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Introduction: Duchenne muscular dystrophy (DMD) is characterized by rapid functional decline. Current available treatment options aim to delay disease progression or stabilize physical function. To aid in healthcare providers' understanding of the symptoms of disease that impact patients' experience, this study explored children's physical functioning, activities of daily living (ADLs), and health-related quality of life (HRQoL) after receiving eteplirsen, a weekly infusion indicated for individuals with DMD with exon 51 skip-amenable mutations. Methods: Fifteen caregivers of male individuals with DMD participated in a 60-min, semi-structured interview. Open-ended questioning explored changes in the children's condition or maintenance in abilities since eteplirsen initiation. Results: Children with DMD (age 7–15 years [mean 10.9]; steroid treatment at interview, n = 8; time since eteplirsen initiation 3–24 months [mean 14.9]) were described by caregivers as ambulatory (n = 9) and non-ambulatory (n = 6). Caregivers of ambulatory children reported improvements or maintenance of walking ability (n = 7/9), running (n = 6/9), and using stairs (n = 4/9). Continued decline in using stairs was reported by two caregivers. In upper-limb functioning, improvements or maintenances in fine-motor movements were reported by nearly half of all caregivers (n = 7/15), with one caregiver noting a continued decline. Subsequent improvements or maintenances in ADLs were described. Improvements or maintenances in fatigue (n = 9/15), muscle weakness (n = 7/15), and pain (n = 6/15) were reported, although some caregivers described a continued decline (n = 3/15 fatigue, n = 1/15 muscle weakness, n = 2/15 pain). Importantly, most caregivers who reported maintenances in ability perceived this as a positive outcome (n = 6/9). Conclusion: This exploratory study indicated that most caregivers perceived improvements or maintenances in aspects of their child's physical functioning, ADLs, and HRQoL since eteplirsen initiation, which they perceived to be a positive outcome. Plain Language Summary: Duchenne muscular dystrophy (DMD) is a rare disease characterized by progressive muscle weakness. Early on, this weakness presents as difficulty walking, but eventually children lose the ability to walk, develop spinal curvature, and experience problems with the heart and lung muscles. People with DMD are missing a key protein in their bodies called dystrophin. Eteplirsen is a weekly, intravenous treatment approved to treat people with a specific DMD genetic misspelling. The goal of the treatment is to slow down the disease and delay the time to losing ability to walk or needing help breathing. Fifteen caregivers of children living with DMD participated in a 60-min telephone interview. Caregivers were asked questions about the child's DMD symptoms and how those symptoms impact the child's daily life. Caregivers discussed their child's experience while receiving eteplirsen treatment and changes since the start of treatment. Caregivers described their child's muscle weakness and how this has affected their movements (e.g., using stairs, running or walking). Since starting eteplirsen treatment, all caregivers reported some improvement or maintenance in parts of their child's physical functioning, activities of daily living (e.g., sports/leisure, getting dressed and self-care), and symptoms (e.g., muscle weakness, pain and fatigue), even though some decline was also reported (e.g., physical functioning, getting dressed, self-care, muscle weakness, pain and fatigue). The results provide insights into physical functioning and quality of life of children with DMD who are receiving eteplirsen. However, more research is needed to fully understand the impact of eteplirsen on these experiences. [ABSTRACT FROM AUTHOR]

Objective: Strategic Targeting of Registries and International Database of Excellence (STRIDE) is an ongoing, international, multicenter registry of real-world ataluren use in individuals with nonsense mutation Duchenne muscular dystrophy (nmDMD) in clinical practice. This updated interim report (data cut-off: January 31, 2022), describes STRIDE patient characteristics and ataluren safety data, as well as the effectiveness of ataluren plus standard of care (SoC) in STRIDE versus SoC alone in the Cooperative International Neuromuscular Research Group (CINRG) Duchenne Natural History Study (DNHS). Methods: Patients are followed up from enrollment for at least 5 years or until study withdrawal. Propensity score matching was performed to identify STRIDE and CINRG DNHS patients who were comparable in established predictors of disease progression. Results: As of January 31, 2022, 307 patients were enrolled from 14 countries. Mean (standard deviation [SD]) ages at first symptoms and at genetic diagnosis were 2.9 (1.7) years and 4.5 (3.7) years, respectively. Mean (SD) duration of ataluren exposure was 1671 (56.8) days. Ataluren had a favorable safety profile; most treatment-emergent adverse events were mild or moderate and unrelated to ataluren. Kaplan–Meier analyses demonstrated that ataluren plus SoC significantly delayed age at loss of ambulation by 4 years (p < 0.0001) and age at decline to %-predicted forced vital capacity of < 60% and < 50% by 1.8 years (p = 0.0021) and 2.3 years (p = 0.0207), respectively, compared with SoC alone. Conclusion: Long-term, real-world treatment with ataluren plus SoC delays several disease progression milestones in individuals with nmDMD. NCT02369731; registration date: February 24, 2015. [ABSTRACT FROM AUTHOR]

Introduction: This study aims to identify stages of Duchenne muscular dystrophy (DMD) and assess the disease burden by progression stage using real-world administrative claims supplemented by relevant electronic medical record (EMR) data. Methods: Claims and EMR data from the Decision Resources Group's Real World Data Repository (2011–2020) were used to identify patients with DMD by diagnosis code and to stratify them into four disease stages by diagnosis and procedure markers reflective of DMD progression. Clinical and medical history data from the Cooperative International Neuromuscular Research Group (CINRG) were used to validate the developed claims-based staging algorithm. The distribution and drivers by disease stage, as well as disease burden, were examined. Results: A total of 938 (94%) of patients with DMD identified in claims/EMR data had sufficient information for stage classification. Patients were classified by stage based on patient characteristics and the presence or absence of progression markers such as genetic testing, wheelchair usage, scoliosis treatment, or ventilation assistance. Average ages at stages 1–4 are 7, 13, 18, and 23 years, respectively. Using natural history data, the claims-based staging algorithm was validated with high sensitivity and specificity rates. Both healthcare resource utilization and medical charges increased by stage. For example, the average annualized total charges were $17,688 (stage 1), $36,868 (stage 2), $72,801 (stage 3), and $167,285 (stage 4). Conclusions: Large-scale claims data supplemented by EMR data can be used to characterize DMD progression and evaluate disease burden which may inform the design of future real-world studies about DMD. [ABSTRACT FROM AUTHOR]

Drug development for rare diseases is challenged by small populations and limited data. This makes development of clinical trial protocols difficult and contributes to the uncertainty around whether or not a potential therapy is efficacious. The use of data standards to aggregate data from multiple sources, and the use of such integrated databases to develop statistical models can inform protocol development and reduce the risks in developing new therapies. Achieving regulatory endorsement of such models through defined pathways at the US Food and Drug Administration and European Medicines Authority allows such tools to be used by the drug development community for defined contexts of use without further need for discussion of the underlying model(s). The Duchenne Regulatory Science Consortium (D-RSC) has brought together multiple stakeholders to develop a clinical trial simulation tool for Duchenne muscular dystrophy using such an approach. Here we describe the work of D-RSC as an example of how such an approach may be effective at reducing uncertainty in drug development for rare diseases, and thus bringing effective therapies to patients faster. [ABSTRACT FROM AUTHOR]

Extensive biomarker discoveries for DMD have occurred in the past 7 years, and a vast array of these biomarkers were confirmed in independent cohorts and across different laboratories. In these previous studies, glucocorticoids and age were two major confounding variables. In this new study, using SomaScan technology and focusing on a subset of young DMD patients who were not yet treated with glucocorticoids, we identified 108 elevated and 70 decreased proteins in DMD relative to age matched healthy controls (p value < 0.05 after adjusting for multiple testing). The majority of the elevated proteins were muscle centric followed by cell adhesion, extracellular matrix proteins and a few pro-inflammatory proteins. The majority of decreased proteins were of cell adhesion, however, some had to do with cell differentiation and growth factors. Subsequent treatment of this group of DMD patients with glucocorticoids affected two major groups of pharmacodynamic biomarkers. The first group consisted of 80 serum proteins that were not associated with DMD and either decreased or increased following treatment with glucocorticoids, and therefore were reflective of a broader effect of glucocorticoids. The second group consisted of 17 serum proteins that were associated with DMD and these tended to normalize under treatment, thus reflecting physiologic effects of glucocorticoid treatment in DMD. In summary, we have identified a variety of circulating protein biomarkers that reflect the complex nature of DMD pathogenesis and response to glucocorticoids. [ABSTRACT FROM AUTHOR]