Long-term safety and functional outcomes of delandistrogene moxeparvovec gene therapy in patients with Duchenne muscular dystrophy: A phase 1/2a nonrandomized trial.

INTRODUCTION/AIMS: Delandistrogene moxeparvovec is indicated in the United States for the treatment of ambulatory pediatric patients aged 4 through 5 years with Duchenne muscular dystrophy (DMD) with a confirmed mutation in the DMD gene. Long-term delandistrogene moxeparvovec microdystrophin protein (a shortened dystrophin that retains key functional domains of the wild-type protein) expression may positively alter disease progression in patients with DMD. We evaluated long-term safety and functional outcomes of delandistrogene moxeparvovec in patients with DMD. METHODS: An open-label, phase 1/2a, nonrandomized controlled trial (Study 101; NCT03375164) enrolled ambulatory males, ≥4 to <8 years old, with DMD. Patients received a single intravenous infusion (2.0 × 1014 vg/kg by supercoiled quantitative polymerase chain reaction) of delandistrogene moxeparvovec and prednisone (1 mg/kg/day) 1 day before to 30 days after treatment. The primary endpoint was safety. Functional outcomes were change from baseline in North Star Ambulatory Assessment (NSAA) and timed function tests. RESULTS: Four patients (mean age, 5.1 years) were enrolled. There were 18 treatment-related adverse events; all occurred within 70 days posttreatment and resolved. Mean NSAA total score increased from 20.5 to 27.5, baseline to year 4, with a mean (standard deviation) change of +7.0 (2.9). Post hoc analysis demonstrated a statistically significant and clinically meaningful 9-point difference in NSAA score, relative to a propensity-score-weighted external control cohort (least-squares mean [standard error] = 9.4 [3.4]; P = .0125). DISCUSSION: Gene transfer therapy with delandistrogene moxeparvovec treatment is well tolerated, with a favorable safety profile. Functional improvements are sustained through 4 years, suggesting delandistrogene moxeparvovec may positively alter disease progression.

Assessing Dysferlinopathy Patients Over Three Years With a New Motor Scale.

OBJECTIVE: Dysferlinopathy is a muscular dystrophy with a highly variable clinical presentation and currently unpredictable progression. This variability and unpredictability presents difficulties for prognostication and clinical trial design. The Jain Clinical Outcomes Study of Dysferlinopathy aims to establish the validity of the North Star Assessment for Limb Girdle Type Muscular Dystrophies (NSAD) scale and identify factors that influence the rate of disease progression using NSAD. METHODS: We collected a longitudinal series of functional assessments from 187 patients with dysferlinopathy over 3 years. Rasch analysis was used to develop the NSAD, a motor performance scale suitable for ambulant and nonambulant patients. Generalized estimating equations were used to evaluate the impact of patient factors on outcome trajectories. RESULTS: The NSAD detected significant change in clinical progression over 1 year. The steepest functional decline occurred during the first 10 years after symptom onset, with more rapid decline noted in patients who developed symptoms at a younger age (p = 0.04). The most rapidly deteriorating group over the study was patients 3 to 8 years post symptom onset at baseline. INTERPRETATION: The NSAD is the first validated limb girdle specific scale of motor performance, suitable for use in clinical practice and clinical trials. Longitudinal analysis showed it may be possible to identify patient factors associated with greater functional decline both across the disease course and in the short-term for clinical trial preparation. Through further work and validation in this cohort, we anticipate that a disease model incorporating functional performance will allow for more accurate prognosis for patients with dysferlinopathy. ANN NEUROL 2021;89:967-978.

Comparison of strength testing modalities in dysferlinopathy.

INTRODUCTION/AIMS: Dysferlinopathy demonstrates heterogeneity in muscle weakness between patients, which can progress at different rates over time. Changing muscle strength due to disease progression or from an investigational product is associated with changing functional ability. The purpose of this study was to compare three methods of strength testing used in the Clinical Outcome Study (COS) for dysferlinopathy to understand which method and which muscle groups were most sensitive to change over time. METHODS: Patients were evaluated at each study visit using functional scales, manual muscle testing, and handheld dynamometry (HHD) at all 15 sites. A fixed-frame system (Fixed) was used at a subset of seven sites. Screening and baseline visits were evaluated for reliability. Data over a 1-year period were analyzed to determine sensitivity to change among strength modalities and individual muscle groups. RESULTS: HHD and Fixed captured significant change across 1 year in summed muscle strength score of four muscle groups (P < .01). Strength summed scores were significantly correlated with functional scales (rho = 0.68-0.92, P < .001). Individual muscle groups, however, showed high levels of variability between visits. DISCUSSION: Although both HHD and Fixed demonstrate change over 12 months, HHD is a less expensive option that provides data on a continuous scale and may be easier to implement. Due to variability in strength measures, researchers should carefully consider use of strength testing as an outcome and may wish to select functional measures with less variability as clinical trial endpoints.

Reliability and construct validity of the Duchenne Video Assessment.

INTRODUCTION: The Duchenne Video Assessment (DVA) assesses quality of movement as an indication of Duchenne muscular dystrophy (DMD) disease severity. Caregivers video record patients performing home-based movement tasks using a mobile application, and physical therapists (PTs) rate the videos using scorecards with prespecified compensatory movement criteria. Reliability and construct validity of the DVA were tested using video and Pediatric Outcomes Data Collection Instrument (PODCI) data from patients with DMD and healthy controls from a separate study. METHODS: Fifteen PTs were trained and certified as DVA raters. All raters scored videos of five subjects performing each movement task; nine raters rescored the same videos four weeks later. Three raters scored videos from an average of 25 subjects for each movement task. Aggregate scores were used to test construct validity. An expert DMD clinician assigned each video to a severity group for known-groups analyses. Differences between rater scores across severity groups were tested and correlations between DVA and PODCI scores were calculated. RESULTS: Inter-rater reliability (intraclass correlation coefficient [ICC]) between all 15 raters ranged from 0.70 to 0.97 for all movement tasks. Mean intra-rater reliability ICC for nine raters ranged from 0.82 to 0.98 for all movement tasks. There were statistically significant differences between known severity groups for all movement tasks. The DVA correlated strongly with related PODCI constructs of physical function and weakly with unrelated constructs. DISCUSSION: The DVA was found to be a reliable and valid tool for measuring quality of movement as an indication of disease severity.

ACTIVE (Ability Captured Through Interactive Video Evaluation) workspace volume video game to quantify meaningful change in spinal muscular atrophy.

AIM: To evaluate the utility of Ability Captured Through Interactive Video Evaluation (ACTIVE) scaled scores to quantify meaningful change in individuals with spinal muscular atrophy (SMA) types 2 or 3 due to disease progression or treatment. METHOD: ACTIVE is a custom-designed video game that measures workspace volume (WSV). Participants included 62 individuals with SMA (mean age [SD] 10y 9mo [5y], range 2y 9mo-24y) and 362 frequency-matched controls (mean age [SD] 10y 9mo [3y 6mo], range 3y 2mo-24y 9mo). Participants completed ACTIVE, other traditional assessments, and patient-reported outcomes. Responsiveness to change was evaluated by comparing longitudinal data on untreated participants to those receiving Spinraza. RESULTS: ACTIVE was significantly correlated to the Hammersmith Functional Motor Scales Expanded and Revised Upper Limb Module (ρ=0.85 and ρ=0.92 respectively; p<0.001). Relevance to patients and families was established by strong correlations to the Patient Reported Outcomes Measurement Information System self- and parent proxy-measures of upper extremity ability (ρ=0.63 and ρ=0.70 respectively; p<0.001). Responsiveness to change was demonstrated by significant change in scaled scores after treatment (median 15.9 points, Wilcoxon signed-rank test p<0.01). A preliminary minimum clinically important difference is presented. INTERPRETATION: These results suggest that ACTIVE WSV scores are a meaningful assessment with which to quantify change over time in individuals with SMA types 2 and 3. WHAT THIS PAPER ADDS: Ability Captured Through Interactive Video Evaluation (ACTIVE) quantifies upper extremity function in spinal muscular atrophy. ACTIVE's scaled workspace volume strongly correlates to self- and parent-report of function. ACTIVE quantifies meaningful change after treatment.

HABILIDAD CAPTURADA A TRAVÉS DE LA EVALUACIÓN DE VIDEO INTERACTIVA (ACTIVE) DEL VOLUMEN DE TRABAJO DE VIDEOJUEGO PARA CUANTIFICAR UN CAMBIO SIGNIFICATIVO EN LA ATROFIA MUSCULAR ESPINAL: OBJETIVO: Evaluar la utilidad de la Habilidad Capturada a través de la Evaluación de Video Interactiva (ACTIVE) escalada para cuantificar un cambio significativo en individuos con atrofia muscular espinal (SMA) tipos 2 o 3 debido a la progresión de la enfermedad o el tratamiento. METHOD: ACTIVE es un videojuego diseñado a medida que mide el volumen del espacio de trabajo (WSV). Los participantes incluyeron 62 individuos con SMA (edad media [SD] 10 años 9 meses [5 años], rango 2 años 9 meses - 24 años) y 362 controles de frecuencia correspondiente (edad media [SD] 10 años 9 meses [3 años 6 meses], rango 3 años 2 meses - 24 años 9 meses). Los participantes completaron ACTIVE, otras evaluaciones tradicionales y los resultados informados por pacientes. La capacidad de respuesta al cambio se evaluó comparando los datos longitudinales de los participantes no tratados con los que recibieron Spinraza. RESULTADOS: ACTIVE se correlacionó significativamente con las Escalas de Motoras Funcionales de Hammersmith y el Módulo de Miembro Superior Revisado (Rho = 0,85 y 0,92 respectivamente; p<0,001). La relevancia para los pacientes y las familias se estableció mediante fuertes correlaciones con las medidas aproximadas propias y parentales de la capacidad de la extremidad superior (Rho = 0,63 y 0,70 respectivamente; p<0,001). La capacidad de respuesta al cambio se demostró mediante un cambio significativo en las puntuaciones escaladas después del tratamiento (mediana de 15,9 puntos, prueba de rango con signo de Wilcoxon p<0,01). Se presenta una diferencia clínicamente importante preliminar mínima. INTERPRETACIÓN: Estos resultados sugieren que las puntuaciones ACTIVE WSV son una evaluación significativa con la cual se puede cuantificar el cambio a lo largo del tiempo en individuos con SMA tipos 2 y 3.

HABILIDADE CAPTURADA POR MEIO DE AVALIAÇÃO VÍDEO-INTERATIVA (ACTIVE) DO VOLUME ESPAÇO DE TRABALHO DE VÍDEO GAME PARA QUANTIFICAR MUDANÇA SIGNIFICATIVA EM ATROFIA MUSCULAR ESPINHAL: OBJETIVO: Avaliar a utilidade dos escores escalares da Habilidade capturada por avaliação vídeo-interativa (ACTIVE) para quantificar mudança significativa devido à progressão da doença ou tratamento em indivíduos com atrofia muscular espinhal (AME) tipos 2 ou 3. MÉTODO: ACTIVE é um vídeo game projetado individualmente que mensura o volume do espaço de trabalho (VET). Os participantes incluíram 62 indivíduos com AME (média de idade [DP] 10a 9m [5a], variação de 2a 9m-24a) e 362 controles pareados por frequência (média de idade [DP] 10a 9m [3a 6m], variação de 3a 2m-24a 9m). Os participantes completaram o ACTIVE, outras avaliações tradicionais, e resultados relatados por pacientes. A responsividade à mudança foi avaliada comparando dados longitudinais de pacientes não tratados em relação àqueles recebendo Spinraza. RESULTADOS: ACTIVE foi significativamente correlacionado com as Escalas Motoras Funcinais Hammersmith e o Módulo de Membro superior revisado (Rho=0,85 e 0,92 respectivamente; p<0,001). A relevância para pacientes e famílias foi estabelecida por fortes correlações com o Sistema de medida de informação de resultados relatados por pacientes (medidas auto-relatadas e relatadas por pais) da capacidade do membro superior (Rho=0,63 e 0,70 respectivamente; p<0,001). A responsividade à mudança foi demonstrada por mudanca significativa nos escores escalares após o tratamento (mediana 15,9 pontos, teste de Wilcoxon signed-rank p<0,01). Uma medida preliminar de mínima diferença clinicamente importante é apresentada. INTERPRETAÇÃO: Estes resultados sugerem que os escores de VET ACTIVE são uma avaliação significativa com a qual quantificar mudança com o passar do tempo em indivíduos com AME tipos 2 e 3.

Twice-weekly glucocorticosteroids in infants and young boys with Duchenne muscular dystrophy.

INTRODUCTION: Glucocorticosteroids (GC) are effective in slowing weakness in boys with Duchenne muscular dystrophy (DMD). METHODS: This is a multisite, 1-year, open-label trial of twice-weekly prednisolone (5 mg/kg/dose) in infants/young boys (0.4-2.4 years) with DMD. We compared changes in Bayley III Scales of Infant Development (Bayley-III) with untreated boys followed for 1 year (historical control cohort [HCC]). Twenty-three of 25 participants completed the study. RESULTS: Treated boys gained an average of 0.5 points on the Bayley-III gross motor scaled score (GMSS) compared with the HCC who, on average, declined 1.3 points (P = 0.03). All boys maintained linear growth, and none developed Cushingoid features. Excessive weight gain occurred in 13 of 23 (56%) boys. DISCUSSION: This study provides evidence that twice-weekly GC is well tolerated in infants and young boys with DMD and improves GMSS. Excessive weight gain is a potential risk. Longer follow-up is required to determine whether early GC initiation is feasible in most infants/boys with DMD. Muscle Nerve 59:650-657, 2019.

Follistatin Gene Therapy for Sporadic Inclusion Body Myositis Improves Functional Outcomes.

Sporadic inclusion body myositis, a variant of inflammatory myopathy, has features distinct from polymyositis/dermatomyositis. The disease affects men more than women, most commonly after age 50. Clinical features include weakness of the quadriceps, finger flexors, ankle dorsiflexors, and dysphagia. The distribution of weakness is similar to Becker muscular dystrophy, where we previously reported improvement following intramuscular injection of an isoform of follistatin (FS344) by AAV1. For this clinical trial, rAAV1.CMV.huFS344, 6 × 1011 vg/kg, was delivered to the quadriceps muscles of both legs of six sporadic inclusion body myositis subjects. The primary outcome for this trial was distance traveled for the 6-min walk test. The protocol included an exercise regimen for each participant. Performance, annualized to a median 1-year change, improved +56.0 m/year for treated subjects compared to a decline of -25.8 m/year (p = 0.01) in untreated subjects (n = 8), matched for age, gender, and baseline measures. Four of the six treated subjects showed increases ranging from 58-153 m, whereas two were minimally improved (5-23 m). Treatment effects included decreased fibrosis and improved regeneration. These findings show promise for follistatin gene therapy for mild to moderately affected, ambulatory sporadic inclusion body myositis patients. More advanced disease with discernible muscle loss poses challenges.

Longitudinal effect of eteplirsen versus historical control on ambulation in Duchenne muscular dystrophy.

OBJECTIVE: To continue evaluation of the long-term efficacy and safety of eteplirsen, a phosphorodiamidate morpholino oligomer designed to skip DMD exon 51 in patients with Duchenne muscular dystrophy (DMD). Three-year progression of eteplirsen-treated patients was compared to matched historical controls (HC). METHODS: Ambulatory DMD patients who were ≥7 years old and amenable to exon 51 skipping were randomized to eteplirsen (30/50mg/kg) or placebo for 24 weeks. Thereafter, all received eteplirsen on an open-label basis. The primary functional assessment in this study was the 6-Minute Walk Test (6MWT). Respiratory muscle function was assessed by pulmonary function testing (PFT). Longitudinal natural history data were used for comparative analysis of 6MWT performance at baseline and months 12, 24, and 36. Patients were matched to the eteplirsen group based on age, corticosteroid use, and genotype. RESULTS: At 36 months, eteplirsen-treated patients (n = 12) demonstrated a statistically significant advantage of 151m (p < 0.01) on 6MWT and experienced a lower incidence of loss of ambulation in comparison to matched HC (n = 13) amenable to exon 51 skipping. PFT results remained relatively stable in eteplirsen-treated patients. Eteplirsen was well tolerated. Analysis of HC confirmed the previously observed change in disease trajectory at age 7 years, and more severe progression was observed in patients with mutations amenable to exon skipping than in those not amenable. The subset of patients amenable to exon 51 skipping showed a more severe disease course than those amenable to any exon skipping. INTERPRETATION: Over 3 years of follow-up, eteplirsen-treated patients showed a slower rate of decline in ambulation assessed by 6MWT compared to untreated matched HC.

Modeling functional decline over time in sporadic inclusion body myositis.

INTRODUCTION: The ability to individualize recommendations or expectations of disease progression based on a patient's unique characteristics has merit for use in sporadic inclusion body myositis (sIBM). METHODS: Fifty-five subjects with sIBM completed a battery of strength and functional outcomes at 2 study visits. These were used to develop mathematical models of disease progression in patients with sIBM for use in clinical and research settings. RESULTS: The 6-minute walk test (6MWT) distance declined by an average of 27.5 meters (12%) per year. Significant factors that predict 6MWT were knee extension and plantarflexion strength and body weight, whereas the ability to stand from a chair was impacted by elbow extension strength. Stepping up on a curb was influenced by the patient's age at diagnosis and by knee extension. Statistical models to predict functional decline in sIBM were developed. CONCLUSION: Statistical models help explain the complex factors that influence decreased walking ability and other functional activities in sIBM. Muscle Nerve 55: 526-531, 2017.

'Learn From Every Patient': implementation and early results of a learning health system.

AIM: The convergence of three major trends in medicine, namely conversion to electronic health records (EHRs), prioritization of translational research, and the need to control healthcare expenditures, has created unprecedented interest and opportunities to develop systems that improve care while reducing costs. However, operationalizing a 'learning health system' requires systematic changes that have not yet been widely demonstrated in clinical practice. METHOD: We developed, implemented, and evaluated a model of EHR-supported care in a cohort of 131 children with cerebral palsy that integrated clinical care, quality improvement, and research, entitled 'Learn From Every Patient' (LFEP). RESULTS: Children treated in the LFEP Program for a 12-month period experienced a 43% reduction in total inpatient days (p=0.030 vs prior 12mo period), a 27% reduction in inpatient admissions, a 30% reduction in emergency department visits (p=0.001), and a 29% reduction in urgent care visits (p=0.046). LFEP Program implementation also resulted in reductions in healthcare costs of 210% (US$7014/child) versus a Time control group, and reductions of 176% ($6596/child) versus a Program Activities control group. Importantly, clinical implementation of the LFEP Program has also driven the continuous accumulation of robust research-quality data for both publication and implementation of evidence-based improvements in clinical care. INTERPRETATION: These results demonstrate that a learning health system can be developed and implemented in a cost-effective manner, and can integrate clinical care and research to systematically drive simultaneous clinical quality improvement and reduced healthcare costs.

Clinical trial readiness in non-ambulatory boys and men with duchenne muscular dystrophy: MDA-DMD network follow-up.

INTRODUCTION: Outcomes sensitive to change over time in non-ambulatory boys/men with Duchenne muscular dystrophy (DMD) are not well-established. METHODS: Subjects (n = 91; 16.8 ± 4.5 years old) were assessed at baseline and 6-month intervals for 2 years. We analyzed all subjects using an intent-to-treat model and a subset of stronger subjects with Brooke Scale score ≤4, using repeated measures. RESULTS: Eight patients (12-33 years old) died during the study. Sixty-six completed 12-month follow-up, and 51 completed 24-month follow-up. Those taking corticosteroids performed better at baseline, but rates of decline were similar. Forced vital capacity percent predicted (FVC% predicted) declined significantly only after 2 years. However, Brooke and Egen Klassifikation (EK) Scale scores, elbow flexion, and grip strength declined significantly over both 1 and 2 years. CONCLUSION: Brooke and EK Scale scores, elbow flexion, and grip strength were outcomes most responsive to change. FVC% predicted was responsive to change over 2 years. Corticosteroids benefited non-ambulatory DMD subjects but did not affect decline rates of measures tested here. Muscle Nerve 54: 681-689, 2016.

A phase 1/2a follistatin gene therapy trial for becker muscular dystrophy.

Becker muscular dystrophy (BMD) is a variant of dystrophin deficiency resulting from DMD gene mutations. Phenotype is variable with loss of ambulation in late teenage or late mid-life years. There is currently no treatment for this condition. In this BMD proof-of-principle clinical trial, a potent myostatin antagonist, follistatin (FS), was used to inhibit the myostatin pathway. Extensive preclinical studies, using adeno-associated virus (AAV) to deliver follistatin, demonstrated an increase in strength. For this trial, we used the alternatively spliced FS344 to avoid potential binding to off target sites. AAV1.CMV.FS344 was delivered to six BMD patients by direct bilateral intramuscular quadriceps injections. Cohort 1 included three subjects receiving 3 × 10(11) vg/kg/leg. The distance walked on the 6MWT was the primary outcome measure. Patients 01 and 02 improved 58 meters (m) and 125 m, respectively. Patient 03 showed no change. In Cohort 2, Patients 05 and 06 received 6 × 10(11) vg/kg/leg with improved 6MWT by 108 m and 29 m, whereas, Patient 04 showed no improvement. No adverse effects were encountered. Histological changes corroborated benefit showing reduced endomysial fibrosis, reduced central nucleation, more normal fiber size distribution with muscle hypertrophy, especially at high dose. The results are encouraging for treatment of dystrophin-deficient muscle diseases.

Reliability and validity of active-seated: An outcome in dystrophinopathy.

INTRODUCTION: Traditional upper extremity measures typically focus on distal abilities and do not quantify the unique progression of decline in dystrophinopathy. We designed ACTIVE-seated to meet this need. Our objective was to establish the tool's validity and reliability. METHODS: ACTIVE-seated uses the Microsoft Kinect gaming interface to quantify functional reaching ability while playing a custom-designed game. A skeletal tracking algorithm was used to determine the furthest arm excursion in all planes in 61 subjects with dystrophinopathy and 16 controls. RESULTS: Total reachable area was scaled based on arm length to standardize comparisons across subjects and accommodate growth. ACTIVE-seated discriminately ranked subjects from normal controls and by Brooke level (P < 0.001). Scores were highly correlated with parent reports of daily activities and mobility (P < 0.05). Test-retest reliability of ACTIVE-seated was excellent (ICC = 0.97, P < 0.0001). CONCLUSIONS: Initial evaluation of reliability and validity suggests that ACTIVE-seated shows promise as a clinical and research outcome for individuals with dystrophinopathy.

Outcome reliability in non-ambulatory boys/men with Duchenne muscular dystrophy.

INTRODUCTION: Therapeutic trials in Duchenne muscular dystrophy (DMD) often exclude non-ambulatory individuals. Here we establish optimal and reliable assessments in a multicenter trial. METHODS: Non-ambulatory boys/men with DMD (N = 91; 16.7 ± 4.5 years of age) were assessed by trained clinical evaluators. Feasibility (percentage completing task) and reliability [intraclass correlation coefficients (ICCs) between morning and afternoon tests] were measured. RESULTS: Forced vital capacity (FVC), assessed in all subjects, showed a mean of 47.8 ± 22% predicted (ICC 0.98). Brooke Upper Extremity Functional Rating (Brooke) and Egen Klassifikation (EK) scales in 100% of subjects showed ICCs ranging from 0.93 to 0.99. Manual muscle testing, range of motion, 9-hole peg test, and Jebsen-Taylor Hand Function Test (JHFT) demonstrated varied feasibility (99% to 70%), with ICCs ranging from 0.99 to 0.64. We found beneficial effects of different forms of corticosteroids for the Brooke scale, percent predicted FVC, and hand and finger strength. CONCLUSIONS: Reliable assessment of non-ambulatory boys/men with DMD is possible. Clinical trials will have to consider corticosteroid use.

Eteplirsen for the treatment of Duchenne muscular dystrophy.

OBJECTIVE: In prior open-label studies, eteplirsen, a phosphorodiamidate morpholino oligomer, enabled dystrophin production in Duchenne muscular dystrophy (DMD) with genetic mutations amenable to skipping exon 51. The present study used a double-blind placebo-controlled protocol to test eteplirsen's ability to induce dystrophin production and improve distance walked on the 6-minute walk test (6MWT). METHODS: DMD boys aged 7 to 13 years, with confirmed deletions correctable by skipping exon 51 and ability to walk 200 to 400 m on 6 MWT, were randomized to weekly intravenous infusions of 30 or 50 mg/kg/wk eteplirsen or placebo for 24 weeks (n = 4/group). Placebo patients switched to 30 or 50 mg/kg eteplirsen (n=2/group) at week 25; treatment was open label thereafter. All patients had muscle biopsies at baseline and week 48. Efficacy included dystrophin-positive fibers and distance walked on the 6MWT. RESULTS: At week 24, the 30 mg/kg eteplirsen patients were biopsied, and percentage of dystrophin-positive fibers was increased to 23% of normal; no increases were detected in placebo-treated patients (p≤0.002). Even greater increases occurred at week 48 (52% and 43% in the 30 and 50 mg/kg cohorts, respectively), suggesting that dystrophin increases with longer treatment. Restoration of functional dystrophin was confirmed by detection of sarcoglycans and neuronal nitric oxide synthase at the sarcolemma. Ambulation-evaluable eteplirsen-treated patients experienced a 67.3 m benefit compared to placebo/delayed patients (p≤0.001). INTERPRETATION: Eteplirsen restored dystrophin in the 30 and 50 mg/kg/wk cohorts, and in subsequently treated, placebo-controlled subjects. Duration, more than dose, accounted for dystrophin production, also resulting in ambulation stability. No severe adverse events were encountered.

Feasibility and utility of in-home body weight support harness system use in young children treated for spinal muscular atrophy: A single-arm prospective cohort study.

PURPOSE: This single-arm prospective cohort study aimed to evaluate the feasibility and utility of in-home body weight support harness system (BWSS) use in children treated for spinal muscular atrophy (SMA). METHODS: Individuals with 2 or 3 copies of SMN2 who received pharmacotherapeutic treatment, had head control, and weight <50lbs were enrolled. Families were provided a BWSS and documented use. Motor outcome assessments were completed at baseline, month 3 and month 6. Families provided feedback in an end of study survey. RESULTS: All 32 participants (2.9 (SD 1.9) yrs), improved or remained stable on all outcomes. Average reported frequency of use was 4.1(2.3) hrs/week. Controlling for other covariates, frequency of use explained over 70% of the variability in change scores. Family feedback was overwhelmingly positive. CONCLUSION: Use of in-home BWSS is a safe, feasible and useful option to increase exercise dosage after treatment in SMA and may help optimize motor abilities. TRIAL REGISTRATION: Study registered with: Clinicaltrials.gov Clinicaltrials.gov identifier: NCT05715749.

Healthcare Stakeholder Perspectives on a Value Assessment Approach for Duchenne Muscular Dystrophy Therapies.

Purpose: Traditional value assessment frameworks are challenged in comprehensively assessing the societal value new therapies bring to individuals with rare, progressive, genetic, fatal, neuromuscular diseases such as Duchenne muscular dystrophy (DMD). The objective of this study was to identify how value assessment frameworks may need to be adapted to measure the value to society of DMD therapies. Patients and Methods: Three stakeholder groups (6 patient advocates, 4 clinicians, 3 health economists; N = 13) participated in semi-structured interviews around the International Society for Pharmacoeconomics and Outcomes Research's Value Flower, which includes elements to consider within value assessments of healthcare technologies. Results: All stakeholders agreed that traditional value assessment frameworks based on the quality-adjusted life year (QALY) are narrow and will undervalue new DMD therapies. All stakeholders expressed some level of concern that using the QALY as a key metric of value discriminates against patients with severe progressive diseases and disabilities. Some stakeholders saw value in using the QALY for cross-disease comparisons in resource-constrained environments if the methodology was appropriate. All stakeholders recommended considering additional elements of value in decision-making around new DMD therapies. These elements reflect: economic and humanistic costs incurred by patients, caregivers, and families with Duchenne, such as indirect out-of-pocket costs, lost productivity, and family spillovers; meaningful attributes for individuals with disabilities and high unmet need, such as severity of disease, value of hope, and real option value; and factors that contribute to improvements in population health, such as insurance value, equity, and scientific spillovers. Conclusion: These findings highlight the need to expand traditional value assessment frameworks and take a holistic approach that incorporates the perspectives of individuals with Duchenne, caregivers, clinicians, and health economists when assessing the societal value of new DMD therapies. Broadening value assessment will prevent restricted or delayed access to therapies for individuals with Duchenne.

Increase in Full-Length Dystrophin by Exon Skipping in Duchenne Muscular Dystrophy Patients with Single Exon Duplications: An Open-label Study.

Single exon duplications account for disease in a minority of Duchenne muscular dystrophy patients. Exon skipping in these patients has the potential to be highly therapeutic through restoration of full-length dystrophin expression. We conducted a 48-week open label study of casimersen and golodirsen in 3 subjects with an exon 45 or 53 duplication. Two subjects (aged 18 and 23 years) were non-ambulatory at baseline. Upper limb, pulmonary, and cardiac function appeared stable in the 2 subjects in whom they could be evaluated. Dystrophin expression increased from 0.94 % ±0.59% (mean±SD) of normal to 5.1% ±2.9% by western blot. Percent dystrophin positive fibers also rose from 14% ±17% at baseline to 50% ±42% . Our results provide initial evidence that the use of exon-skipping drugs may increase dystrophin levels in patients with single-exon duplications.

Gene therapy with bidridistrogene xeboparvovec for limb-girdle muscular dystrophy type 2E/R4: phase 1/2 trial results.

Limb-girdle muscular dystrophy 2E/R4 is caused by mutations in the ß-sarcoglycan (SGCB) gene, leading to SGCB deficiency and consequent muscle loss. We developed a gene therapy approach based on functional replacement of the deficient SCB protein. Here we report interim results from a first-in-human, open-label, nonrandomized, phase 1/2 trial evaluating the safety and efficacy of bidridistrogene xeboparvovec, an adeno-associated virus-based gene therapy containing a codon-optimized, full-length human SGCB transgene. Patients aged 4-15 years with confirmed SGCB mutations at both alleles received one intravenous infusion of either 1.85 × 1013 vector genome copies kg-1 (Cohort 1, n = 3) or 7.41 × 1013 vector gene copies kg-1 (Cohort 2, n = 3). Primary endpoint was safety, and secondary endpoint was change in SGCB expression in skeletal muscle from baseline to Day 60. We report interim Year 2 results (trial ongoing). The most frequent treatment-related adverse events were vomiting (four of six patients) and gamma-glutamyl transferase increase (three of six patients). Serious adverse events resolved with standard therapies. Robust SGCB expression was observed: Day 60 mean (s.d.) percentage of normal expression 36.2% (2.7%) in Cohort 1 and 62.1% (8.7%) in Cohort 2. Post hoc exploratory analysis showed preliminary motor improvements using the North Star Assessment for Limb-girdle Type Muscular Dystrophies maintained through Year 2. The 2-year safety and efficacy of bidridistrogene xeboparvovec support clinical development advancement. Further studies are necessary to confirm the long-term safety and efficacy of this gene therapy. ClinicalTrials.gov registration: NCT03652259 .

Correlation of knee strength to functional outcomes in Becker muscular dystrophy.

INTRODUCTION: The correlation of strength with performance on functional outcomes has not been evaluated in Becker muscular dystrophy (BMD), yet the determination of proper outcome measures is critical to the success of upcoming trials designed to improve strength. METHODS: Lower extremity strength and performance on functional outcome measures were tested in 25 ambulatory subjects with BMD. RESULTS: All subjects demonstrated marked knee extensor and flexor muscle weakness. Knee extensor strength was correlated with performance on the Berg Balance Scale and stair climbing. Knee flexor strength was highly correlated with performance on all functional outcomes, including timed walking distances. CONCLUSIONS: This profile differs from that previously reported in other neuromuscular diseases and demonstrates the importance of designing outcome measures for clinical trials in muscle disorders with considerations for the disease process, the mode, and the target of intervention. The findings emphasize that 1 set of outcomes is not appropriate for all neuromuscular diseases.