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Objectives: Magnetic resonance imaging (MRI) constitutes a powerful outcome measure in neuromuscular disorders, yet there is a broad diversity of approaches in data acquisition and analysis. Since each neuromuscular disease presents a specific pattern of muscle involvement, the recommended analysis is assumed to be the muscle-by-muscle approach. We, therefore, performed a comparative analysis of different segmentation approaches, including global muscle segmentation, to determine the best strategy for evaluating disease progression., Methods: In 102 patients (21 immune-mediated necrotizing myopathy/IMNM, 21 inclusion body myositis/IBM, 10 GNE myopathy/GNEM, 19 Duchenne muscular dystrophy/DMD, 12 dysferlinopathy/DYSF, 7 limb-girdle muscular dystrophy/LGMD2I, 7 Pompe disease, 5 spinal muscular atrophy/SMA), two MRI scans were obtained at a 1-year interval in thighs and lower legs. Regions of interest (ROIs) were drawn in individual muscles, muscle groups, and the global muscle segment. Standardized response means (SRMs) were determined to assess sensitivity to change in fat fraction (ΔFat%) in individual muscles, muscle groups, weighted combinations of muscles and muscle groups, and in the global muscle segment., Results: Global muscle segmentation gave high SRMs for ΔFat% in thigh and lower leg for IMNM, DYSF, LGMD2I, DMD, SMA, and Pompe disease, and only in lower leg for GNEM and thigh for IBM., Conclusions: Global muscle segment Fat% showed to be sensitive to change in most investigated neuromuscular disorders. As compared to individual muscle drawing, it is a faster and an easier approach to assess disease progression. The use of individual muscle ROIs, however, is still of interest for exploring selective muscle involvement., Key Points: • MRI-based evaluation of fatty replacement in muscles is used as an outcome measure in the assessment of 1-year disease progression in 8 different neuromuscular diseases. • Different segmentation approaches, including global muscle segmentation, were evaluated for determining 1-year fat fraction changes in lower limb skeletal muscles. • Global muscle segment fat fraction has shown to be sensitive to change in lower leg and thigh in most of the investigated neuromuscular diseases.

NMD670 is an inhibitor of skeletal muscle-specific chloride channel protein 1 (ClC-1) that enhances neuromuscular transmission and is being developed for the treatment of neuromuscular diseases, including myasthenia gravis (MG), in which neuromuscular junction (NMJ) transmission is impaired. Despite available treatments, MG patients struggle with symptoms of prominent muscle weakness and fatigue. In a recent phase 1 proof-of-mechanism study of NMD670 in 12 MG patients with mild symptoms, a single dose of NMD670 led to significant and clinically meaningful improvements as assessed with the Quantitative MG (QMG) score. Furthermore, NMD670 was shown to be safe and well tolerated thus supporting further clinical development in MG (Sci Transl Med. 2024). Therefore, a dose-finding study in adult patients with MG who have antibodies against Muscle Specific Kinase (MuSK) or the Acetylcholine Receptor (AchR) is planned to start in 2024. The aim of this study is to evaluate the efficacy and safety of 3 dose levels of NMD670, administered twice a day for 21 days vs. placebo. Male and female patients, aged 18-75 years, diagnosed with MG and with a Myasthenia Gravis Foundation of America (MGFA) class II-IV, a QMG score of 11 or more and an MG-Activities of Daily-Living score of 6 or more at screening are planned to be enrolled at 40 sites across Europe and North America. Endpoints of this study include changes in the QMG total score MG-ADL, MG Composite (MGC), MG Quality of Life 15 revised (QOL15r), and Neuro Qol Fatigue Short Form total scores. A more detailed study design, target population, and other key updates will be provided by NMD Pharma A/S at the 29th Annual Congress of the World Muscle Society in October 2024. [ABSTRACT FROM AUTHOR]

NMD670, developed by NMD Pharma, is a first-in-class neuromuscular transmission enhancer targeting the skeletal muscle chloride channel 1 (ClC-1). It is designed to address neuromuscular disorders characterized by impaired neuromuscular transmission. Partial ClC-1 inhibition by NMD670 has recently been shown to improve NMJ transmission in preclinical models of myasthenia gravis and Charcot-Marie-Tooth and symptoms in patients with myasthenia gravis. Charcot-Marie-Tooth (CMT) is an inherited peripheral neuropathy leading to muscle weakness and fatigue, with no approved treatments and significant unmet medical needs. Emerging data from recent studies, including an observational study (NCT04980807) by NMD Pharma, suggest that NMJ transmission contributes to symptoms of weakness and fatigue in CMT. Correlations were observed between jitter, blocking, and impaired strength, mobility, balance, and endurance in CMT patients. Consequently, NMD670 emerges as a promising candidate for CMT treatment, prompting the initiation of the SYNAPSE-CMT study. SYNAPSE-CMT is a phase 2 study aiming to assess the efficacy, safety, and tolerability of NMD670 in ambulatory adults with CMT. Approximately 80 participants diagnosed with CMT type 1 and 2 will be randomized across 19 sites in North America and Europe. Participants will receive NMD670 or placebo twice daily for 21 days. Endpoints include the 6-minute walk test, the 10-meter walk/run test, the timed up-and-go test, and the CMT-FOM composite assessments comparing the effects of NMD670 to placebo. Enrollment of the first subject is planned for 2024. Detailed study design, target population, and updates will be provided by NMD Pharma at the 29th Annual Congress of the World Muscle Society in October 2024. [ABSTRACT FROM AUTHOR]

X-linked myotubular myopathy (XLMTM) is a rare neuromuscular disorder caused by mutations in the myotubularin (MTM1) gene, affecting 1:50000 male births. The clinical severity varies, however the need for ventilatory support is often inevitable. At present, no approved therapies are available for XLMTM. Patient management is mainly supportive. A first MTM1 gene replacement therapy tested in a clinical trial showed notable improvements on ventilator dependence and motor function but raised serious safety concerns. Forty patients have been enrolled in our European prospective natural history study of patients with XL-MTM designed to characterize the disease course by using standardized evaluations adjusted for age, ambulatory and respiratory status. At 3-year follow-up, data were available for 26 patients (65%) with a mean age of 14.3 (min 3.4, max 53.8) years. Drop-outs were due to loss to follow-up (n=1), death (n=1) and early withdrawal from the study (n=3). Nineteen percent (5/26) of patients were under the age of 6 years old. Among non-ambulant patients at baseline (n=19), only 1 acquired the ability to walk during the study. Respiratory function, strength and motor function did not statistically change. Muscle strength measured by MyoPinch and MyoGrip showed a mean decline of -1,04 kg (n=20) and -0.33kg (n=20) respectively. MFM D1 showed the most important decline of -2.98% at 36 months. Nine patients presented with a mean increase of grip strength of 1.5kg (SD 4.18) (n=13). Ten patients showed a mean increase of the pinch strength of 0.16kg (SD 0.71) (n=14). Correlation data will be presented. This first multicentric longitudinal natural history in all types of patients with XL-MTM demonstrates clearly that patients experience a decline over years that can be reliably measured. We have identified several strength-, functional and respiratory outcomes that can be used to build robust clinical trials in this population. [ABSTRACT FROM AUTHOR]

Myotonic dystrophy type 1 (DM1) is an autosomal dominant disease for which treatments are being developed. There is a need to define reliable and reproducible criteria to evaluate neuromuscular function in order to assess their effects. The main aim of our study consists of a follow-up of the natural history of DM1 patients over 3 years. Here, baseline values for the 6-min walk distance (6MWD), the lower limb muscle strength and balance measured by the movement rate of the centre of foot pressure on a force plateform are compared between patients and age- and sex-matched healthy controls. DM1 patients and healthy controls (10 females and 7 males between 26 and 49 years old in each group) of similar mean height and weight were compared. The 6MWD in percentage of predicted value was significantly reduced in DM1 patients by about 50% (Mann Whitney, p < 0.001). No significant difference in balance was found but ankle muscle strength weakness could account for the reduced 6MWD. Indeed, no significant difference of the movement rate of the centre of foot pressure was observed with age or between patients and healthy subjects (ANCOVA) but significant decreases in ankle dorsi- and plantarflexion strength measured by a homemade ankle dynamometer were detected between patients and healthy subjects (Mann Whitney p < 0.001 and p < 0.01, respectively). Balance defect, however, seems affected for the weakest ankle muscle strengths. Moreover, the 6MWD was positively correlated to ankle dorsiflexion (rho 0.671, p < 0.01) and plantarflexion in patients (rho 0.637, p < 0.01), while it was positively correlated to plantarflexion only in healthy controls (rho 0.586, p < 0.05). No significant difference in hip flexion, knee extension, ankle dorsiflexion and big toe extension assessed by hand-held dynamometry could be evidenced between patients and healthy controls. Walking ability is thus mainly affected by weakness in ankle dorsi- and plantarflexion when measured by appropriate method. [ABSTRACT FROM AUTHOR]