AAV gene therapy for Duchenne muscular dystrophy: the EMBARK phase 3 randomized trial.

Duchenne muscular dystrophy (DMD) is a rare, X-linked neuromuscular disease caused by pathogenic variants in the DMD gene that result in the absence of functional dystrophin, beginning at birth and leading to progressive impaired motor function, loss of ambulation and life-threatening cardiorespiratory complications. Delandistrogene moxeparvovec, an adeno-associated rh74-viral vector-based gene therapy, addresses absent functional dystrophin in DMD. Here the phase 3 EMBARK study aimed to assess the efficacy and safety of delandistrogene moxeparvovec in patients with DMD. Ambulatory males with DMD, ≥4 years to <8 years of age, were randomized and stratified by age group and North Star Ambulatory Assessment (NSAA) score to single-administration intravenous delandistrogene moxeparvovec (1.33 × 1014 vector genomes per kilogram; n = 63) or placebo (n = 62). At week 52, the primary endpoint, change from baseline in NSAA score, was not met (least squares mean 2.57 (delandistrogene moxeparvovec) versus 1.92 (placebo) points; between-group difference, 0.65; 95% confidence interval (CI), -0.45, 1.74; P = 0.2441). Secondary efficacy endpoints included mean micro-dystrophin expression at week 12: 34.29% (treated) versus 0.00% (placebo). Other secondary efficacy endpoints at week 52 (between-group differences (95% CI)) included: Time to Rise (-0.64 (-1.06, -0.23)), 10-meter Walk/Run (-0.42 (-0.71, -0.13)), stride velocity 95th centile (0.10 (0.00, 0.19)), 100-meter Walk/Run (-3.29 (-8.28, 1.70)), time to ascend 4 steps (-0.36 (-0.71, -0.01)), PROMIS Mobility and Upper Extremity (0.05 (-0.08, 0.19); -0.04 (-0.24, 0.17)) and number of NSAA skills gained/improved (0.19 (-0.67, 1.06)). In total, 674 adverse events were recorded with delandistrogene moxeparvovec and 514 with placebo. There were no deaths, discontinuations or clinically significant complement-mediated adverse events; 7 patients (11.1%) experienced 10 treatment-related serious adverse events. Delandistrogene moxeparvovec did not lead to a significant improvement in NSAA score at week 52. Some of the secondary endpoints numerically favored treatment, although no statistical significance can be claimed. Safety was manageable and consistent with previous delandistrogene moxeparvovec trials. ClinicalTrials.gov: NCT05096221.

Characterization of patients with Duchenne muscular dystrophy across previously developed health states.

Project HERCULES has developed a natural history model (NHM) of disease progression in Duchenne muscular dystrophy (DMD) that comprises eight ordered health states (two ambulatory states, one transfer state indicating increased caregiver burden in which patients cannot walk/run 10m or rise from floor but can still support their own weight, and five non-ambulatory states). The current study used data from nine sources (clinical trial placebo arms, one real-world dataset, and three natural history datasets) to further characterize patients with DMD according to these health states. The study included 1,173 patients across 5,306‬ visits. Patients were on average older and exhibited worse ambulatory, pulmonary, upper limb, and cardiac functions with each successive health state. Mean±SE ages increased monotonically across health states, starting with 8.47±0.07 for early ambulatory, 10.86±0.13 for late ambulatory, 11.65±0.35 for transfer state, and ranging from 13.17±0.32 to 16.84±0.37 for the non-ambulatory states. North Star Ambulatory Assessment (NSAA) total score, which measures motor function and ranges from 34 (best) to 0 (worst), was 23.7 (interquartile range [IQR]: 20-30) for early ambulatory patients, 12.7 (IQR: 9-16) for late ambulatory patients, and 3.9 (IQR: 2-5) for transfer patients. Pulmonary function as measured by mean±SE of forced vital capacity percent predicted (FVC%p) was 94.5±0.8 for early ambulatory, 89.1±1.4 for late ambulatory, and 80.2±2.8 for transfer states, and decreased from 77.2±1.7 to 20.6±1.6 across the five non-ambulatory health states. In summary, these findings further characterize health states and their interpretation in economic modeling and decision-making in DMD management.

Functional trajectories before and after loss of ambulation in Duchenne muscular dystrophy and implications for clinical trials.

This study examined functional trajectories of subjects during the transition phase between ambulatory and non-ambulatory Duchenne muscular dystrophy (DMD) to inform clinical trial designs for new therapeutics. Ambulatory, pulmonary, and upper limb function leading up to loss of ambulation (LoA) and non-ambulatory measures following LoA were quantified; time ordering of pulmonary and upper limb milestones relative to LoA were determined; and the 10-second time threshold for 10-meter walk/run (10MWR) as a marker of approaching LOA was explored. Included in this analysis were 51 subjects aged between 7 and 18 years who experienced LoA during follow-up in the PRO-DMD-01 natural history study. Mean age at LoA was 12.7 (7.1-18.6) years. Mean annual rates of decline in forced vital capacity (FVC) <80%-predicted and performance of upper limb (PUL) 1.2 total score were smaller before than after LoA, but not significantly (FVC %-predicted: 5.6% vs. 10.1%, p = 0.21; PUL 1.2 total score: 2.3 vs. 3.8 units, p = 0.20). More than half of patients experienced clinically significant deficits in FVC %-predicted and PUL 1.2 before experiencing LoA. Among subjects with baseline 10MWR >10 s, those with <1 year to LoA had similar mean ages but significantly worse mean ambulatory function at baseline compared to those with ≥1 year to LoA. Enriching DMD clinical trials for patients with declining pulmonary or upper limb function is achievable without restricting enrollment to non-ambulatory patients. The sequencing of LoA and initial deficits in pulmonary and upper limb function varied across patients and highlights the potential for composite outcomes or multi-outcome trial designs to assess disease-modifying therapies more comprehensively.

Factors Associated With Early Motor Function Trajectories in DMD After Glucocorticoid Initiation: Post Hoc Analysis of the FOR-DMD Trial.

BACKGROUND AND OBJECTIVES: Clinical trials in Duchenne muscular dystrophy (DMD) require 3-6 months of stable glucocorticoids, and the primary outcome is explored at 48-52 weeks. The factors that influence the clinical outcome assessment (COA) trajectories soon after glucocorticoid initiation are relevant for the design and analysis of clinical trials of novel drugs. We describe early COA trajectories, associated factors, and the time from glucocorticoid initiation to COA peak. METHODS: This was a prospective 18-month analysis of the Finding the Optimum Corticosteroid Regimen for Duchenne Muscular Dystrophy study. Four COAs were investigated: rise from supine velocity (RFV), 10-meter walk/run velocity (10MWRV), North Star Ambulatory Assessment (NSAA) total score, and 6-minute walk test distance (6MWT). The relationships of baseline age (4-5 vs 6-7 years), COA baseline performance, genotype, and glucocorticoid regimen (daily vs intermittent) with the COA trajectories were evaluated using linear mixed-effects models. RESULTS: One hundred ninety-six glucocorticoid-naïve boys with DMD aged 4-7 years were enrolled. The mean age at baseline was 5.9 ± 1.0 years, 66% (n = 130) were on daily regimens, 55% (n = 107) showed a 6MWT distance >330 metres; 41% (n = 78) showed RFV >0.2 rise/s; 76% (n = 149) showed 10MWRV >0.142 10m/s, and 41.0% (n = 79) showed NSAA total score >22 points. Mean COA trajectories differed by age at glucocorticoid initiation (p < 0.01 for RFV, 10MWRV, and NSAA; p < 0.05 for 6MWT) and regimen (p < 0.01 for RFV, 10MWRV, and NSAA). Boys younger than 6 years reached their peak performance 12-18 months after glucocorticoid initiation. Boys aged 6 years or older on a daily regimen peaked between months 9 and 12 and those on an intermittent regimen by 9 months. The baseline COA performance was associated with the NSAA (p < 0.01) and the 6MWT trajectory in boys younger than 6 years on a daily regimen (p < 0.01). Differences in the mean trajectories by genotype were not significant. DISCUSSION: Glucocorticoid regimen, age, duration of glucocorticoid exposure, and baseline COA performance need to be considered in the design and analysis of clinical trials in young boys with DMD.

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.

Safety and efficacy of givinostat in boys with Duchenne muscular dystrophy (EPIDYS): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: Duchenne muscular dystrophy, the most common childhood muscular dystrophy, is caused by dystrophin deficiency. Preclinical and phase 2 study data have suggested that givinostat, a histone deacetylase inhibitor, might help to counteract the effects of this deficiency. We aimed to evaluate the safety and efficacy of givinostat in the treatment of Duchenne muscular dystrophy. METHODS: This multicentre, randomised, double-blind, placebo-controlled, phase 3 trial was done at 41 tertiary care sites in 11 countries. Eligible participants were ambulant, male, and aged at least 6 years, had a genetically confirmed diagnosis of Duchenne muscular dystrophy, completed two four-stair climb assessments with a mean of 8 s or less (≤1 s variance), had a time-to-rise of at least 3 s but less than 10 s, and had received systemic corticosteroids for at least 6 months. Participating boys were randomly assigned (2:1, allocated according to a list generated by the interactive response technology provider) to receive either oral givinostat or matching placebo twice a day for 72 weeks, stratified by concomitant steroid use. Boys, investigators, and site and sponsor staff were masked to treatment assignment. The dose was flexible, based on weight, and was reduced if not tolerated. Boys were divided into two groups on the basis of their baseline vastus lateralis fat fraction (VLFF; measured by magnetic resonance spectroscopy): group A comprised boys with a VLFF of more than 5% but no more than 30%, whereas group B comprised boys with a VLFF of 5% or less, or more than 30%. The primary endpoint compared the effects of givinostat and placebo on the change in results of the four-stair climb assessment between baseline and 72 weeks, in the intention-to-treat, group A population. Safety was assessed in all randomly assigned boys who received at least one dose of study drug. When the first 50 boys in group A completed 12 months of treatment, an interim futility assessment was conducted, after which the sample size was adapted using masked data from the four-stair climb assessments. Furthermore, the starting dose of givinostat was reduced following a protocol amendment. This trial is registered with ClinicalTrials.gov, NCT02851797, and is complete. FINDINGS: Between June 6, 2017, and Feb 22, 2022, 359 boys were assessed for eligibility. Of these, 179 were enrolled into the study (median age 9·8 years [IQR 8·1-11·0]), all of whom were randomly assigned (118 to receive givinostat and 61 to receive placebo); 170 (95%) boys completed the study. Of the 179 boys enrolled, 120 (67%) were in group A (81 givinostat and 39 placebo); of these, 114 (95%) completed the study. For participants in group A, comparing the results of the four-stair climb assessment at 72 weeks and baseline, the geometric least squares mean ratio was 1·27 (95% CI 1·17-1·37) for boys receiving givinostat and 1·48 (1·32-1·66) for those receiving placebo (ratio 0·86, 95% CI 0·745-0·989; p=0·035). The most common adverse events in the givinostat group were diarrhoea (43 [36%] of 118 boys vs 11 [18%] of 61 receiving placebo) and vomiting (34 [29%] vs 8 [13%]); no treatment-related deaths occurred. INTERPRETATION: Among ambulant boys with Duchenne muscular dystrophy, results of the four-stair climb assessment worsened in both groups over the study period; however, the decline was significantly smaller with givinostat than with placebo. The dose of givinostat was reduced after an interim safety analysis, but no new safety signals were reported. An ongoing extension study is evaluating the long-term safety and efficacy of givinostat in patients with Duchenne muscular dystrophy. FUNDING: Italfarmaco.

Practical Considerations for Delandistrogene Moxeparvovec Gene Therapy in Patients With Duchenne Muscular Dystrophy.

BACKGROUND: Delandistrogene moxeparvovec is a gene transfer therapy approved in the United States, United Arab Emirates, and Qatar for the treatment of ambulatory patients aged four through five years with a confirmed Duchenne muscular dystrophy (DMD)-causing mutation in the DMD gene. This therapy was developed to address the underlying cause of DMD through targeted skeletal, respiratory, and cardiac muscle expression of delandistrogene moxeparvovec micro-dystrophin, an engineered, functional dystrophin protein. METHODS: Drawing on clinical trial experience from Study 101 (NCT03375164), Study 102 (NCT03769116), and ENDEAVOR (Study 103; NCT04626674), we outline practical considerations for delandistrogene moxeparvovec treatment. RESULTS: Before infusion, the following are recommended: (1) screen for anti-adeno-associated virus rhesus isolate serotype 74 total binding antibody titers <1:400; (2) assess liver function, platelet count, and troponin-I; (3) ensure patients are up to date with vaccinations and avoid vaccine coadministration with infusion; (4) administer additional corticosteroids starting one day preinfusion (for patients already on corticosteroids); and (5) postpone dosing patients with any infection or acute liver disease until event resolution. Postinfusion, the following are recommended: (1) monitor liver function weekly (three months postinfusion) and, if indicated, continue until results are unremarkable; (2) monitor troponin-I levels weekly (first month postinfusion, continuing if indicated); (3) obtain platelet counts weekly (two weeks postinfusion), continuing if indicated; and (4) maintain the corticosteroid regimen for at least 60 days postinfusion, unless earlier tapering is indicated. CONCLUSIONS: Although the clinical safety profile of delandistrogene moxeparvovec has been consistent, monitorable, and manageable, these practical considerations may mitigate potential risks in a real-world clinical practice setting.

Efficacy and Safety of Vamorolone Over 48 Weeks in Boys With Duchenne Muscular Dystrophy: A Randomized Controlled Trial.

BACKGROUND AND OBJECTIVES: Vamorolone is a dissociative agonist of the glucocorticoid receptor that has shown similar efficacy and reduced safety concerns in comparison with prednisone in Duchenne muscular dystrophy (DMD). This study was conducted to determine the efficacy and safety of vamorolone over 48 weeks and to study crossover participants (prednisone to vamorolone; placebo to vamorolone). METHODS: A randomized, double-blind, placebo-controlled and prednisone-controlled clinical trial of 2 doses of vamorolone was conducted in participants with DMD, in the ages from 4 years to younger than 7 years at baseline. The interventions were 2 mg/kg/d of vamorolone and 6 mg/kg/d of vamorolone for 48 weeks (period 1: 24 weeks + period 2: 24 weeks) and 0.75 mg/kg/d of prednisone and placebo for the first 24 weeks (before crossover). Efficacy was evaluated through gross motor outcomes and safety through adverse events, growth velocity, body mass index (BMI), and bone turnover biomarkers. This analysis focused on period 2. RESULTS: A total of 121 participants with DMD were randomized. Vamorolone at a dose of 6 mg/kg/d showed maintenance of improvement for all motor outcomes to week 48 (e.g., for primary outcome, time to stand from supine [TTSTAND] velocity, week 24 least squares mean [LSM] [SE] 0.052 [0.0130] rises/s vs week 48 LSM [SE] 0.0446 [0.0138]). After 48 weeks, vamorolone at a dose of 2 mg/kg/d showed similar improvements as 6 mg/kg/d for North Star Ambulatory Assessment (NSAA) (vamorolone 6 mg/kg/d-vamorolone 2 mg/kg/d LSM [SE] 0.49 [1.14]; 95% CI -1.80 to 2.78, p = 0.67), but less improvement for other motor outcomes. The placebo to vamorolone 6 mg/kg/d group showed rapid improvements after 20 weeks of treatment approaching benefit seen with 48-week 6 mg/kg/d of vamorolone treatment for TTSTAND, time to run/walk 10 m, and NSAA. There was significant improvement in linear growth after crossover in the prednisone to vamorolone 6 mg/kg/d group, and rapid reversal of prednisone-induced decline in bone turnover biomarkers in both crossover groups. There was an increase in BMI after 24 weeks of treatment that then stabilized for both vamorolone groups. DISCUSSION: Improvements of motor outcomes seen with 6 mg/kg/d of vamorolone at 24 weeks of treatment were maintained to 48 weeks of treatment. Vamorolone at a dose of 6 mg/kg/d showed better maintenance of effect compared with vamorolone at a dose of 2 mg/kg/d for most (3/5) motor outcomes. Bone morbidities of prednisone (stunting of growth and declines in serum bone biomarkers) were reversed when treatment transitioned to vamorolone. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov Identifier: NCT03439670. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that for boys with DMD, the efficacy of vamorolone at a dose of 6 mg/kg/d was maintained over 48 weeks.

Gait Characterization in Duchenne Muscular Dystrophy (DMD) Using a Single-Sensor Accelerometer: Classical Machine Learning and Deep Learning Approaches.

Differences in gait patterns of children with Duchenne muscular dystrophy (DMD) and typically developing (TD) peers are visible to the eye, but quantifications of those differences outside of the gait laboratory have been elusive. In this work, we measured vertical, mediolateral, and anteroposterior acceleration using a waist-worn iPhone accelerometer during ambulation across a typical range of velocities. Fifteen TD and fifteen DMD children from 3 to 16 years of age underwent eight walking/running activities, including five 25 m walk/run speed-calibration tests at a slow walk to running speeds (SC-L1 to SC-L5), a 6-min walk test (6MWT), a 100 m fast walk/jog/run (100MRW), and a free walk (FW). For clinical anchoring purposes, participants completed a Northstar Ambulatory Assessment (NSAA). We extracted temporospatial gait clinical features (CFs) and applied multiple machine learning (ML) approaches to differentiate between DMD and TD children using extracted temporospatial gait CFs and raw data. Extracted temporospatial gait CFs showed reduced step length and a greater mediolateral component of total power (TP) consistent with shorter strides and Trendelenberg-like gait commonly observed in DMD. ML approaches using temporospatial gait CFs and raw data varied in effectiveness at differentiating between DMD and TD controls at different speeds, with an accuracy of up to 100%. We demonstrate that by using ML with accelerometer data from a consumer-grade smartphone, we can capture DMD-associated gait characteristics in toddlers to teens.

Gait Event Detection and Travel Distance Using Waist-Worn Accelerometers across a Range of Speeds: Automated Approach.

Estimation of temporospatial clinical features of gait (CFs), such as step count and length, step duration, step frequency, gait speed, and distance traveled, is an important component of community-based mobility evaluation using wearable accelerometers. However, accurate unsupervised computerized measurement of CFs of individuals with Duchenne muscular dystrophy (DMD) who have progressive loss of ambulatory mobility is difficult due to differences in patterns and magnitudes of acceleration across their range of attainable gait velocities. This paper proposes a novel calibration method. It aims to detect steps, estimate stride lengths, and determine travel distance. The approach involves a combination of clinical observation, machine-learning-based step detection, and regression-based stride length prediction. The method demonstrates high accuracy in children with DMD and typically developing controls (TDs) regardless of the participant's level of ability. Fifteen children with DMD and fifteen TDs underwent supervised clinical testing across a range of gait speeds using 10 m or 25 m run/walk (10 MRW, 25 MRW), 100 m run/walk (100 MRW), 6-min walk (6 MWT), and free-walk (FW) evaluations while wearing a mobile-phone-based accelerometer at the waist near the body's center of mass. Following calibration by a trained clinical evaluator, CFs were extracted from the accelerometer data using a multi-step machine-learning-based process and the results were compared to ground-truth observation data. Model predictions vs. observed values for step counts, distance traveled, and step length showed a strong correlation (Pearson's r = -0.9929 to 0.9986, p < 0.0001). The estimates demonstrated a mean (SD) percentage error of 1.49% (7.04%) for step counts, 1.18% (9.91%) for distance traveled, and 0.37% (7.52%) for step length compared to ground-truth observations for the combined 6 MWT, 100 MRW, and FW tasks. Our study findings indicate that a single waist-worn accelerometer calibrated to an individual's stride characteristics using our methods accurately measures CFs and estimates travel distances across a common range of gait speeds in both DMD and TD peers.

The IAAM LTBP4 Haplotype is Protective Against Dystrophin-Deficient Cardiomyopathy.

Background: Dilated cardiomyopathy (DCM) is a major complication of, and leading cause of mortality in Duchenne muscular dystrophy (DMD). Its severity, age at onset, and rate of progression display wide variability, whose molecular bases have been scarcely elucidated. Potential DCM-modifying factors include glucocorticoid (GC) and cardiological treatments, DMD mutation type and location, and variants in other genes. Methods and Results: We retrospectively collected 3138 echocardiographic measurements of left ventricular ejection fraction (EF), shortening fraction (SF), and end-diastolic volume (EDV) from 819 DMD participants, 541 from an Italian multicentric cohort and 278 from the Cooperative International Neuromuscular Group Duchenne Natural History Study (CINRG-DNHS). Using generalized estimating equation (GEE) models, we estimated the yearly rate of decrease of EF (-0.80%) and SF (-0.41%), while EDV increase was not significantly associated with age. Utilizing a multivariate generalized estimating equation (GEE) model we observed that mutations preserving the expression of the C-terminal Dp71 isoform of dystrophin were correlated with decreased EDV (-11.01 mL/m2, p = 0.03) while for dp116 were correlated with decreased EF (-4.14%, p = <0.001). The rs10880 genotype in the LTBP4 gene, previously shown to prolong ambulation, was also associated with increased EF and decreased EDV (+3.29%, p = 0.002, and -10.62 mL/m2, p = 0.008) with a recessive model. Conclusions: We quantitatively describe the progression of systolic dysfunction progression in DMD, confirm the effect of distal dystrophin isoform expression on the dystrophin-deficient heart, and identify a strong effect of LTBP4 genotype of DCM in DMD.

Findings from the Longitudinal CINRG Becker Natural History Study.

BACKGROUND: Becker muscular dystrophy is an X-linked, genetic disorder causing progressive degeneration of skeletal and cardiac muscle, with a widely variable phenotype. OBJECTIVE: A 3-year, longitudinal, prospective dataset contributed by patients with confirmed Becker muscular dystrophy was analyzed to characterize the natural history of this disorder. A better understanding of the natural history is crucial to rigorous therapeutic trials. METHODS: A cohort of 83 patients with Becker muscular dystrophy (5-75 years at baseline) were followed for up to 3 years with annual assessments. Muscle and pulmonary function outcomes were analyzed herein. Age-stratified statistical analysis and modeling were conducted to analyze cross-sectional data, time-to-event data, and longitudinal data to characterize these clinical outcomes. RESULTS: Deletion mutations of dystrophin exons 45-47 or 45-48 were most common. Subgroup analysis showed greater pairwise association between motor outcomes at baseline than association between these outcomes and age. Stronger correlations between outcomes for adults than for those under 18 years were also observed. Using cross-sectional binning analysis, a ceiling effect was seen for North Star Ambulatory Assessment but not for other functional outcomes. Longitudinal analysis showed a decline in percentage predicted forced vital capacity over the life span. There was relative stability or improved median function for motor functional outcomes through childhood and adolescence and decreasing function with age thereafter. CONCLUSIONS: There is variable progression of outcomes resulting in significant heterogeneity of the clinical phenotype of Becker muscular dystrophy. Disease progression is largely manifest in adulthood. There are implications for clinical trial design revealed by this longitudinal analysis of a Becker natural history dataset.

Sleep Disordered Breathing in Children with Neuromuscular Disease.

Sleep disordered breathing (SDB) in children with neuromuscular disease (NMD) is more prevalent compared to the general population, and often manifests as sleep-related hypoventilation, sleep-related hypoxemia, obstructive sleep apnea, central sleep apnea, and/or disordered control of breathing. Other sleep problems include, sleep fragmentation, abnormal sleep architecture, and nocturnal seizures in certain neuromuscular diseases. The manifestation of sleep disordered breathing in children depends on the extent, type, and progression of neuromuscular weakness, and in some instances, may be the first sign of a neuromuscular weakness leading to diagnosis of an NMD. In-lab diagnostic polysomnography (PSG) remains the gold standard for the diagnosis of sleep disordered breathing in children, but poses several challenges, including access to many children with neuromuscular disease who are non-ambulatory. If SDB is untreated, it can result in significant morbidity and mortality. Hence, we aimed to perform a comprehensive review of the literature of SDB in children with NMD. This review includes pathophysiological changes during sleep, clinical evaluation, diagnosis, challenges in interpreting PSG data using American Academy of Sleep (AASM) diagnostic criteria, management of SDB, and suggests areas for future research.

Delandistrogene Moxeparvovec Gene Therapy in Ambulatory Patients (Aged ≥4 to <8 Years) with Duchenne Muscular Dystrophy: 1-Year Interim Results from Study SRP-9001-103 (ENDEAVOR).

OBJECTIVE: Delandistrogene moxeparvovec is approved in the USA for the treatment of ambulatory patients (4-5 years) with Duchenne muscular dystrophy. ENDEAVOR (SRP-9001-103; NCT04626674) is a single-arm, open-label study to evaluate delandistrogene moxeparvovec micro-dystrophin expression, safety, and functional outcomes following administration of commercial process delandistrogene moxeparvovec. METHODS: In cohort 1 of ENDEAVOR (N = 20), eligible ambulatory males, aged ≥4 to <8 years, received a single intravenous infusion of delandistrogene moxeparvovec (1.33 × 1014 vg/kg). The primary endpoint was change from baseline (CFBL) to week 12 in delandistrogene moxeparvovec micro-dystrophin by western blot. Additional endpoints evaluated included: safety; vector genome copies; CFBL to week 12 in muscle fiber-localized micro-dystrophin by immunofluorescence; and functional assessments, including North Star Ambulatory Assessment, with comparison with a propensity score-weighted external natural history control. RESULTS: The 1-year safety profile of commercial process delandistrogene moxeparvovec in ENDEAVOR was consistent with safety data reported in other delandistrogene moxeparvovec trials (NCT03375164 and NCT03769116). Delandistrogene moxeparvovec micro-dystrophin expression was robust, with sarcolemmal localization at week 12; mean (SD) CFBL in western blot, 54.2% (42.6); p < 0.0001. At 1 year, patients demonstrated stabilized or improved North Star Ambulatory Assessment total scores; mean (SD) CFBL, +4.0 (3.5). Treatment versus a propensity score-weighted external natural history control demonstrated a statistically significant difference in least squares mean (standard error) CFBL in North Star Ambulatory Assessment, +3.2 (0.6) points; p < 0.0001. INTERPRETATION: Results confirm efficient transduction of muscle by delandistrogene moxeparvovec. One-year post-treatment, delandistrogene moxeparvovec was well tolerated, and demonstrated stabilized or improved motor function, suggesting a clinical benefit for patients with Duchenne muscular dystrophy. ANN NEUROL 2023;94:955-968.

Expression of SRP-9001 dystrophin and stabilization of motor function up to 2 years post-treatment with delandistrogene moxeparvovec gene therapy in individuals with Duchenne muscular dystrophy.

Introduction: Delandistrogene moxeparvovec (SRP-9001) is an investigational gene transfer therapy designed for targeted expression of SRP-9001 dystrophin protein, a shortened dystrophin retaining key functional domains of the wild-type protein. Methods: This Phase 2, double-blind, two-part (48 weeks per part) crossover study (SRP-9001-102 [Study 102]; NCT03769116) evaluated delandistrogene moxeparvovec in patients, aged ≥4 to <8 years with Duchenne muscular dystrophy. Primary endpoints (Part 1) were change from baseline (CFBL) in SRP-9001 dystrophin expression (Week 12), by Western blot, and in North Star Ambulatory Assessment (NSAA) score (Week 48). Safety assessments included treatment-related adverse events (TRAEs). Patients were randomized and stratified by age to placebo (n = 21) or delandistrogene moxeparvovec (n = 20) and crossed over for Part 2. Results: SRP-9001 dystrophin expression was achieved in all patients: mean CFBL to Week 12 was 23.82% and 39.64% normal in Parts 1 and 2, respectively. In Part 1, CFBL to Week 48 in NSAA score (least-squares mean, LSM [standard error]) was +1.7 (0.6) with treatment versus +0.9 (0.6) for placebo; p = 0.37. Disparity in baseline motor function between groups likely confounded these results. In 4- to 5-year-olds with matched baseline motor function, CFBL to Week 48 in NSAA scores was significantly different (+2.5 points; p = 0.0172), but not significantly different in 6-to-7-year-olds with imbalanced baseline motor function (-0.7 points; p = 0.5384). For patients treated with delandistrogene moxeparvovec in Part 2, CFBL to Week 48 in NSAA score was +1.3 (2.7), whereas for those treated in Part 1, NSAA scores were maintained. As all patients in Part 2 were exposed to treatment, results were compared with a propensity-score-weighted external control (EC) cohort. The LSM difference in NSAA score between the Part 2 treated group and EC cohort was statistically significant (+2.0 points; p = 0.0009). The most common TRAEs were vomiting, decreased appetite, and nausea. Most occurred within the first 90 days and all resolved. Discussion: Results indicate robust expression of SRP-9001 dystrophin and overall stabilization in NSAA up to 2 years post-treatment. Differences in NSAA between groups in Part 1 were not significant for the overall population, likely because cohorts were stratified only by age, and other critical prognostic factors were not well matched at baseline.

Assessing the value of delandistrogene moxeparvovec (SRP-9001) gene therapy in patients with Duchenne muscular dystrophy in the United States.

Background: Delandistrogene moxeparvovec (SRP-9001) is an investigational gene therapy that may delay progression of Duchenne muscular dystrophy (DMD), a severe, rare neuromuscular disease caused by DMD gene mutations. Early cost-effectiveness analyses are important to help contextualize the value of gene therapies for reimbursement decision making. Objective: To determine the potential value of delandistrogene moxeparvovec using a cost-effectiveness analysis. Study design: A simulation calculated lifetime costs and equal value of life years gained (evLYG). Inputs included extrapolated clinical trial results and published utilities/costs. As a market price for delandistrogene moxeparvovec has not been established, threshold analyses established maximum treatment costs as they align with value, including varying willingness-to-pay up to $500,000, accounting for severity/rarity. Setting: USA, healthcare system perspective Patients: Boys with DMD Intervention: Delandistrogene moxeparvovec plus standard of care (SoC; corticosteroids) versus SoC alone Main outcome measure: Maximum treatment costs at a given willingness-to-pay threshold Results: Delandistrogene moxeparvovec added 10.30 discounted (26.40 undiscounted) evLYs. The maximum treatment cost was approximately $5 M, assuming $500,000/evLYG. Varying the benefit discount rate to account for the single administration increased the estimated value to #$5M, assuming $500,000/evLYG. Conclusion: In this early economic model, delandistrogene moxeparvovec increases evLYs versus SoC and begins to inform its potential value from a healthcare perspective.

Efficacy and Safety of Viltolarsen in Boys With Duchenne Muscular Dystrophy: Results From the Phase 2, Open-Label, 4-Year Extension Study.

BACKGROUND: Duchenne muscular dystrophy (DMD) is caused by DMD gene mutations, resulting in absence of functional dystrophin protein. Viltolarsen, an exon 53 skipping therapy, significantly increased dystrophin levels in patients with DMD. Presented here are completed study results of > 4 years of functional outcomes in viltolarsen-treated patients compared to a historical control group (Cooperative International Neuromuscular Research Group Duchenne Natural History Study [CINRG DNHS]). OBJECTIVE: To evaluate the efficacy and safety of viltolarsen for an additional 192 weeks in boys with DMD. METHODS: This phase 2, open-label, 192-week long-term extension (LTE) study (NCT03167255) evaluated the efficacy and safety of viltolarsen in participants aged 4 to < 10 years at baseline with DMD amenable to exon 53 skipping. All 16 participants from the initial 24-week study enrolled into this LTE. Timed function tests were compared to the CINRG DNHS group. All participants received glucocorticoid treatment. The primary efficacy outcome was time to stand from supine (TTSTAND). Secondary efficacy outcomes included additional timed function tests. Safety was continuously assessed. RESULTS: For the primary efficacy outcome (TTSTAND), viltolarsen-treated patients showed stabilization of motor function over the first two years and significant slowing of disease progression over the following two years compared with the CINRG DNHS control group which declined. Viltolarsen was well tolerated, with most reported treatment-emergent adverse events being mild or moderate. No participants discontinued drug during the study. CONCLUSIONS: Based on the results of this 4-year LTE, viltolarsen can be an important treatment strategy for DMD patients amenable to exon 53 skipping.

Safety and effectiveness of ataluren in patients with nonsense mutation DMD in the STRIDE Registry compared with the CINRG Duchenne Natural History Study (2015-2022): 2022 interim analysis.

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.

Disease progression rates in ambulatory Duchenne muscular dystrophy by steroid type, patient age and functional status.

Aim: To examine benefits of corticosteroids for Duchenne muscular dystrophy (DMD) by age and disease progression. Methods: Data from daily steroid users (placebo-treated) were pooled from four phase 2b/3 trials in DMD. Outcomes assessed overall and among subgroups included changes from baseline to 48 weeks in six-minute walk distance (6MWD), timed function tests and North Star Ambulatory Assessment total score. Results: Among 231 patients receiving deflazacort (n = 127) or prednisone (n = 104), observed differences in 6MWD favoring deflazacort over prednisone were significant for patients with relatively older age (≥8-years-old), greater disease progression (baseline timed stand from supine ≥5 s), or longer corticosteroid use (>3 years). Conclusion: Daily deflazacort had greater benefits than daily prednisone particularly among older/more progressed patients.