etc. Here, we use the CINRG Duchenne natural history study to gain insight into comparative safety of Pred versus Dfz treatment through GC-responsive pharmacodynamic (PD) biomarkers. Longitudinal trajectories of SOMAscan® protein data obtained on serum of DMD boys aged 4 to 10 (Pred: n = 7; Dfz: n = 8) were analyzed after accounting for age and time on treatment. Out of the pre-specified biomarkers, seventeen candidate proteins were differentially altered between the two drugs (p < 0.05). These include IGFBP-2 and AGER associated with diabetes complications, and MMP-3 associated with extracellular remodeling. As a follow-up, IGFBP-2, MMP-3, and IGF-I were quantified with an ELISA using a larger sample size of DMD biosamples (Dfz: n = 17, Pred: n = 12; up to 76 sera samples) over a longer treatment duration. MMP-3 and IGFBP-2 validated the SOMAscan® signal, however, IGF-I did not. This study identified GC-responsive biomarkers, some associated with safety, that highlight differential PD response between Dfz and Pred.

Is Exercise-Induced Fatigue a Problem in Children with Duchenne Muscular Dystrophy?

2020 ◽  
Vol 51 (05) ◽  
pp. 342-348
Author(s):  
Astrid Blaschek ◽  
Martin Rodrigues ◽  
Lena Ille ◽  
Mohammed Idriess ◽  
Therese Well ◽  
...  
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Muscular Atrophy ◽  
Diagnostic Value ◽  
Outcome Parameter ◽  
New Therapeutic Approaches ◽  
Relevant Role ◽  
Exercise Induced ◽  
6 Minute Walk Test ◽  
The Impact

Abstract Objective Duchenne muscular dystrophy (DMD) is a devastating X-linked muscular disorder. The number of studies investigating new therapeutic approaches is substantially increasing. This study aims to investigate the impact and diagnostic value of exercise-induced fatigue in DMD, which has been proposed as a suitable outcome parameter in other conditions like spinal muscular atrophy. Patients and Methods A cohort of 55 DMD patients (49 of them treated with steroids and 9 with ataluren) underwent a total of 241 6MWT (mean 4.4 tests/patient) which were retrospectively analyzed. Exercise-induced fatigue was assessed by the ratio between the distance achieved in the sixth minute and the distance in the second minute of the 6MWT. In previous studies a quotient above 1 was defined as a sign of fatigue. Results The average fatigue quotient in the whole cohort of patients was 1.0. In a further analysis no impact of age, steroid therapy, ataluren therapy, overall disability, and distance in the 6-minute walk test (6MWT) on fatigue in DMD patients could be shown. Conclusion Our data show that fatigue does not play a relevant role in DMD. Analysis of fatigue is not a useful outcome parameter in DMD studies. For this reason we suggest the 2MWT, which is better accepted by the patients, as an alternative to the commonly 6MWT.

Proteins in the Urine Associated with Duchenne Muscular Dystrophy and other Neuromuscular Diseases

1981 ◽  
Vol 61 (2) ◽  
pp. 141-149 ◽  
Author(s):  
N. Frearson ◽  
R. D. Taylor ◽  
S. V. Perry
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Physical Disabilities ◽  
Protein Pattern ◽  
Neuromuscular Diseases ◽  
Two Dimensional Electrophoresis ◽  
Characteristic Features ◽  
Neuromuscular Conditions ◽  
Dimensional Electrophoresis ◽  
Healthy Persons

1. Up to 200 protein staining spots could be detected on two-dimensional electrophoresis of urine from healthy persons. Other minor spots were occasionally present. 2. Although the electropherograms exhibited constant characteristic features some variation in protein pattern was observed between individuals and with a given individual at different times. 3. Two additional proteins, spots C and D, were consistently present in urine from boys with Duchenne muscular dystrophy. Spot C was also present in the urine of about 60% of obligatory carriers of this dystrophy. 4. The protein responsible for spot C had a molecular weight of 26000 and an isoelectric point of 5.3. 5. Spot C was also detected in the urine of patients with other neuromuscular conditions. Neither spot C nor spot D could be detected in the urine of patients with physical disabilities other than those of neuromuscular origin. 6. It is concluded that the urinary excretion of spot C, and probably of spot D, is a consequence of muscle damage and that their detection has potential as a diagnostic tool.

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