Eteplirsen Treatment for Duchenne Muscular Dystrophy: A Qualitative Patient Experience Study.

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.

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.

Survival among patients receiving eteplirsen for up to 8 years for the treatment of Duchenne muscular dystrophy and contextualization with natural history controls.

INTRODUCTION/AIMS: Eteplirsen, approved in the US for patients with Duchenne muscular dystrophy (DMD) with exon 51 skip-amenable variants, is associated with attenuated ambulatory/pulmonary decline versus DMD natural history (NH). We report overall survival in a US cohort receiving eteplirsen and contextualize these outcomes versus DMD NH. METHODS: US patients with DMD receiving eteplirsen were followed through a patient support program, with data collected on ages at eteplirsen initiation and death/end of follow-up. Individual DMD NH data were extracted by digitizing Kaplan-Meier (KM) curves from published systematic and targeted literature reviews. Overall survival age was analyzed using KM curves and contextualized with DMD NH survival curves; subanalyses considered age groups and duration of eteplirsen exposure. Overall survival time from treatment initiation was also evaluated. RESULTS: A total of 579 eteplirsen-treated patients were included. During a total follow-up of 2119 person-years, median survival age was 32.8 years. DMD NH survival curves extracted from four publications (follow-up for 1224 DMD NH controls) showed overall pooled median survival age of 27.4 years. Eteplirsen-treated patients had significantly longer survival from treatment initiation versus age-matched controls (age-adjusted hazard ratio [HR], 0.65; 95% confidence interval [CI], 0.44-0.98; p < .05). Longer treatment exposure was associated with improved survival (HR, 0.15; 95% CI, 0.05-0.41; p < .001). Comparisons using different DMD NH cohorts to address common risks of bias yielded consistent findings. DISCUSSION: Data suggest eteplirsen may prolong survival in patients with DMD across a wide age range. As more data become available, the impact of eteplirsen on survival will be further elucidated.

Real-world evidence of eteplirsen treatment effects in patients with Duchenne muscular dystrophy in the USA.

Aim: To evaluate treatment effects of eteplirsen among patients with Duchenne muscular dystrophy. Methods: Using real-world claims and electronic medical record data, this retrospective comparative analysis assessed eteplirsen-treated and control cohorts matched by age, disease progression state, and pre-index period healthcare resource utilization. Poisson regression was used to evaluate eteplirsen effects on healthcare resource utilization outcomes. Results: Eteplirsen was associated with statistically significant reductions in rates of hospital encounters (31%), emergency room visits (31%), need for pulmonary management (33%), cardiac management (21%), tracheostomy (86%), and assisted ventilation (39%) versus the control group. Other assessed outcomes favored eteplirsen numerically but did not all reach statistical significance. Conclusion: Eteplirsen-treated patients had reduced rates of multiple healthcare resource utilization measures versus matched controls.

Delays in pulmonary decline in eteplirsen-treated patients with Duchenne muscular dystrophy.

INTRODUCTION/AIMS: Pulmonary decline is a major issue in patients with Duchenne muscular dystrophy (DMD). Eteplirsen is a United States-approved treatment for patients with DMD and exon 51 skip-amenable mutations. Previous analyses have shown that eteplirsen is associated with a statistically significant attenuation of pulmonary decline. In this study we evaluate the effect of eteplirsen treatment from newly available data sources on pulmonary function over time in patients with DMD. METHODS: We used a post hoc pooled analysis to compare the percentage of predicted forced vital capacity (FVC%p) and projected time with pulmonary function milestones in patients with DMD and exon 51 skip-amenable mutations receiving eteplirsen (Studies 204 and 301) or standard of care (SoC; Cooperative International Neuromuscular Research Group Duchenne Natural History Study). A mixed model for repeated-measures framework was applied to evaluate the impact of eteplirsen. RESULTS: An average annual rate of FVC%p decline for eteplirsen-treated patients was estimated to be 3.47%, a statistically significant attenuation from the 5.95% rate of decline estimated in SoC patients (P = .0001). Using linear extrapolations of the model-estimated decline in FVC%p, the attenuation in FVC%p decline for eteplirsen-treated patients corresponded to a delay of 5.72 years in time to needing continuous ventilation, 3.31 years in time to needing nighttime ventilation, and 2.11 years in time to needing a cough assist device compared with SoC patients. DISCUSSION: The attenuation of FVC%p decline suggests that eteplirsen-treated patients had statistically significant and clinically meaningful attenuations in pulmonary decline compared with SoC patients.

Disease Progression Stages and Burden in Patients with Duchenne Muscular Dystrophy Using Administrative Claims Supplemented by Electronic Medical Records.

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.

Rasch Analysis of the Pediatric Quality of Life Inventory 4.0 Generic Core Scales Administered to Patients With Duchenne Muscular Dystrophy.

OBJECTIVES: The objective of this study was to examine the psychometric properties of the Pediatric Quality of Life Inventory 4.0 Generic Core Scales (PedsQL 4.0 GCS) in Duchenne muscular dystrophy (DMD), a rare, severely debilitating, and ultimately fatal neuromuscular disease. METHODS: Patients with DMD were recruited from 20 centers across 9 countries as part of the Cooperative International Neuromuscular Research Group Duchenne Natural History Study (NCT00468832). The psychometric properties of the PedsQL 4.0 GCS were examined using Rasch analysis. RESULTS: In total, 329 patients with DMD (mean age 9 years, range 3-18 years, 75% ambulatory) completed the PedsQL 4.0 GCS. The most difficult instrument items, expressing the greatest loss in health-related quality of life, were those associated with emotional well-being (eg, being teased by other children, feeling sad, and not making friends), as opposed to somatic disability (eg, lifting heavy objects, participating in sports, and running). The mean item and person fit residuals were estimated at 0.301 (SD: 1.385) and -0.255 (1.504), respectively. In total, 87% (20 of 23) of items displayed disordered thresholds, and many exhibited nontrivial dependency. The overall item-trait interaction χ2 value was 178 (115 degrees of freedom, P<.001). Our analysis also revealed significant issues with differential item functioning, and by investigating residual principal component loadings, the PedsQL 4.0 GCS total score was found to be multidimensional. CONCLUSIONS: The PedsQL 4.0 GCS records information clinically relevant to patients with DMD, but the total scale score may not be fit for purpose as a measure health-related quality of life in this disease population.

Systematic review and meta-analysis of the additional benefit of local prophylactic antibiotic therapy for infection rates in open tibia fractures treated with intramedullary nailing.

PURPOSE: This analysis compared the rate of deep wound infections in patients with open tibia fractures, treated with intramedullary nails, receiving additional locally-delivered antibiotics to those receiving standard care. METHODS: Two systematic literature searches identified studies reporting infection rates in patients treated with intramedullary nails for tibia fractures receiving systemic antibiotics only (search one) and in patients receiving adjunctive locally-administered antibiotics peri-operatively at the tissue-implant interface (search two). After applying inclusion and exclusion criteria, 14 and seven papers from searches one and two, respectively, were included in meta-analyses. RESULTS: The absolute rate of infection was lower for all Gustilo-Anderson grades of tibia fractures when local antibiotics were administered as adjunctive prophylactic therapy. For severe fractures, classified as GAIII fractures, patients receiving systemic antibiotics only had an infection rate of 14.4 % [95 % CI: 10.5 %, 18.5 %]; adding local antibiotics reduced the rate to 2.4 % [0.0 %, 9.4 %], with an odds ratio of 0.17. Risk of deep wound infections increased with severity of fracture, rising to over 31 % in GIIIB&C fractures for patients receiving systematic antibiotics only, but to below 9 % with additional local antibiotics. CONCLUSION: The findings support consideration of augmenting the antibiotic prophylaxis regimen to include locally-delivered antibiotics. Patients with severe fractures will obtain greatest benefit from infections avoided. No trial directly compared the two treatments for open tibia fractures, limiting the ability to attribute the differences in observed infection rates directly to the treatments themselves. A large comparative study to improve the evidence on relative effect size is merited. LEVEL OF EVIDENCE: Level III.

Differential proteomic analysis of STAT6 knockout mice reveals new regulatory function in liver lipid homeostasis.

Increased inflammatory signaling is a key feature of metabolic disorders. In this context, the role of increased pro-inflammatory signals has been extensively studied. By contrast, no efforts have been dedicated to study the contrasting scenario: the attenuation of anti-inflammatory signals and their role in metabolic homeostasis. IL-4 and IL-13 are anti-inflammatory cytokines signaling through the Signal Transducer and Activator of Transcription 6 (STAT6). Our study was aimed at evaluating the lack of STAT6 signaling on liver homeostasis. To this end we analyzed the liver proteome of wild type and STAT6 knock-out mice using 2D nanoscale LC-MS/MS with iTRAQ labeling technique. The coordinated changes in proteins identified by this quantitative proteome analysis indicated disturbed lipid homeostasis and a state of hepatocellular stress. Most significantly, the expression of the liver fatty acid binding protein (FABP1) was increased in the knock-out mice. In line with the elevated FABP1 expression we found latent liver lipid accumulation in the STAT6-deficient mice which was further aggravated when mice were challenged by a high fat diet. In conclusion, our study revealed a so far uncharacterized role for STAT6 in regulating liver lipid homeostasis and demonstrates the importance of anti-inflammatory signaling in the defense against the development of liver steatosis.