Lessons Learned from Discontinued Clinical Developments in Duchenne Muscular Dystrophy

Markati, Theodora; Waele, Liesbeth De; Schara-Schmidt, Urlike; Servais, Laurent

doi:10.3389/fphar.2021.735912

Cited by 21 publications

(12 citation statements)

References 91 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…For example, Duchenne muscular dystrophy (DMD) is the most frequently inherited pediatric neuromuscular disease, however, there remains limited treatment options for this patient population despite almost three decades of preclinical and clinical research. In fact, 16 compounds have been discontinued during clinical development for DMD and this has largely been attributed to the lack of an animal model that is representative of the human disease [1].…”

Section: Introductionmentioning

confidence: 99%

Evaluation of the DBA/2J mouse as a potential background strain for genetic models of cardiomyopathy

Hart

Lee

Hammers

et al. 2022

Preprint

View full text Add to dashboard Cite

The potential use of the D2.mdx mouse (the mdx mutation on the DBA/2J genetic background) as a preclinical model of the cardiac aspects of Duchenne muscular dystrophy (DMD) has been criticized based on speculation that the DBA/2J genetic background displays an inherent hypertrophic cardiomyopathy phenotype. Accordingly, the goal of the current study was to further examine the cardiac status of this mouse strain over a 12-month period. DBA/2J mice have been scrutinized for the presence of cardiac lesions, however, in the current study we find that DBA/2J mice contain equivalent amounts of left ventricular collagen as healthy canine and human samples. In a longitudinal echocardiography study, neither sedentary or exercised DBA/2J mice demonstrated left ventricular wall thickening or cardiac functional deficits. In summary, we find no evidence of hypertrophic cardiomyopathy, or any other cardiac pathology, and thus propose that it is an appropriate background strain for genetic modeling of cardiac diseases, including the cardiomyopathy associated with DMD.

show abstract

Section: Introductionmentioning

confidence: 99%

Evaluation of the DBA/2J mouse as a potential background strain for genetic models of cardiomyopathy

Hart

Lee

Hammers

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

“…[22][23][24][25][26][27][28][29][30][31] Further, genetic modifiers as well the beneficial effects of oral corticosteroids-the standard-of-care-in DMD 32 significantly alter the trajectory of disease course. Given the resource-intense nature of clinical trials in DMD, and several Phase 2/3 clinical trials failing to demonstrate a treatment effect on the primary outcome measure, 33 better understanding of prognostic factors that contribute to disease heterogeneity can help not only clinical trial design but can inform patient care and management.…”

Section: Discussionmentioning

confidence: 99%

Association between neurodevelopmental impairments and motor function in Duchenne muscular dystrophy

Thangarajh,

McDermott,

Guglieri

et al. 2023

Ann Clin Transl Neurol

View full text Add to dashboard Cite

ObjectiveWe explored various prognostic factors of motor outcomes in corticosteroid‐naive boys with Duchenne Muscular Dystrophy (DMD).MethodsThe associations between parent‐reported neurodevelopmental concerns (speech delay, speech and language difficulties (SLD), and learning difficulties), DMD mutation location, and motor outcomes (6‐minute walk distance (6MWD), North Star Ambulatory Assessment (NSAA) total score, 10‐meter walk/run velocity, and rise from floor velocity) were studied in 196 corticosteroid‐naive boys from ages 4 to less than 8 years.ResultsParticipants with SLD walked 25.8 fewer meters in 6 minutes than those without SLD (p = 0.005) but did not demonstrate statistical differences in NSAA total score, 10‐meter walk/run velocity, and rise from floor velocity. Participants with distal DMD mutations with learning difficulties walked 51.8 fewer meters in 6 minutes than those without learning difficulties (p = 0.0007). Participants with distal DMD mutations were slower on 10‐meter walk/run velocity, and rise from floor velocity (p = 0.02) than those with proximal DMD mutations. Participants with distal DMD mutations, who reported speech delay or learning difficulties, were slower on rise from floor velocity (p = 0.04, p = 0.01) than those with proximal DMD mutations. The mean NSAA total score was lower in participants with learning difficulties than in those without (p = 0.004).InterpretationCorticosteroid‐naive boys with DMD with distal DMD mutations may perform worse on some timed function tests, and that those with learning difficulties may perform worse on the NSAA. Pending confirmatory studies, our data underscore the importance of considering co‐existing neurodevelopmental symptoms on motor outcome measures.

show abstract

“…The number of approved DMD therapies is very low compared to the number of compounds that have been investigated over the past years. The reasons for this high failure rate are varied, but the lack of sensitive outcome measures appears to have an important role in a disease with high phenotypic variability and variable disease trajectory (Markati et al, 2021). Recently, the regulatory qualification of the Stride Velocity 95th Centile (SV95C) as the first digital clinical-outcome measure captured via a wearable device as a secondary endpoint, has paved the way for the wider acceptance of digital endpoints in drug efficacy clinical trials (Servais et al, 2021(Servais et al, , 2022.…”

Section: Introductionmentioning

confidence: 99%

Patient-led development of digital endpoints and the use of computer vision analysis in assessment of motor function in rare diseases

Ferrer-Mallol¹,

Matthews²,

Stoodley³

et al. 2022

Front. Pharmacol.

View full text Add to dashboard Cite

Digital health technologies are transforming the way health outcomes are captured and measured. Digital biomarkers may provide more objective measurements than traditional approaches as they encompass continuous and longitudinal data collection and use of automated analysis for data interpretation. In addition, the use of digital health technology allows for home-based disease assessments, which in addition to reducing patient burden from on-site hospital visits, provides a more holistic picture of how the patient feels and functions in the real world. Tools that can robustly capture drug efficacy based on disease-specific outcomes that are meaningful to patients, are going to be key to the successful development of new treatments. This is particularly important for people living with rare and chronic complex conditions, where therapeutic options are limited and need to be developed using a patient-focused approach to achieve the biggest impact. Working in partnership with patient Organisation Duchenne UK, we co-developed a video-based approach, delivered through a new mobile health platform (DMD Home), to assess motor function in patients with Duchenne muscular dystrophy (DMD), a genetic, rare, muscular disease characterized by the progressive loss of muscle function and strength. Motor function tasks were selected to reflect the “transfer stage” of the disease, when patients are no longer able to walk independently but can stand and weight-bear to transfer. This stage is important for patients and families as it represents a significant milestone in the progression of DMD but it is not routinely captured and/or scored by standard DMD clinical and physiotherapy assessments. A total of 62 videos were submitted by eight out of eleven participants who onboarded the app and were analysed with pose estimation software (OpenPose) that led to the extraction of objective, quantitative measures, including time, pattern of movement trajectory, and smoothness and symmetry of movement. Computer vision analysis of video tasks to identify voluntary or compensatory movements within the transfer stage merits further investigation. Longitudinal studies to validate DMD home as a new methodology to predict progression to the non-ambulant stage will be pursued.

show abstract

Lessons Learned from Discontinued Clinical Developments in Duchenne Muscular Dystrophy

Cited by 21 publications

References 91 publications

Evaluation of the DBA/2J mouse as a potential background strain for genetic models of cardiomyopathy

Evaluation of the DBA/2J mouse as a potential background strain for genetic models of cardiomyopathy

Association between neurodevelopmental impairments and motor function in Duchenne muscular dystrophy

Patient-led development of digital endpoints and the use of computer vision analysis in assessment of motor function in rare diseases

Contact Info

Product

Resources

About