The North Star Ambulatory Assessment (NSAA) and North Star Assessment for Limb-Girdle type muscular dystrophies (NSAD) are motor performance scales specifically developed for Duchenne muscular dystrophy (DMD) and Limb Girdle muscular dystrophy (LGMD), respectively. Both have been used in natural history studies of Becker muscular dystrophy (BMD), a dystrophinopathy sharing clinical characteristics of DMD and LGMD. We examined the psychometric performance of the NSAA and NSAD across three clinical trials of sevasemten (EDG-5506) enrolling ambulant subjects with BMD aged between 12 and 65 years. Data were examined using Rasch Unidimensional Measurement Model (RUMM) as an innovative strategy for understanding the suitability of the NSAA and NSAD to measure the motor function of individuals with BMD. Psychometric evaluation was completed examining NSAA and NSAD performance in seven areas: targeting, response categories, fit, reliability, dependency, stability and unidimensionality using RUMM2030 software. A total of 182 assessments included screening and/or baseline visits for participants in the EDG-5506-002 (NCT05160415), EDG-5506-201 (NCT05291091) and EDG-5506-202 studies were utilized. NSAA and NSAD both demonstrated unidimensional construct of functional motor performance and high reliability with a Person Separation Index (PSI) of 0.96. Although a ceiling effect still existed for the strongest symptomatic subjects, the motor performance of ambulant subjects was targeted successfully by the items of the NSAA and NSAD. 28/29 NSAD items and 14/17 NSAA items demonstrated ordered response categories, meaning the scoring categories for each item are logical and appropriate for BMD. The items fit well together to make use of the total score appropriate. The NSAA and NSAD perform well in BMD, with the NSAD providing additional items to test both non-ambulant and those very able individuals with BMD. This analysis supports use of NSAA and NSAD as clinically meaningful outcomes in clinical trials of BMD.

Life expectancy in individuals with Duchenne muscular dystrophy (DMD) has been extended due to implementation of multidisciplinary care. This has led to an increased population of adults with DMD which has not been thoroughly characterized. We describe clinical and psychosocial characteristics in a cohort of adults with DMD followed up in a highly specialized neuromuscular centre. Clinical and functional (Egen Klassifikation scale) data were retrospectively collected from clinical records of 112 adults with DMD (> 16 years, mean age 23.4 SD 5.2 years; SD, standard deviation) between 1986 and 2022. Scoliosis was reported in 61.6% individuals, of whom 42 underwent spinal surgery at a mean age 15.0 SD 2.3 years (all spinal surgeries took place between 1998 - 2013). Individuals maintained on glucocorticoids after loss of ambulation had a lower risk and delayed time to scoliosis surgery compared to glucocorticoid naïve ones. Fifty-nine percent had at least one surgical intervention. After scoliosis surgery, percutaneous endoscopic gastrostomy (PEG) was the most frequent intervention (16.0%, mean age 20 SD 5.5 years). Assistance with feeding was required in 51.8% and 39.3% reported dysphagia. Individuals on glucocorticoids after loss of ambulation had a lower frequency of dysphagia compared to glucocorticoid naïve ones. Difficulties coughing, speaking, controlling head position and a vital force capacity below 30% were associated with dysphagia. Constipation was reported by 36.6% and urinary incontinence in 16.0%. Older age and PEG-feeding were associated with constipation. Mood disorders were reported by 46.6% of whom 42.3% received treatment for the condition. No specific factors were identified as associated with mood disorders. At last follow up, 26.8% were not employed or involved in formal educational activities. Excluding glucocorticoids, the median number of medications per patient was 5 (min 0 – max 18). The most frequent prescribed medications were Angiotensin-converting enzyme inhibitor/Angiotensin II receptor antagonists, 90.2%; beta-blockers, 85.7%; and vitamin D, 62.5%. The mean vitamin D level was 58.6 SD 27.8 nmol/L, 30% with insufficient levels. Detailed knowledge about the frequency of comorbidities in adults living with DMD informs clinical care and service requirements. The high number of concomitant medications taken by this population should be further investigated, especially regarding possible interactions. Life expectancy in individuals with Duchenne muscular dystrophy (DMD) has been extended due to implementation of multidisciplinary care. This has led to an increased population of adults with DMD which has not been thoroughly characterized. We describe clinical and psychosocial characteristics in a cohort of adults with DMD followed up in a highly specialized neuromuscular centre. Clinical and functional (Egen Klassifikation scale) data were retrospectively collected from clinical records of 112 adults with DMD (> 16 years, mean age 23.4 SD 5.2 years; SD, standard deviation) between 1986 and 2022. Scoliosis was reported in 61.6% individuals, of whom 42 underwent spinal surgery at a mean age 15.0 SD 2.3 years (all spinal surgeries took place between 1998 - 2013). Individuals maintained on glucocorticoids after loss of ambulation had a lower risk and delayed time to scoliosis surgery compared to glucocorticoid naïve ones. Fifty-nine percent had at least one surgical intervention. After scoliosis surgery, percutaneous endoscopic gastrostomy (PEG) was the most frequent intervention (16.0%, mean age 20 SD 5.5 years). Assistance with feeding was required in 51.8% and 39.3% reported dysphagia. Individuals on glucocorticoids after loss of ambulation had a lower frequency of dysphagia compared to glucocorticoid naïve ones. Difficulties coughing, speaking, controlling head position and a vital force capacity below 30% were associated with dysphagia. Constipation was reported by 36.6% and urinary incontinence in 16.0%. Older age and PEG-feeding were associated with constipation. Mood disorders were reported by 46.6% of whom 42.3% received treatment for the condition. No specific factors were identified as associated with mood disorders. At last follow up, 26.8% were not employed or involved in formal educational activities. Excluding glucocorticoids, the median number of medications per patient was 5 (min 0 – max 18). The most frequent prescribed medications were Angiotensin-converting enzyme inhibitor/Angiotensin II receptor antagonists, 90.2%; beta-blockers, 85.7%; and vitamin D, 62.5%. The mean vitamin D level was 58.6 SD 27.8 nmol/L, 30% with insufficient levels. Detailed knowledge about the frequency of comorbidities in adults living with DMD informs clinical care and service requirements. The high number of concomitant medications taken by this population should be further investigated, especially regarding possible interactions.

Corticosteroids (CS) improve muscle function in boys with DMD and are part of the care recommendations. However, there is uncertainty about optimum regimen and dosage leading to great variability in CS use worldwide. The FOR DMD study (Find the Optimum corticosteroid Regimen for Duchenne Muscular Dystrophy) compared efficacy and side effects of the 3 most commonly prescribed CS regimens in young boys with DMD. We completed a randomized, double-blind, parallel-group clinical trial (32 sites, 5 countries). Boys were randomized 1:1:1 to daily prednisone (0.75 mg/kg), daily deflazacort (0.9 mg/kg), or intermittent prednisone (0.75 mg/kg 10 days on/10 days off). A total of 196 corticosteroid-naïve boys with DMD ages 4-7 years were enrolled and followed up for 3 years. The primary outcome comprised rise from the floor velocity, forced vital capacity, and participant/parent global satisfaction with treatment. Secondary efficacy outcomes (10 meter walk/run velocity, 6-minute walking distance and North Star Ambulatory Assessment total score) and safety outcomes (height, weight, behavioral measures, adverse events) were monitored. Daily prednisone and daily deflazacort resulted in significantly better efficacy outcomes compared to intermittent, 10 days on 10 days off, prednisone. There were no significant differences in efficacy between the 2 daily regimens. Results were consistent between age groups (4-5 vs. 6-7). There was no significant difference in weight gain between the daily and intermittent prednisone groups, both of which gained more weight than the deflazacort group. Slowing of growth was less severe with the intermittent than with the daily regimens, with daily deflazacort associated with the greatest slowing of growth. This study supports use of a daily corticosteroid regimen over an intermittent prednisone regimen that alternates dosing with 10 days on and 10 days off as initial treatment for boys with DMD.

Suvodirsen (WVE-210201) is an investigational stereopure oligonucleotide that is being developed as a potential disease-modifying therapy for patients with Duchenne muscular dystrophy (DMD) amenable to exon 51 skipping. Safety and tolerability data from the suvodirsen Phase 1 clinical trial (NCT03508947) support the initiation of a Phase 2/3 trial. Wave's planned Phase 2/3 trial for suvodirsen has been selected for the US Food and Drug Administration (FDA) pilot program for complex innovative trial designs. We present the design of the Phase 2/3 trial of suvodirsen in patients with DMD amenable to exon 51 skipping. This is a global, multicenter, randomized, double-blind, placebo-controlled trial to determine the efficacy and safety of suvodirsen in approximately 150 ambulatory male patients 5–12 years of age (inclusive). Key endpoints include change from baseline in dystrophin protein levels and motor function by North Star Ambulatory Assessment over 48 weeks. Two interim analyses will assess dystrophin protein levels from open biopsies of deltoid muscle using western blot. Additional endpoints include assessment of upper/lower limb function, respiratory function, and stride velocity (measured by a wearable device). As part of the design, DMD historical control data will be leveraged to help minimize the number of patients required in the placebo arm to deliver conclusive clinical efficacy results and potentially accelerate study completion. The extent of the clinical efficacy of exon skipping therapies is currently not fully established. With feedback from the FDA and the global DMD community, the innovative design of the Phase 2/3 clinical trial may allow for a more resourceful determination of suvodirsen's clinical efficacy in patients with DMD. It may also inform designs of future rare disease clinical trials.

The field of translational research in Duchenne muscular dystrophy (DMD) has been transformed in the last decade by a number of therapeutic targets, mostly studied in ambulant patients. A paucity of studies focus on measures that capture the non-ambulant stage of the disease, and the transition between the ambulant and non-ambulant phase. In this prospective natural history study, we report the results of a comprehensive assessment of respiratory, upper limb function and upper limb muscle strength in a group of 89 DMD boys followed in 3 European countries, 81 receiving corticosteroids, spanning a wide age range (5-18 years) and functional abilities, from ambulant (n = 60) to non-ambulant (n = 29). Respiratory decline could be detected in the early ambulatory phase using Peak Expiratory Flow percentage predicted (PEF%), despite glucocorticoid use (mean annual decline: 4.08, 95% CI [-7.44,-0.72], p = 0.02 in ambulant; 4.81, 95% CI [-6.79,-2.82], p < 0.001 in non-ambulant). FVC% captured disease progression in non-ambulant DMD subjects, with an annual loss of 5.47% (95% CI [-6.48,-4.45], p < 0.001). Upper limb function measured with the Performance of Upper Limb (PUL 1.2) showed an annual loss of 4.13 points (95% CI [-4.79,3.47], p < 0.001) in the non-ambulant cohort. Measures of upper limb strength (MyoGrip and MyoPinch) showed a continuous decline independent of the ambulatory status, when reported as percentage predicted (grip force -5.51%, 95% CI [-6.54,-4.48], p < 0.001 in ambulant and a slower decline -2.86%; 95% CI -3.29,-2.43, p < 0.001, in non-ambulant; pinch force: -2.66%, 95% CI [-3.82,-1.51], p < 0.001 in ambulant and -2.23%, 95% CI [-2.92,-1.53], p < 0.001 in non-ambulant). Furthermore, we also explored the novel concept of a composite endpoint by combining respiratory, upper limb function and force domains: we were able to identify clear clinical progression in patients in whom an isolated measurement of only one of these domains failed to appreciate the yearly change. Our study contributes to the field of natural history of DMD, linking the ambulant and non-ambulant phases of the disease, and suggests that composite scores should be explored further.

The Clinical Outcome Study for Dysferlinopathy is a multi-centre natural history study in dysferlinopathy patients. 203 patients (11 to 86 years old) were enrolled. Patients underwent physiotherapy, medical and MRI assessments. 74 patients underwent upper limb muscle MRI at baseline and 61 patients had upper limb muscle MRI at year 3. Muscles were scored on axial T1-weighted sequences with the semi quantitative Mercuri visual scale modified by Fisher. Physiotherapy assessments included muscle strength and functional ability evaluations. Change between baseline and year 3 muscle MRI was assessed using Wilcoxon“s Signed Rank Tests and statistical significance was set at p < 0.05.

Suvodirsen (WVE-210201) is an investigational stereopure oligonucleotide that is being developed as a potential disease-modifying therapy for patients with Duchenne muscular dystrophy (DMD) amenable to exon 51 skipping. A Phase 1, multicenter, double-blind, placebo-controlled clinical trial of suvodirsen with 12-week follow-up (NCT03508947) and an open-label extension study are ongoing. We report results of this Phase 1 clinical trial evaluating the safety, tolerability, and pharmacokinetics (PK) of suvodirsen in patients with DMD amenable to exon 51 skipping. The trial enrolled 36 ambulatory and nonambulatory male patients, 5–18 years old (inclusive), with a confirmed dystrophin (DMD) gene mutation amenable to exon 51 skipping. Patients were randomized 3:1 to receive a single intravenous infusion of suvodirsen or placebo in 5 ascending dose cohorts. Safety assessments included adverse events, physical exam, vital signs, electrocardiogram, and clinical laboratory evaluations at specified time points through week 12. Plasma PK samples were collected predose, at the end of infusion (EOI), and at specified intervals up to 7 days after EOI. Mean (SD) age was 8.1 (2.1) years; mean (SD) time since diagnosis was 4.7 (2.8) years. Thirty-two patients were ambulatory, and 6 were previously on eteplirsen. Safety and tolerability data from the suvodirsen Phase 1 clinical trial support the initiation of a global, placebo-controlled Phase 2/3 efficacy and safety clinical trial of suvodirsen in patients with DMD amenable to exon 51 skipping. Final safety, tolerability, and PK data will be presented.

We report on use of the Performance of upper limb in the Jain clinical outcome study of dysferlinopathy. Dysferlinopathy clinically presents as a spectrum of muscle weakness including both distal and proximal phenotypes and variable rates of progression. This variability presents challenges for developing clinical trial outcome measures. Currently, no dysferlinopathy specific tools exist to measure upper limb motor function. The Jain COS Consortium aims to overcome these challenges by collecting and analysing observational data from 203 genetically confirmed patients (aged 12–88) in eight countries over three years. One aim of the COS study is to establish robust functional rating scales for use in ambulant and non-ambulant patients with dysferlinopathy. The performance of upper limb (PUL) was introduced to the study at Year 2 to assess upper limb performance. The PUL was reviewed using modern psychometric methods – Rasch analysis (Rumm 2030). This analysis investigates the ability of the individual items of PUL to measure the construct of upper limb motor performance, whether the items target the range of abilities of the study subjects and whether the item order of difficulty match clinical knowledge of the condition. Over 200 patient assessments, from 15 centres with either one or two assessments from each subject were analysed. The individual item scoring threshold map demonstrates excellent ordered thresholds. The item locations have good spread indicating that the PUL defines a good continuum with little overlap of items. Targeting suggests a possible ceiling effect of the current items with the scale measuring less able people better. This work shows that the Performance of Upper Limb is a useful outcome measure of upper limb performance in dysferlinopathy. The ability of the PUL to measure change over time will be investigated as well as its relationship to North Star Ambulatory Assessment for Dysferlinopathy and its relationship to upper limb MRI T1W data over the course of the study.

An aim of the COS study is to establish robust functional rating scales for use in ambulant and non-ambulant patients with dysferlinopathy. Functional outcome measures were reviewed for suitability and robustness. Functional ability, as measured by the motor function measure (MFM) and North Star Ambulatory Assessment for Dysferlinopathy (NSAA), was reviewed using modern psychometric methods (Rumm 2030). Analysis of 156 patients, with between one and four visits (n = 199), investigated the ability of the individual items of both scales to measure the underlying construct of the scale.

We performed a qualitative study in spinal muscular atrophy (SMA) to assess factors influencing disease progression in SMA from the patient's perspective, focusing on physiotherapy, interventions, life events and external circumstances. Semi-structured interviews were conducted in a total of eight SMA type II and type III patients, children and adults. Interview content was analysed by two researches using NVIVO software with responses aligned to the international classification of functioning, disability and health (ICF) framework. A total of 346 references were analysed and 202(58%) allocated to body function component, 125(36%) to environmental factors and 19(6%) to activities and participation. For body function the most represented themes were function (36%), strength-fatigue-endurance (44%) and range of motion (ROM)(21%). For environmental factors, the most common themes were exercise which included physiotherapy38%), spinal management (18%) and mobility aids (17%) which were mainly related to clinical care. In relationship to activities and participation, references were related to participation, knowledge, work and nutrition, covering the social dimension of the condition. Out of 82 references related to disease progression 58 (71%) described deterioration (from 7/8 individuals), 7(9%) improvement (n = 4/8) and 17(20%) stability (n = 5/8). Patients reported a similar pattern of disease progression as that described in the literature, however contractures and hyperlaxity were perceived as ‘normal’. Efficacy of interventions such as splints, stretches, physiotherapy and physical activity was reported only if done regularly (2–3 times/week). However poor access to all of these interventions was widely reported especially as they reached adulthood. The intermediate and long-term impact of spinal surgery is different and its influence on trunk and upper limb function is worthy of further exploration. Capturing patient's perception will help us understand disease progression as well as review our current management and model of care for this group.

The North Star Assessment for dysferlinopathy (NSAD) was developed to measure motor performance in ambulant and non-ambulant subjects as part of the clinical outcome study of dysferlinopathy. The clinical outcome study of dysferlinopathy is an international study evaluating 203 patients with genetically confirmed dysferlinopathy with the intention of improving trial readiness in dysferlinopathy. This novel scale comprises clinically relevant items from the adapted North Star Ambulatory Assessment and motor function measure-20. The NSAD was developed following examination of the year 1 data, and was introduced at the year 2 study visit. The scale was reviewed for suitability and robustness using modern psychometric measures (RUMM2030). This Rasch analysis performed on data from 143 individuals at the year 2 visit demonstrated the items of the NSAD represent the construct of motor performance for dysferlinopathy and demonstrate good item fit, logical scoring progression and appropriate targeting as well as measuring ambulant and non-ambulant patients on a single scale. We will describe the longitudinal performance of the NSAD through examination of over 100 available year 3 visit data using modern psychometric measures.

Duchenne muscular dystrophy (DMD) is the most common inherited muscle disease in children and thanks to the introduction of standards of care the survival rate has now increased with patients now living well in their 30s. With DMD patients living longer, care needs will need to be adapted to guarantee good quality of life for this growing adult DMD population. At present only few adults with DMD achieve independent living and this is likely to become more common in future and adequate planning and support needs to be provided to achieve this. The DMD population currently followed up at the John Walton muscular dystrophy research centre (Newcastle upon Tyne) consists of 166 patients (60% children, 40% adults). The mean age of the paediatric population is 11.9 years (range 2.5 years to <18 years), and mean age of the adult population is 23.4 years (range 18.3–36.7 years). Of the adult patients all are wheelchair users, with only very few patients still being able to transfer independently and one patients still ambulant; 56% are on non-invasive ventilation, 80.5% have cardiomyopathy and 86.5% are on cardiac medication; 41% are still on steroids; 50.7% had spinal surgery; 34% report dysphagia and 22% have a PEG; 27% have anxiety or depression. Life expectancy for patients with DMD has increased thanks to improvements in care management, and patients are now reaching adulthood with relatively good quality of life. Development of outcome measures to monitor progression in adult men with Duchenne is fundamental. In addition, to ensure good quality of life transition of care to adulthood needs timely planning, to allow care handover, ideally to a multidisciplinary team, to monitor and address promptly care needs arising in an adult men with DMD and maximise health.

Background: Ataluren is the first drug to treat the underlying cause of nmDMD. Methods: Phase 2 and 3 studies of ataluren in nmDMD were reviewed, with efficacy and safety/tolerability findings summarized. Results: Ataluren nmDMD trials include: a Phase 2a proof-of-concept study (N=38); a Phase 2b randomized controlled trial (RCT) (N=174); an ongoing US-based open-label safety extension study (N=108); an ongoing non-US-based open-label safety/efficacy extension study (N=94); and a Phase 3 RCT, ACT DMD (N=228), whose primary endpoint was change in six-minute walk distance (6MWD) over 48 weeks. The proof-of-concept study demonstrated increased dystrophin production in post-treatment muscle biopsies from ataluren-treated patients with nmDMD. The Phase 2b results demonstrated an ataluren treatment effect in 6MWD, timed function tests, and other measures of physical functioning, The Phase 3 ACT DMD results demonstrated an ataluren treatment effect in patients with nmDMD in both primary and secondary endpoints, particularly in those with a baseline 6MWD of 300-400m. Ataluren was consistently well-tolerated in all three trials, as well as in the ongoing extension studies. Trial findings will be presented in detail. Conclusions: The totality of the results demonstrates that ataluren enables nonsense mutation readthrough in the dystrophin mRNA, producing functional dystrophin and slowing disease progression.Supported by: PTC Therapeutics Inc.